Andrew S. Bomback

Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).

Summary Background and objectives The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. Design, setting, participants, & measurements In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. Results The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria. Conclusions Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

National guidelines disagree on who should be screened for undiagnosed diabetes. No existing diabetes risk score is highly generalizable or widely followed.To develop a new diabetes screening score and compare it with other available screening instruments (Centers for Disease Control and Prevention, American Diabetes Association, and U.S. Preventive Services Task Force guidelines; 2 American Diabetes Association risk questionnaires; and the Rotterdam model).Cross-sectional data.NHANES (National Health and Nutrition Examination Survey) 1999 to 2004 for model development and 2005 to 2006, plus a combined cohort of 2 community studies, ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study), for validation.U.S. adults aged 20 years or older.A risk-scoring algorithm for undiagnosed diabetes, defined as fasting plasma glucose level of 7.0 mmol/L (126 mg/dL) or greater without known diabetes, was developed in the development data set. Logistic regression was used to determine which participant characteristics were independently associated with undiagnosed diabetes. The new algorithm and other methods were evaluated by standard diagnostic and feasibility measures.Age, sex, family history of diabetes, history of hypertension, obesity, and physical activity were associated with undiagnosed diabetes. In NHANES (ARIC/CHS), the cut-point of 5 or more points selected 35% (40%) of persons for diabetes screening and yielded a sensitivity of 79% (72%), specificity of 67% (62%), positive predictive value of 10% (10%), and positive likelihood ratio of 2.39 (1.89). In contrast, the comparison scores yielded a sensitivity of 44% to 100%, specificity of 10% to 73%, positive predictive value of 5% to 8%, and positive likelihood ratio of 1.11 to 1.98.Data during pregnancy were not available.This easy-to-implement diabetes screening score seems to demonstrate improvements over existing methods. Studies are needed to evaluate it in diverse populations in real-world settings.Clinical and Translational Science Center at Weill Cornell Medical College.

Significance Statement More than one third of hospitalized patients with coronavirus disease 2019 (COVID-19) develop AKI. The pathogenesis of AKI in this setting is poorly understood, and pathologic descriptions are limited. The authors examined kidney histopathology of 42 patients who died of COVID-19. The most significant findings included mild acute tubular injury as well as the absence of classic viral nephropathy, diffuse thrombotic microangiopathy, or acute GN. In situ hybridization could not identify definitive positivity for SARS-CoV-2. The finding of only mild acute tubular injury in the setting of severe creatinine elevation suggests a pathogenesis involving tubular injury and hemodynamic factors (such as aggressive fluid management) and potential for recovery of renal function upon resolution of infection. Background AKI is common among hospitalized patients with coronavirus disease 2019 (COVID-19) and is an independent risk factor for mortality. Although there are numerous potential mechanisms underlying COVID-19–associated AKI, our current knowledge of kidney pathologic findings in COVID-19 is limited. Methods We examined the postmortem kidneys from 42 patients who died of COVID-19. We reviewed light microscopy findings in all autopsies and performed immunofluorescence, electron microscopy, and in situ hybridization studies for SARS-CoV-2 on a subset of samples. Results The cohort had a median age of 71.5 years (range, 38–97 years); 69% were men, 57% were Hispanic, and 73% had a history of hypertension. Among patients with available data, AKI developed in 31 of 33 patients (94%), including 6 with AKI stage 1, 9 with stage 2, and 16 with stage 3. The predominant finding correlating with AKI was acute tubular injury. However, the degree of acute tubular injury was often less severe than predicted for the degree of AKI, suggesting a role for hemodynamic factors, such as aggressive fluid management. Background changes of hypertensive arterionephrosclerosis and diabetic glomerulosclerosis were frequent but typically mild. We identified focal kidney fibrin thrombi in 6 of 42 (14%) autopsies. A single Black patient had collapsing FSGS. Immunofluorescence and electron microscopy were largely unrevealing, and in situ hybridization for SARS-CoV-2 showed no definitive positivity. Conclusions Among a cohort of 42 patients dying with COVID-19, autopsy histologic evaluation revealed acute tubular injury, which was typically mild relative to the degree of creatinine elevation. These findings suggest potential for reversibility upon resolution of SARS-CoV-2 infection.

Summary Background and objectives Renal biopsies performed in diabetic patients are increasing in number and complexity. This study sought to determine the usefulness of renal biopsy in patients with diabetes and the predictability of diagnosing diabetic nephropathy (DN) versus nondiabetic renal disease (NDRD) from clinical and laboratory data. Design, setting, participants, & measurements To assess modern trends, a retrospective study was performed of clinical-pathologic findings in all patients with diabetes who had a biopsy in 2011. Among 2642 native kidney biopsies, 620 (23.5%) were from patients with diabetes. Results The cohort included 371 men (60.7%) aged a median (interquartile range) 62 years (52–69) with 10-year (5–15) duration of diabetes mellitus (DM). Median serum creatinine was 2.5 mg/dl (1.6–4.4), and 52% of patients had stage 4–5 CKD. On biopsy, 37% of patients had DN alone, 36% had NDRD alone, and 27% had DN plus NDRD. In NDRD alone, FSGS (22%), hypertensive nephrosclerosis (18%), acute tubular necrosis (ATN) (17%), IgA nephropathy (11%), membranous GN (8%), and pauci-immune GN (7%) comprised 80% of diagnoses, compared with ATN (43%), hypertensive nephrosclerosis (19%), FSGS (13%), and IgA nephropathy (7%) for DN plus NDRD. In multivariate analyses, longer duration of DM was associated with a greater likelihood of DN and a lower likelihood of NDRD: each added year of DM reduced the odds of NDRD by 5% (odds ratio, 0.95; 95% confidence interval, 0.91 to 0.98; P =0.004). DM duration ≥12 years was the best predictor (58% sensitivity, 73% specificity) of DN alone. Conclusions Approximately one-quarter of all renal biopsies are performed in patients with DM. Judicious use of renal biopsy has uncovered NDRD alone or superimposed on DN in the majority of such biopsies. ATN is emerging as an important category of NDRD, which has not been reported previously.

Elderly individuals with chronic kidney disease (CKD) have high rates of comorbid conditions, including cardiovascular disease and its risk factors, and CKD-related complications. In individuals aged > or = 65 years, we sought to describe the prevalence of CKD determined from laboratory test results in the Kidney Early Evaluation Program (KEEP; n = 27,017) and National Health and Nutrition Examination Survey (NHANES) 1999-2006 (n = 5,538) and the prevalence of diagnosed CKD determined from billing codes in the Medicare 5% sample (n = 1,236,946). In all 3 data sources, we also explored comorbid conditions and CKD-related complications.CKD was identified as decreased estimated glomerular filtration rate (<60 mL/min/1.73 m(2)) or increased albumin-creatinine ratio in KEEP and NHANES; CKD was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes in Medicare. Investigated comorbid conditions included diabetes, hypertension, high cholesterol level, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and cancer, and CKD-related complications included anemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism.The prevalence of CKD was approximately 44% in both KEEP and NHANES participants, and the prevalence of diagnosed CKD was 7% in Medicare beneficiaries. In all 3 data sets, the prevalence of CKD or diagnosed CKD was higher in participants aged > or = 80 years and those with comorbid conditions. For KEEP and NHANES participants, the prevalence of most comorbid conditions and CKD complications increased with decreasing estimated glomerular filtration rate. For participants with CKD stages 3-5, a total of 29.2% (95% CI, 27.8-30.6) in KEEP and 19.9% (95% CI, 17.0-23.1) in NHANES had anemia, 0.7% (95% CI, 0.4-0.9) and 0.6% (95% CI, 0.3-1.3) had hypocalcemia, 5.4% (95% CI, 4.7-6.1) and 6.4% (95% CI, 5.1-8.0) had hyperphosphatemia, and 52.0% (95% CI, 50.4-53.6) and 30.0% (95% CI, 25.9-34.3) had hyperparathyroidism, respectively.CKD is common in the elderly population and is associated with high frequencies of concomitant comorbid conditions and biochemical abnormalities. Because CKD is not commonly diagnosed, greater emphasis on physician education may be beneficial.

Glomerulonephritis (GN) is an important cause of morbidity and mortality in patients of all ages throughout the world. Because these disorders are relatively rare, it is difficult to perform randomized clinical trials to define optimal treatment for many of the specific glomerulopathies. In the absence of high-grade evidence to guide the care of glomerular diseases, in June 2012, KDIGO (Kidney Disease: Improving Global Outcomes) published an international clinical guideline for GN. The Work Group report represents an important review of the literature in this area and offers valid and useful guidelines for the most common situations that arise in the management of patients with glomerular disease. This commentary, developed by a panel of clinical experts convened by the National Kidney Foundation, attempts to put the GN guideline into the context of the US health care system. Overall, we support the vast majority of the recommendations and highlight select areas in which epidemiological factors and medical practice patterns in this country justify modifications and adjustments in order to achieve favorable outcomes. There remain large gaps in our knowledge of the best approaches to treat glomerular disease and we strongly endorse an expanded clinical research effort to improve the health and long-term outcomes of children and adults with GN. Glomerulonephritis (GN) is an important cause of morbidity and mortality in patients of all ages throughout the world. Because these disorders are relatively rare, it is difficult to perform randomized clinical trials to define optimal treatment for many of the specific glomerulopathies. In the absence of high-grade evidence to guide the care of glomerular diseases, in June 2012, KDIGO (Kidney Disease: Improving Global Outcomes) published an international clinical guideline for GN. The Work Group report represents an important review of the literature in this area and offers valid and useful guidelines for the most common situations that arise in the management of patients with glomerular disease. This commentary, developed by a panel of clinical experts convened by the National Kidney Foundation, attempts to put the GN guideline into the context of the US health care system. Overall, we support the vast majority of the recommendations and highlight select areas in which epidemiological factors and medical practice patterns in this country justify modifications and adjustments in order to achieve favorable outcomes. There remain large gaps in our knowledge of the best approaches to treat glomerular disease and we strongly endorse an expanded clinical research effort to improve the health and long-term outcomes of children and adults with GN. KDIGO (Kidney Disease: Improving Global Outcomes) is an organization with the mission to develop and implement clinical practice guidelines for worldwide use. In June 2012, KDIGO published a guideline for glomerulonephritis (GN).1Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO Clinical Practice Guideline for Glomerulonephritis.Kidney Inter Suppl. 2012; 2: 139-274Google Scholar This is the first guideline on GN ever published and is comprehensive in scope (143 pages in length). It addresses a major aspect of the clinical care provided by nephrologists to patients of all ages around the globe. KDIGO guidelines are developed for international application; however, implementation of the guideline needs to be put in the context of regional health care systems. To accomplish this, the NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) program organized a work group of experts to review the GN guideline and comment on the applicability of the recommendations to the practice of nephrology in the United States. As the first document of its kind that focuses exclusively on GN, the KDIGO report is in the enviable position of defining the terms of the conversation in this area for the immediate future. Nonetheless, as we are sure the authors of the KDIGO GN guideline will readily acknowledge, it is unlikely to be the final word on the topic. As it says in the rabbinical teachings compiled in Ethics of the Fathers (chapter 2, paragraph 16), “It is not incumbent upon you to finish the task, but neither are you free to absolve yourself from it.” We congratulate the KDIGO GN Work Group on its preparation of a wide-ranging up-to-date review and for initiating a careful analysis of the evidence regarding the diagnosis and management of GN. We offer this KDOQI Commentary to help identify areas of consensus in the management of GNs, highlight areas in which more work is needed to define optimal clinical practice guidelines, and define research needs for specific types of GN (summarized in the closing section) in GNs. Most importantly, we hope that our review promotes ongoing dialogue in this heretofore neglected area of nephrology. This KDIGO guideline focuses on the evaluation and treatment of GN in both adults and children beginning at the point when the diagnosis has been established by biopsy. It was written primarily for nephrologists, but other health care professionals involved in the care of patients with GN will find it useful. The guideline addresses the following forms of GN: •Steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) in children•Minimal-change disease (MCD) and idiopathic focal segmental glomerulosclerosis (FSGS) in children and adults•Idiopathic membranous nephropathy (IMN)•Idiopathic membranoproliferative glomerulonephritis (MPGN)•GN associated with infections•Immunoglobulin A (IgA) nephropathy (IgAN) and Henoch-Schönlein purpura (hsp) nephritis•Lupus nephritis (LN)•Renal vasculitis•Anti–glomerular basement membrane (anti-GBM) GN The guideline was developed by an 18-member international work group with the support of a professional evidence review team, who conducted literature searches, managed the abstract and article screening process, coordinated the methodological and analytic processes of the report, defined standardized methods for performing these searches and data extraction, and prepared summaries of the evidence. The work group evaluated the evidence and developed the recommendation statements and supporting rationale. The recommendations were then classified by the strength of the recommendation and the quality of the supporting evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) evidence grading scale (see Table 1). Reflecting the general lack of evidence in this area, and as stated in the foreward to the guideline, there were just 4 (2%) recommendations for which the overall quality of evidence was graded A, while 34 (20%) were graded B, 66 (40%) were graded C, and 63 (38%) were graded D. Even though there can be reasons besides quality of evidence to assign a grade 1 or 2 recommendation, overall, there is a correlation between the quality of overall evidence and the strength of the recommendation. Thus, there were 46 (28%) recommendations graded 1 and 121 (72%) graded 2. There were 4 (2%) recommendations graded 1A, 24 (14%) were 1B, 15 (9%) were 1C, and 3 (2%) were 1D. There were 0 (0%) graded 2A, 10 (6%) were 2B, 51 (31%) were 2C, and 60 (36%) were 2D. There were 28 (14%) statements that were not graded.Table 1Nomenclature and Description for Ratings of Recommendation Statement Strength and Quality of EvidenceRating Strength of RecommendationGradeaThe additional category “Not Graded” was used, typically to provide guidance based on common sense or when the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.Implications for PatientsImplications for CliniciansImplications for PolicyLevel 1 “We recommend”Most people in your situation would want the recommended course of action and only a small proportion would not.Most patients should receive the recommended course of action.The recommendation can be evaluated as a candidate for developing a policy or a performance measure.Level 2 “We suggest”The majority of people in your situation would want the recommended course of action, but many would not.Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences.The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined.Rating Quality of EvidenceGradeQuality of EvidenceMeaningAHighWe are confident that the true effect lies close to that of the estimate of the effect.BModerateThe true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.CLowThe true effect may be substantially different from the estimate of the effect.DVery LowThe estimate of effect is very uncertain, and often will be far from the truth.Note: Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of the supporting evidence is shown as A, B, C, or D.a The additional category “Not Graded” was used, typically to provide guidance based on common sense or when the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations. Open table in a new tab Note: Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or Not Graded, and the quality of the supporting evidence is shown as A, B, C, or D. KDOQI convened a work group to review this international guideline and interpret the relevance and applicability of the recommendations to the US health care system and patients. Consideration was given to differences in epidemiology of the diseases (prevalence, etc) compared to the worldwide population, unique demographic considerations or comorbid condition differences, issues unique to US health care (eg, therapies or tests not available in the United States), and issues related to implementation of treatment recommendations, such as familiarity and current practices, relative costs, regulatory issues, and logistic hurdles to a treatment guideline. Through a series of teleconferences, the work group reached a general consensus on the following commentary. For ease of navigation, the headings of this commentary specify the chapter and section of the KDIGO guideline being discussed. Numbered text within horizontal rules in the body of the article is quoted directly from the KDIGO document, using the same numbering scheme as in the original. All material is reproduced with permission of KDIGO. A list of key abbreviations used in the guideline excerpts included in this commentary is provided in Box 1.Box 1Abbreviations Used in Guideline RecommendationsACE-I: angiotensin-converting enzyme inhibitorAKI: acute kidney injuryANCA: antineutrophil cytoplasmic antibodyARB: angiotensin receptor blockerCKD: chronic kidney diseaseCNI: calcineurin inhibitorESRD: end-stage renal diseaseFR: frequently relapsingFSGS: focal segmental glomerulosclerosisGBM: glomerular basement membraneGFR: glomerular filtration rateGN: glomerulonephritisHBV: hepatitis B virusHCV: hepatitis C virusHIV: human immunodeficiency virusHSP: Henoch-Schönlein purpuraIgAN: immunoglobulin A nephropathyIMN: idiopathic membranous nephropathyi.v.: intravenousLN: lupus nephritisMCD: minimal-change diseaseMMF: mycophenolate mofetilMN: membranous nephropathyMPGN: membranoproliferative glomerulonephritisNS: nephrotic syndromeNSAIDs: nonsteroidal anti-inflammatory drugsRAS: renin-angiotensin systemRCT: randomized controlled trialSCr: serum creatinineSD: steroid-dependentSRNS: steroid-resistant nephrotic syndromeSSNS: steroid-sensitive nephrotic syndrome ACE-I: angiotensin-converting enzyme inhibitor AKI: acute kidney injury ANCA: antineutrophil cytoplasmic antibody ARB: angiotensin receptor blocker CKD: chronic kidney disease CNI: calcineurin inhibitor ESRD: end-stage renal disease FR: frequently relapsing FSGS: focal segmental glomerulosclerosis GBM: glomerular basement membrane GFR: glomerular filtration rate GN: glomerulonephritis HBV: hepatitis B virus HCV: hepatitis C virus HIV: human immunodeficiency virus HSP: Henoch-Schönlein purpura IgAN: immunoglobulin A nephropathy IMN: idiopathic membranous nephropathy i.v.: intravenous LN: lupus nephritis MCD: minimal-change disease MMF: mycophenolate mofetil MN: membranous nephropathy MPGN: membranoproliferative glomerulonephritis NS: nephrotic syndrome NSAIDs: nonsteroidal anti-inflammatory drugs RAS: renin-angiotensin system RCT: randomized controlled trial SCr: serum creatinine SD: steroid-dependent SRNS: steroid-resistant nephrotic syndrome SSNS: steroid-sensitive nephrotic syndrome 3.1.1: We recommend that corticosteroid therapy (prednisone or prednisolone)* be given for at least 12 weeks. (1B)3.1.1.1: We recommend that oral prednisone be administered as a single daily dose (1B) starting at 60 mg/m2/d or 2 mg/kg/d to a maximum 60 mg/d. (1D)3.1.1.2: We recommend that daily oral prednisone be given for 4-6 weeks (1C) followed by alternate-day medication as a single daily dose starting at 40 mg/m2 or 1.5 mg/kg (maximum 40 mg on alternate days) (1D) and continued for 2-5 months with tapering of the dose. (1B)*Prednisone and prednisolone are equivalent, used in the same dosage, and have both been used in RCTs depending on the country of origin. All later references to prednisone in this chapter refer to prednisone or prednisolone. All later references to oral corticosteroids refer to prednisone or prednisolone. 3.1.1: We recommend that corticosteroid therapy (prednisone or prednisolone)* be given for at least 12 weeks. (1B) 3.1.1.1: We recommend that oral prednisone be administered as a single daily dose (1B) starting at 60 mg/m2/d or 2 mg/kg/d to a maximum 60 mg/d. (1D) 3.1.1.2: We recommend that daily oral prednisone be given for 4-6 weeks (1C) followed by alternate-day medication as a single daily dose starting at 40 mg/m2 or 1.5 mg/kg (maximum 40 mg on alternate days) (1D) and continued for 2-5 months with tapering of the dose. (1B) *Prednisone and prednisolone are equivalent, used in the same dosage, and have both been used in RCTs depending on the country of origin. All later references to prednisone in this chapter refer to prednisone or prednisolone. All later references to oral corticosteroids refer to prednisone or prednisolone. We agree with the general recommendations in Section 3.1. However, the impact of patient adherence when treating the initial episode of nephrotic syndrome (NS) for more than 8 weeks needs to be addressed. Patients and parents should be counseled regarding treatment adherence and that steroid therapy extended beyond the child's initial response may decrease the long-term risk of frequent relapses. Because more than 80% of children with new-onset NS relapse, altering the timing and frequency of future relapses is of broad import. As stated in the guideline, many of the steroid dosing recommendations are empirical in nature and draw on the International Study of Kidney Disease in Children (ISKDC) protocols designed more than 4 decades ago. Dose regimens can be tailored for an individual patient, for example, slow tapering versus abrupt cessation of alternate-day regimens, based on both experience gained over time with regard to the child's prior response to steroids during relapses and insight gained from the ongoing dialogue between the nephrologist and parent/guardian on the effect of varying steroid doses on key neurobehavioral sequelae. For example, slower tapering of the steroid dose may help some children maintain a remission and prevent the need for higher steroid doses that may affect behavior or activity deleteriously, whereas the shortest possible exposure to steroids may be the better approach with other children. A recent study suggests that if steroid therapy is extended beyond the standard course, the actual cumulative dosage prescribed is more important than simply prolonging therapy in maintaining remission.2Teeninga N. Kist-van Holthe J.E. van Rijswijk N. et al.Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome.J Am Soc Nephrol. 2013; 24: 149-159Crossref PubMed Scopus (3) Google Scholar Dosing steroids in children who are significantly overweight should probably be based on ideal body weight, which may spare unnecessary steroid exposure. There may be consideration of a maximum dose of prednisone of 80 mg daily. In children who have gained significant weight related to steroid therapy, a best estimate of premorbid weight may be useful. 3.2.1: Corticosteroid therapy for children with infrequent relapses of SSNS:3.2.1.1: We suggest that infrequent relapses of SSNS in children be treated with a single-daily dose of prednisone 60 mg/m2 or 2 mg/kg (maximum of 60 mg/d) until the child has been in complete remission for at least 3 days. (2D)3.2.1.2: We suggest that, after achieving complete remission, children be given prednisone as a single dose on alternate days (40 mg/m2 per dose or 1.5 mg/kg per dose: maximum 40 mg on alternate days) for at least 4 weeks. (2C)3.2.2: Corticosteroid therapy for frequently relapsing (FR) and steroid-dependent (SD) SSNS:3.2.2.1: We suggest that relapses in children with FR or SD SSNS be treated with daily prednisone until the child has been in remission for at least 3 days, followed by alternate-day prednisone for at least 3 months. (2C)3.2.2.2: We suggest that prednisone be given on alternate days in the lowest dose to maintain remission without major adverse effects in children with FR and SD SSNS. (2D)3.2.2.3: We suggest that daily prednisone at the lowest dose be given to maintain remission without major adverse effects in children with SD SSNS where alternate-day prednisone therapy is not effective. (2D)3.2.2.4: We suggest that daily prednisone be given during episodes of upper respiratory tract and other infections to reduce the risk for relapse in children with FR and SD SSNS already on alternate-day prednisone. (2C) 3.2.1: Corticosteroid therapy for children with infrequent relapses of SSNS: 3.2.1.1: We suggest that infrequent relapses of SSNS in children be treated with a single-daily dose of prednisone 60 mg/m2 or 2 mg/kg (maximum of 60 mg/d) until the child has been in complete remission for at least 3 days. (2D) 3.2.1.2: We suggest that, after achieving complete remission, children be given prednisone as a single dose on alternate days (40 mg/m2 per dose or 1.5 mg/kg per dose: maximum 40 mg on alternate days) for at least 4 weeks. (2C) 3.2.2: Corticosteroid therapy for frequently relapsing (FR) and steroid-dependent (SD) SSNS: 3.2.2.1: We suggest that relapses in children with FR or SD SSNS be treated with daily prednisone until the child has been in remission for at least 3 days, followed by alternate-day prednisone for at least 3 months. (2C) 3.2.2.2: We suggest that prednisone be given on alternate days in the lowest dose to maintain remission without major adverse effects in children with FR and SD SSNS. (2D) 3.2.2.3: We suggest that daily prednisone at the lowest dose be given to maintain remission without major adverse effects in children with SD SSNS where alternate-day prednisone therapy is not effective. (2D) 3.2.2.4: We suggest that daily prednisone be given during episodes of upper respiratory tract and other infections to reduce the risk for relapse in children with FR and SD SSNS already on alternate-day prednisone. (2C) We agree with the overall recommendations in Section 3.2. While daily administration of corticosteroids during upper respiratory tract illnesses in children with frequently relapsing (FR) or steroid-dependent (SD) NS can prevent relapses, it does not lower cumulative steroid exposure.3Gulati A. Sinha A. Sreenivas V. Math A. Hari P. Bagga A. Daily corticosteroids reduce infection-associated relapses in frequently relapsing nephrotic syndrome: a randomized controlled trial.Clin J Am Soc Nephrol. 2011; 6: 63-69Crossref PubMed Scopus (10) Google Scholar Therefore, the efficacy of this strategy should be assessed periodically to make sure there are no significant side effects from the ongoing use of and cumulative exposure to corticosteroids. 3.3.1: We recommend that corticosteroid-sparing agents be prescribed for children with FR SSNS and SD SSNS, who develop steroid-related adverse effects. (1B)3.3.2: We recommend that alkylating agents, cyclophosphamide or chlorambucil, be given as corticosteroid-sparing agents for FR SSNS. (1B) We suggest that alkylating agents, cyclophosphamide or chlorambucil, be given as corticosteroid-sparing agents for SD SSNS. (2C)3.3.2.1: We suggest that cyclophosphamide (2 mg/kg/d) be given for 8-12 weeks (maximum cumulative dose 168 mg/kg). (2C)3.3.2.2: We suggest that cyclophosphamide not be started until the child has achieved remission with corticosteroids. (2D)3.3.2.3: We suggest that chlorambucil (0.1-0.2 mg/kg/d) may be given for 8 weeks (maximum cumulative dose 11.2 mg/kg) as an alternative to cyclophosphamide. (2C)3.3.2.4: We suggest that second courses of alkylating agents not be given. (2D)3.3.3: We recommend that levamisole be given as a corticosteroid-sparing agent. (1B)3.3.3.1: We suggest that levamisole be given at a dose of 2.5 mg/kg on alternate days (2B) for at least 12 months (2C) as most children will relapse when levamisole is stopped.3.3.4: We recommend that the calcineurin inhibitors cyclosporine or tacrolimus be given as corticosteroid-sparing agents. (1C)3.3.4.1: We suggest that cyclosporine be administered at a dose of 4-5 mg/kg/d (starting dose) in two divided doses. (2C)3.3.4.2: We suggest that tacrolimus 0.1 mg/kg/d (starting dose) given in two divided doses be used instead of cyclosporine when the cosmetic side-effects of cyclosporine are unacceptable. (2D)3.3.4.3: Monitor CNI levels during therapy to limit toxicity. (Not Graded)3.3.4.4: We suggest that CNIs be given for at least 12 months, as most children will relapse when CNIs are stopped. (2C)3.3.5: We suggest that MMF be given as a corticosteroid-sparing agent. (2C)3.3.5.1: We suggest that MMF (starting dose 1200 mg/m2/d) be given in two divided doses for at least 12 months, as most children will relapse when MMF is stopped. (2C)3.3.6: We suggest that rituximab be considered only in children with SD SSNS who have continuing frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing agents, and/or who have serious adverse effects of therapy. (2C)3.3.7: We suggest that mizoribine not be used as a corticosteroid-sparing agent in FR and SD SSNS. (2C)3.3.8: We recommend that azathioprine not be used as a corticosteroid-sparing agent in FR and SD SSNS. (1B) 3.3.1: We recommend that corticosteroid-sparing agents be prescribed for children with FR SSNS and SD SSNS, who develop steroid-related adverse effects. (1B) 3.3.2: We recommend that alkylating agents, cyclophosphamide or chlorambucil, be given as corticosteroid-sparing agents for FR SSNS. (1B) We suggest that alkylating agents, cyclophosphamide or chlorambucil, be given as corticosteroid-sparing agents for SD SSNS. (2C) 3.3.2.1: We suggest that cyclophosphamide (2 mg/kg/d) be given for 8-12 weeks (maximum cumulative dose 168 mg/kg). (2C) 3.3.2.2: We suggest that cyclophosphamide not be started until the child has achieved remission with corticosteroids. (2D) 3.3.2.3: We suggest that chlorambucil (0.1-0.2 mg/kg/d) may be given for 8 weeks (maximum cumulative dose 11.2 mg/kg) as an alternative to cyclophosphamide. (2C) 3.3.2.4: We suggest that second courses of alkylating agents not be given. (2D) 3.3.3: We recommend that levamisole be given as a corticosteroid-sparing agent. (1B) 3.3.3.1: We suggest that levamisole be given at a dose of 2.5 mg/kg on alternate days (2B) for at least 12 months (2C) as most children will relapse when levamisole is stopped. 3.3.4: We recommend that the calcineurin inhibitors cyclosporine or tacrolimus be given as corticosteroid-sparing agents. (1C) 3.3.4.1: We suggest that cyclosporine be administered at a dose of 4-5 mg/kg/d (starting dose) in two divided doses. (2C) 3.3.4.2: We suggest that tacrolimus 0.1 mg/kg/d (starting dose) given in two divided doses be used instead of cyclosporine when the cosmetic side-effects of cyclosporine are unacceptable. (2D) 3.3.4.3: Monitor CNI levels during therapy to limit toxicity. (Not Graded) 3.3.4.4: We suggest that CNIs be given for at least 12 months, as most children will relapse when CNIs are stopped. (2C) 3.3.5: We suggest that MMF be given as a corticosteroid-sparing agent. (2C) 3.3.5.1: We suggest that MMF (starting dose 1200 mg/m2/d) be given in two divided doses for at least 12 months, as most children will relapse when MMF is stopped. (2C) 3.3.6: We suggest that rituximab be considered only in children with SD SSNS who have continuing frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing agents, and/or who have serious adverse effects of therapy. (2C) 3.3.7: We suggest that mizoribine not be used as a corticosteroid-sparing agent in FR and SD SSNS. (2C) 3.3.8: We recommend that azathioprine not be used as a corticosteroid-sparing agent in FR and SD SSNS. (1B) We agree with the overall recommendations in Section 3.3. However, it is important to emphasize that the number of relapses by itself should not drive a decision to use a second-line agent. It is as important to assess how the child is tolerating steroids and whether there is a need to reduce steroid burden due to actual sequelae, including neurobehavioral effects.4Ruth E.M. Kemper M.J. Leumann E.P. Laube G.F. Neuhaus T.J. Children with steroid-sensitive nephrotic syndrome come of age: long-term outcome.J Pediatr. 2005; 147: 202-207Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Since reduction in long-term therapy-related sequelae may be as important as reduction in the actual relapse rate, this should be considered in the decision to begin steroid-sparing drugs. A second-line agent that is more likely to result in long-lived steroid-free remission, but at the expense of significant short-term or long-term sequelae, may be less preferable than an alternative agent that may not reduce relapse rate as dramatically but has a lower risk of new clinical complications. The ordering of the agents enumerated in this section should not be interpreted as a strict hierarchy of preference for these steroid-sparing drugs. In view of the permanent toxicity associated with alkylating agents (gonadal and bladder), it is questionable whether they should be considered as the best initial option even though there are more historical experience and randomized controlled trials (RCTs) for this class of drugs compared with other agents. Only a single course of an alkylating agent should be given to most children with FR NS or SD NS. Although there is little head-to-head comparison of cyclosporine and tacrolimus, the favorable side-effect profile and comparable cost probably make tacrolimus an agent that is being used more widely in practice. Although levamisole is not commercially available, it is effective and can be utilized for children whose parents have access to supplies of the drug from abroad. However, levamisole should always be administered under the care and supervision of a pediatric nephrologist experienced with its use. We would suggest that mycophenolate mofetil (MMF) be considered as a valid option as second-line therapy because of its widespread availability, ease of administration, and favorable side-effect profile compared with alkylating agents or calcineurin inhibitors (CNIs). While there are few randomized studies comparing MMF with other drugs, it has been given to more than 125 children with FR NS or SD NS in open-label studies with reasonable efficacy and suitable patient tolerance. We agree that there may be a role for rituximab in certain cases of SSNS, most notably with cases of FR NS or SD NS with suboptimal response to second-line agents. The best use and most optimal dosing of rituximab (amount per dose and frequency of administration) for children with SSNS requires further clarification in controlled clinical trials. Novel immunomodulatory therapies or new formulations of current agents are frequently offered as potential treatment options in patients with FR NS and SD NS. It is difficult to endorse their use in the absence of controlled clinical trials or widespread experience demonstrating added efficacy or other specific benefit over standard therapy. We do not recommend use of ACTH (adrenocorticotropic hormone; corticotropin) as a steroid-like option as it is very expensive and has not been studied in children with SSNS or SRNS. 3.4.1: Indications for kidney biopsy in children with SSNS are (Not Graded): •late failure to respond following initial response to corticosteroids;•a high index of suspicion for a different underlying pathology;•decreasing kidney function in children receiving CNIs. 3.4.1: Indications for kidney biopsy in children with SSNS are (Not Graded): •late failure to respond following initial response to corticosteroids;•a high index of suspicion for a

A major shift in our understanding of the membranoproliferative glomerulonephritis (MPGN) lesion is the focus on which components of the complement pathway are involved in mediating renal injury. Hence, MPGN is no longer classified solely by ultrastructural findings on biopsy but instead divided into immune complex-mediated lesions versus complement-mediated lesions. This emphasis on complement, in turn, leads to interest in therapies that target complement as potential disease-modifying agents. Eculizumab, the first available anticomplement therapy, blocks at the level of C5 and has revolutionized the treatment of complement-mediated diseases such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Whether this agent will work equally well for the far more heterogeneous complement-mediated MPGN lesions, also known as C3 glomerulopathy, remains unclear. To date, the experience and published data on using eculizumab in MPGN suggests this agent will work for some, but not all, patients with this pathologic lesion.

Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1–3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of ‘C3 only’ captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, ‘C3 only’ is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation. Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1–3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of ‘C3 only’ captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, ‘C3 only’ is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation. The clinical and pathologic approach to membranoproliferative glomerulonephritis (MPGN) has evolved markedly in recent years. The term MPGN was originally introduced in the 1970s to describe a morphologic pattern of glomerular proliferation with mesangial interposition and duplication of glomerular basement membranes as defined by light and electron microscopy.1.Mandalenakis N. Mendoza N. Pirani C.L. et al.Lobular glomerulonephritis and membranoproliferative glomerulonephritis: a clinical and pathologic study based on renal biopsies.Medicine. 1971; 50: 319-355Crossref PubMed Scopus (65) Google Scholar This proliferation occurs in response to deposition of immunoglobulins (Igs) and/or complement in the glomerular capillary walls. Historically, three major forms of MPGN have been recognized. In type 1, there is mesangial proliferation with regular circumferential mesangial interposition and double contouring of glomerular basement membranes in response to subendothelial electron-dense deposits.2.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoroliferative glomerulonephritis with subendothelial deposits (Type I MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (40) Google Scholar Type 2, also known as dense deposit disease (DDD), is characterized by distinctive, highly electron-dense, ribbon-like intramembranous deposits that transform the lamina densa, often associated with ring-shaped mesangial deposits and variable hump-shaped subepithelial deposits.3.Habib R. Gubler M.C. Loirat C. et al.Dense deposit disease: a variant of membranoproliferative glomerulonephritis.Kidney Int. 1975; 7: 204-215Abstract Full Text PDF PubMed Scopus (168) Google Scholar In type 3 of Strife and Anders, there are more complex and ill-defined intramembranous deposits associated with subendothelial and subepithelial deposits, causing disruption and fraying of the lamina densa.4.Strife C.F. McEnery P.T. McAdams A.J. et al.Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.Clin Nephrol. 1977; 7: 65-72PubMed Google Scholar By contrast, type 3 of Burkholder is characterized by more discrete subendothelial, intramembranous, and subepithelial deposits, often with overlapping features of MPGN type 1 and membranous glomerulopathy4.Strife C.F. McEnery P.T. McAdams A.J. et al.Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.Clin Nephrol. 1977; 7: 65-72PubMed Google Scholar,5.Burkholder P.M. Hyman L.R. Krueger R.P. Characterization of mixed membranous and proliferative glomerulonephritis: recognition of three varieties.Perspect Nephrol Hypertens. 1973; 1: 557-589PubMed Google Scholar (Figure 1). These categories were cumbersome to apply because of their complexity, the frequent occurrence of morphologic heterogeneity in a given case, and the lack of pathogenetic specificity. For example, many cases of DDD lack membranoproliferative features altogether, causing the term MPGN type 2 to be discarded.6.Walker P.D. Ferrario F. Joh K. et al.Dense deposit disease is not a membranoproliferative glomerulonephritis.Mod Pathol. 2007; 20: 605-616Crossref PubMed Scopus (101) Google Scholar With greater understanding of etiology over the past decade, there has been a major shift away from morphologic patterns to focus on composition of the deposits as defined by immunofluorescence (IF). Those cases with substantial deposits of Ig are considered immune complex mediated and should prompt an investigation of underlying autoimmune, infectious, or paraprotein-related disease.7.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar The term C3 glomerulopathy (C3G), proposed to encompass those cases with deposition of C3 only, includes DDD and those forms of MPGN type 1 and type 3 with predominant deposits of C3.8.Sethi S. Fervenza F.C. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification.Semin Nephrol. 2011; 31: 341-348Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar,9.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (268) Google Scholar A major breakthrough was the recognition that abnormal control of the alternative pathway (AP) of complement underlies C3G, irrespective of morphologic appearance. Potential abnormalities include genetic deficiencies in regulators of the alternative complement pathway (such as complement factor (CF)H, CFHR1–5, CFI, and CD46)10.Habbig S. Mihatsch M.J. Heinen S. et al.C3 deposition glomerulopathy due to a functional factor H defect.Kidney Int. 2009; 75: 1230-1234Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar,11.Abrera-Abeleda M.A. Nishimura C. Frees K. et al.Allelic variants of complement genes associated with dense deposit disease.J Am Soc Nephrol. 2011; 22: 1551-1559Crossref PubMed Scopus (78) Google Scholar and autoantibodies to factor H, factor B, and the C3 convertase (known as C3 nephritic factors).12.Strobel S. Zimmering M. Papp K. et al.Anti-factor B autoantibody in dense deposit disease.Mol Immunol. 2010; 47: 1476-1483Crossref PubMed Scopus (85) Google Scholar, 13.Goodship T.H. Pappworth I.Y. Toth T. et al.Factor H autoantibodies in membranoproliferative glomerulonephritis.Mol Immunol. 2012; 52: 200-206Crossref PubMed Scopus (59) Google Scholar, 14.Ohi H. Watanabe S. Fujita T. et al.Significance of C3 nephritic factor (C3NeF) in non-hypocomplementaemic serum with membranoproliferative glomerulonephritis (MPGN).Clin Exp Immunol. 1992; 89: 479-484Crossref PubMed Scopus (28) Google Scholar Proteomic analysis by mass spectrometry performed on laser-captured glomeruli has identified complement debris (including C5, C6, C7, C8, and C9) in the glomerular deposits, consistent with activation of the AP in the fluid phase.15.Sethi S. Gamez J.D. Vrana J.A. et al.Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway.Kidney Int. 2009; 75: 952-960Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar With the advent of specific clinical testing for abnormalities of the AP and specific therapies targeting the AP,16.Zuber J. Fakhouri F. Roumenina L.T. et al.Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.Nat Rev Nephrol. 2012; 8: 643-657Crossref PubMed Scopus (391) Google Scholar these distinctions are gaining greater clinical relevance. An impediment in the diagnosis of C3G is the lack of a working definition of IF criteria that has been developed and validated in a well-defined disease cohort. Although the term ‘C3 only’ is often applied as a theoretical construct, it is not clear whether such a strict definition is practicable. For example, pathologists recognize that IgM is frequently trapped in areas of sclerosis and in thickened glomerular capillary walls in diverse glomerular diseases.17.Bolton W.K. Benton F.R. Maclay J.G. et al.Spontaneous glomerular sclerosis in aging Sprague-Dawley rats. I. Lesions associated with mesangial IgM deposits.Am J Pathol. 1976; 85: 277-302PubMed Google Scholar A major question is whether C3 dominance might occur on a background of less intense deposition or trapping of other immune reactants, including IgG, IgA, and C1q. We aimed to examine these questions by testing different set points for IF definition of C3G in a cohort of DDD as the gold standard. Once optimal criteria were found, we applied these criteria to a group of primary MPGN type 1 and type 3 to determine the incidence of C3G, define the relationship of C3G to the Strife and Anders versus Burkholder subgroups of primary MPGN type 3, and explore clinical and demographic correlates. A total of 796 biopsies with diagnoses of MPGN 1–3 were identified from 1999 to 2012. After exclusion of 396 cases with clear underlying etiology (secondary MPGN due to hepatitis C infection, cryoglobulinemia, paraprotein deposition, and so on), 58 cases with inadequate tissue for IF or previous treatment with eculizumab, and 23 repeat biopsies, a total of 319 cases of primary MPGN were recruited into the study. As shown in Table 1, the largest number of primary cases was from MPGN1 (n=200), followed by MPGN3 (n=77) and MPGN2/DDD (n=42). Using MPGN2/DDD as the prototype for C3G, application of the strictest definition of C3-only staining (criterion 1) captured only 50% of the total cases. Allowing for low-level IgM deposition (criterion 2) increased the case recovery to 71.4%. Further broadening the criteria to permit low-level IgG, IgM, IgA, and/or C1q staining (criterion 3) identified 88.1% of total MPGN2/DDD cases. Broadening to criterion 4 added only 4.8% of DDD cases, while this change added 26.5% of MPGN1 cases and 13% of MPGN3 cases, suggesting loss of specificity. Therefore, the first three criteria were chosen as cutoffs for the gold-standard group of DDD and used as optimal ‘defining criteria’ for C3G. We then applied these criteria to cases of MPGN1 and MPGN3 to determine the incidence of C3G in these groups. Sixty-one cases (30.5%) of MPGN1 and 30 cases (39%) of MPGN3 successfully met the defining criteria for C3G (Table 1). Of the 30 C3G cases recovered from MPGN3, 90% were Strife and Anders variant and 10% were Burkholder variant.Table 1Primary membranoproliferative glomerulonephritis (MPGN) cases meeting criteria 1–3DiagnosisNumber of primary casesCriterion 1: C3 only (%)Criterion 2: C3 dominant and up to 1+ IgM only (%)Criterion 3: C3 dominant and ≥2 orders of intensity greater than any combination of IgG, IgM, IgA, and C1q (%)Criteria 1, 2, or 3 (%)MPGN 120016 (8%)13 (6.5%)32 (16%)61 (30.5%)MPGN2/DDD4221 (50%)9 (21.4%)7 (16.7%)aSeven cases that fulfilled criterion 3 displayed C3-dominant staining with the following immunofluorescence patterns: two cases with IgG only; one case with IgM only; two cases with C1 only; and two cases with IgG, IgM, IgA, and C1.37 (88.1%)MPGN 3778 (10.4%)11 (14.3%)11(14.3%)30 (39%)Total31945 (14.1%)33 (10.3%)50 (15.7%)128 (40.1%)Abbreviations: DDD, dense deposit disease; Ig, immunoglobulin.a Seven cases that fulfilled criterion 3 displayed C3-dominant staining with the following immunofluorescence patterns: two cases with IgG only; one case with IgM only; two cases with C1 only; and two cases with IgG, IgM, IgA, and C1. Open table in a new tab Abbreviations: DDD, dense deposit disease; Ig, immunoglobulin. Cases of MPGN 1–3 that did not meet the third cutoff for C3G are outlined in Table 2. Five MPGN2/DDD cases failed to meet the defining C3G IF criteria: two cases with C3 dominance and >1+ IgG or IgM, two cases with C3 co-dominance with IgG or IgM, and one case (an outside consult) reported as negative for C3 and other immune reactants. Of note, no DDD case exhibited stronger staining intensity for Ig than C3. A significant subset of MPGN1 (26.5%) and MPGN3 (13%) cases also exhibited C3-dominant staining that failed to meet the C3G criteria. Co-dominant staining of C3 with IgG or IgM was observed more frequently in primary MPGN1 and MPGN3 than in MPGN2/DDD. The incidence of IgG-dominant staining, which was never observed in MPGN2/DDD, was higher in cases of MPGN3 than in those of MPGN1.Table 2Primary membranoproliferative glomerulonephritis (MPGN) cases not meeting criteria 1–3Criterion 5: C3 co-dominantDiagnosisNumber of cases NOT meeting criteria 1–3 (%)Criterion 4: C3 dominant and >1+any Ig/C1q (%)5a: C3/IgM co-dominant (%)5b: C3/IgG co-dominant (%)Criterion 6: IgM dominant IgM>C3 (%)Criterion 7: IgG dominant IgG>C3 (%)Criterion 8: C3 negative (%)MPGN1139 (69.5%)53 (26.5%)18 (9%)25 (18%)14 (7%)16 (8%)13 (6.5%)MPGN2/DDD5 (11.9%)2 (4.8%)1 (2.4%)1 (2.4%)001 (2.4%)MPGN347 (61%)10 (13%)4 (5.2%)15 (19.5%)1 (1.3%)16 (20.8%)1 (1.3%)Total191 (59.9%)65 (20.4%)23 (7.2%)41 (12.9%)15 (4.7%)32 (10%)15 (4.7%)Abbreviations: DDD, dense deposit disease; Ig, immunoglobulin. Open table in a new tab Abbreviations: DDD, dense deposit disease; Ig, immunoglobulin. Twenty-three patients underwent repeat biopsies, including 12 with MPGN1, 8 with DDD, and 3 with MPGN3. Subsequent biopsies for each patient were then separately categorized and summarized. Overall, 13 of the 23 patients maintained the same IF staining patterns on initial and follow-up biopsies (Table 3). On repeat biopsy, 2 of the 23 patients met a more stringent criterion for C3G, and 4 of the 23 met a more liberal criterion for C3G. Only two C3G patients had follow-up biopsies not meeting the C3G criteria, although in both cases C3 staining was stronger than IgG. Two patients showed the opposite trend, with initial biopsies that showed C3-dominant staining not meeting the criteria but with repeat biopsy meeting the C3G criteria. Of the three patients initially diagnosed with acute post-infectious glomerulonephritis who had repeat biopsies diagnosed as C3G, two had MPGN1 and one had MPGN3 on repeat biopsy.Table 3Primary membranoproliferative glomerulonephritis (MPGN) cases with serial biopsiesIF criterion of initial biopsyIF criterion of repeat biopsy12345a5b14122611aTwo patients (8.7%) had an initial biopsy that failed to meet criteria 1–3 and a subsequent biopsy that did meet criteria.31131aTwo patients (8.7%) had an initial biopsy that failed to meet criteria 1–3 and a subsequent biopsy that did meet criteria.41bTwo patients (8.7%) had an initial biopsy that did meet criteria 1–3 and a subsequent biopsy that did not.5a1bTwo patients (8.7%) had an initial biopsy that did meet criteria 1–3 and a subsequent biopsy that did not.5bAbbreviation: IF, immunofluorescence.Thirteen of 23 patients (57%) had no change in immunofluorescence criteria (bolded).a Two patients (8.7%) had an initial biopsy that failed to meet criteria 1–3 and a subsequent biopsy that did meet criteria.b Two patients (8.7%) had an initial biopsy that did meet criteria 1–3 and a subsequent biopsy that did not. Open table in a new tab Abbreviation: IF, immunofluorescence. Thirteen of 23 patients (57%) had no change in immunofluorescence criteria (bolded). Of the 128 cases that met classification criteria as C3G, 72 (56%) were male with a mean age of 34.4 years (Table 4). In this cohort, 65 of the 98 patients (66%) with reported data on race/ethnicity were white. On average, these patients presented with renal insufficiency (mean serum creatinine 2.6; median 1.6mg/dl and mean estimated glomerular filtration rate 59.3; median 48.8ml/min per 1.73m2) and nephrotic-range proteinuria (mean 24-hour proteinuria 4.5; median 3.6g/day). Serum complement levels were low in ∼75% of patients, primarily in the pattern of low C3 with normal-range C4 levels.Table 4Clinical and biological features of C3G patientsAll C3G (n=128)C3G in MPGN1 (n=61)C3G in MPGN2 (n=37)C3G in MPGN3 (n=30)P-valueaP-value from analysis of variance, testing null hypothesis that mean is equal among all three categories.IF criterion 1 (n=45)IF criterion 2 (n=33)IF criterion 3 (n=50)P-valueaP-value from analysis of variance, testing null hypothesis that mean is equal among all three categories.Mean age (years)34.435.735.930.10.438.126.936.10.06Female (%)43.852.529.743.30.0933.330.362.00.003Race/ethnicity (%) White50.854.148.746.70.857.854.642.00.3 Hispanic16.49.816.230.00.0517.824.210.00.2 Black6.36.65.46.71.00.09.110.00.1 Asian3.13.32.73.31.00.00.08.00.04 Unknown23.426.227.013.30.324.412.130.00.2Mean disease duration (months)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36).41.529.748.453.50.241.153.628.40.2Median serum creatinine (mg/dl)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36).1.61.91.61.00.051.91.31.50.04Median eGFR (ml/min per 1.73m2)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36).48.835.848.886.70.0139.065.051.50.09Median 24-h proteinuria (g/day)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36).3.63.62.64.20.61.54.44.90.004Median serum albumin (g/dl)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36).3.22.83.93.40.023.83.42.40.0001Serum complements (%)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36). Normal24.521.817.437.50.227.626.720.90.8 Low C3 and normal C460.854.682.654.20.0562.163.358.10.9 Low C3 and low C414.723.60.08.30.0210.310.020.90.3 Low C3 overall75.578.282.662.50.272.473.379.10.8Hematuria (%)bExcludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36). None16.34.625.928.60.0123.312.013.50.4 Microscopic68.586.462.371.40.0766.780.081.10.3 Gross15.29.111.10.00.0233.38.05.40.003Hypertension (%)46.147.551.436.70.542.239.454.00.4Abbreviations: C3G, C3 glomerulopathy; eGFR, estimated glomerular filtration rate; IF, immunofluorescence; MPGN, membranoproliferative glomerulonephritis.a P-value from analysis of variance, testing null hypothesis that mean is equal among all three categories.b Excludes missing data for subjects on disease duration (n=51), serum creatinine (n=11), proteinuria (n=49), serum albumin (n=59), serum complements (n=26), and hematuria (n=36). Open table in a new tab Abbreviations: C3G, C3 glomerulopathy; eGFR, estimated glomerular filtration rate; IF, immunofluorescence; MPGN, membranoproliferative glomerulonephritis. These presenting historical and clinical data were examined according to original histopathologic diagnoses—MPGN1, MPGN2, or MPGN3—as well as by our proposed IF criteria schemes for diagnosing C3G. Age and sex distribution were relatively similar among the C3G patients originally classified as MPGN1, MPGN2/DDD, and MPGN3. In contrast, Hispanic patients were more likely to demonstrate the MPGN2 and MPGN3 pattern than MPGN1. Patients with MPGN3 were also marked by significantly lower presenting serum creatinine (and correspondingly higher estimated glomerular filtration rate) than patients with MPGN1 or MPGN2. Although the presence of low C3 levels overall did not differ between the MPGN subtypes, interestingly, no patients with MPGN2 demonstrated low C3 and low C4 in contrast to a small proportion of those patients with MPGN1 and MPGN3 with this complement profile. Women were overrepresented in the subgroup of C3G patients who were included based on IF criterion 3. This subgroup also included the only Asian patients in the cohort. Patients who met the strictest IF criterion 1 for diagnosis of C3G presented with the highest incidence of gross hematuria and the most severe renal dysfunction, with mean serum creatinine 3.5; median 1.9mg/dl and mean estimated glomerular filtration rate 50.2; median 39.0ml/min per 1.73m2 (which, in turn, likely influenced their significantly lower level of proteinuria than IF criteria 2 and 3 subgroups). Notably, the prevalence of low C3 and/or low C4 serum levels did not significantly differ among these IF criteria subgroups. We retrospectively reviewed a random subset of 125 biopsies of secondary MPGN, including 45 hepatitis C–associated MPGN (of which 18 also had cryoglobulinemia), 30 cryoglobulinemic glomerulonephritis, 30 lupus nephritis with membranoproliferative pattern, 10 hepatitis B–associated MPGN, 5 combined hepatitis B and HIV–associated MPGN, and 5 combined hepatitis B and C–associated MPGN. Only one case of hepatitis C–associated MPGN (without cryoglobulinemia) met the IF criterion 2; one case of hepatitis B–associated MPGN met IF criterion 3; and no case met IF criterion 1. These data indicate that our proposed IF criteria for C3G are rarely found in biopsies with secondary MPGN. C3G is a histopathologic diagnosis that aims to be both descriptive, by relaying the findings of IF microscopy, and physiologic, by implicating a complement-mediated (rather than immune complex–mediated) glomerulonephritis. Although C3G is defined by IF findings in the proper clinical and morphologic context, no prior studies have investigated what the precise IF criteria for diagnosis should be in pragmatic terms. We applied a hierarchical set of IF criteria to define the optimal cutoff for the diagnosis of C3G using MPGN2/DDD as a gold standard. A definition of ‘C3 only’ identified only half of the DDD patients, whereas a definition of C3 dominance of at least two orders of magnitude stronger than any other immune reactant captured 88.1% of DDD patients. Further relaxing the defining criteria captured a few additional DDD patients but many more MPGN1 and MPGN3 patients, suggesting reduced specificity. Our results indicate that the theoretical definition of C3G as ‘C3 only’ staining is too stringent if the goal of diagnosing C3G is to identify suitable candidates for AP evaluation. Allowing for IgM staining increased the retrieval to 71.4% of MPGN2/DDD. The presence of IgM staining in other glomerular diseases has been attributed to nonspecific trapping in areas of sclerosis or glomerular capillary wall thickening, without necessarily contributing to disease pathogenesis.17.Bolton W.K. Benton F.R. Maclay J.G. et al.Spontaneous glomerular sclerosis in aging Sprague-Dawley rats. I. Lesions associated with mesangial IgM deposits.Am J Pathol. 1976; 85: 277-302PubMed Google Scholar The potential for low-level IgG staining also may exist in C3G. Serologic evidence of AP dysregulation has been recently identified in more than half of a single cohort of patients with MPGN1,18.Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar with C3NeF, an acquired autoantibody of C3 convertase, identified in MPGN1 as frequently as it was in C3G. In that study, IF revealed concomitant C3 and IgG deposits in a subset of patients who had clear serologic evidence of AP abnormalities. Our findings agree that the presence of IgG does not exclude C3G. Our proposed working definition of C3G as C3 dominance of at least two orders of magnitude more intense than any other immune reactant, beyond identifying 88.1% of MPGN2/DDD cases, qualified 30.5% of cases of MPGN1 and 39% of cases of MPGN3 as C3G. Among cases of MPGN3, the vast majority was Strife and Anders (90%) variant, which is consistent with the previously reported finding of C3-dominant deposits in Strife and Anders variant in a smaller cohort.19.Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (117) Google Scholar Although our biopsy database archived cases according to historical MPGN categories, it should be emphasized that C3G is not restricted to a membranoproliferative pattern and may exhibit other histological phenotypes. A diagnosis of C3G should prompt an investigation of the alternative complement pathway, specifically testing for mutations in regulators (e.g. factor B) and inhibitors (e.g. factor H) of the AP, autoantibodies directed at such regulators and inhibitors, and a functional assessment of AP activity. These investigations are noninvasive and, in most cases, can influence therapeutic decisions, allowing for the opportunity to tailor therapies to detected defects in the AP.20.Nester C.M. Smith R.J. Treatment options for C3 glomerulopathy.Curr Opin Nephrol Hypertens. 2013; 22: 231-237Crossref PubMed Scopus (46) Google Scholar Given the importance of such testing, any diagnostic criteria for C3G should veer toward being more inclusive rather than exclusive. In the largest study of 56 cases of C3G to date, for example, acquired and genetic complement abnormalities were found in patients with phenotypes of MPGN1 and MPGN2/DDD.18.Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar Clinical features of C3G have also been reported in a pediatric cohort21.He R.J. Xiao H.J. Wang S.X. et al.[Characteristics of pediatric C3 glomerulopathy with decreased factor H in 3 cases].Zhonghua Er Ke Za Zhi. 2012; 50: 939-943PubMed Google Scholar and familial C3G.22.Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Crossref PubMed Scopus (109) Google Scholar,23.Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar Analysis of a subset of patients with diverse causes of secondary MPGN found only 2 of 125 (1.6%) cases meeting these proposed IF criteria for C3G. Our data now provide a practicable, nonconstrictive, pathologic definition of C3G that identifies those patients most likely to benefit from genetic and functional studies of AP dysregulation. Analysis of repeat biopsies in 23 patients provides further support for our definition of C3G. After initial biopsy diagnosis of C3G by meeting IF criteria 1–3 in 23 patients, repeat biopsies in the majority (13/23) met the identical IF criterion as the first biopsy. On the other hand, 2/23 C3G patients met a more stringent criterion and 4/23 met a more liberal criterion, while still fulfilling the definition for C3G on repeat biopsy. Further, two patients meeting criterion 4 on initial biopsy met C3G criteria 2 and 3, respectively, on repeat biopsy. Conversely, only two patients fulfilling C3G criterion 1 on initial biopsy met criteria 4 and 5a, respectively, on repeat biopsy. These data support fluidity between these subgroups and the ability to transform from one criterion class to another over time. These data also support the importance of a less constrictive definition that allows for such fluidity. It is not clear as to why some patients had a repeat biopsy that transformed to a more liberal criterion beyond criterion 3. This finding is consistent with the small percentage of MPGN2/DDD patients who manifested variable intensities of Ig staining on initial biopsy while never exceeding the staining intensity for C3. Conceivably, glomeruli may be subjected to other forms of immunologic injury, and harboring an abnormality in AP regulation does not exclude the possibility of other immune assaults that could promote IgG or other Ig deposition, including classical pathway activation. More studies are needed to address the potential for multiple immunologic ‘hits’ in this population. Whether glomerular staining for IgG represents inconsequential passive ‘trapping’ of a circulating plasma protein or superimposed active immune-mediated injury capable of promoting glomerular leukocyte infiltration and proliferation requires further study. Clinical analysis of this C3G cohort revealed that patients with MPGN2/DDD were more likely to have isolated reduction in serum C3 (82.6%) compared with those with MPGN1 and MPGN3 (54.6% and 54.2%, respectively). No patient with MPGN2/DDD had low serum C3 and C4, as compared with a small percentage (23.6% and 8.3%, respectively) of MPGN1 and MPGN3 with this complement profile. These findings support the concept that classical complement activation may contribute to glomerular injury in some C3G patients with MPGN1 and MPGN3 phenotypes.24.D'Agati V.D. Bomback A.S. C3 glomerulopathy: what’s in a name?.Kidney Int. 2012; 82: 379-381Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar In other respects, those patients meeting defining criteria of C3G within the three major pathologic subcategories of MPGN had similar demographic and clinical presenting features, supporting the thesis that the IF pattern is a more important diagnostic criterion than the light and electron microscopic patterns. Interestingly, C3G patients who met the strictest IF criterion 1 for diagnosis of C3G presented with the highest incidence of gross hematuria, more severe renal dysfunction, and lower-level proteinuria than those meeting criteria 2 and 3. This tendency to an acute nephritic (as opposed to nephrotic) presentation resembles the typical clinical presentation of postinfectious glomerulonephritis. Further study is needed to determine differences in the incidence of preceding infections among these IF criteria subgroups. Notably, the prevalence of low C3 and/or low C4 levels did not significantly differ among these IF criteria subgroups. The most liberal criterion (criterion 3) for diagnosing C3G demonstrated a trend toward greater prevalence of low C4 than stricter criteria (1 and 2); however, that again raises the issue of whether a defect in AP may heighten susceptibility to or amplify injury from immune complex deposition in some C3G cases. The finding of several cases initially diagnosed as postinfectious glomerulonephritis but fulfilling criteria for C3G on subsequent biopsy underscores the potential difficulty in diagnosing C3G in such patients without clinical follow-up and repeat biopsy.25.Sandhu G. Bansal A. Ranade A. et al.C3 glomerulopathy masquerading as acute postinfectious glomerulonephritis.Am J Kidney Dis. 2012; 60: 1039-1043Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,26.Zand L. Kattah A. Fervenza F.C. et al.C3 glomerulonephritis associated with monoclonal gammopathy: a case series.Am J Kidney Dis. 2013; 62: 506-514Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Our study has a number of limitations. First, as a retrospective study, it is based on IF recordings in the biopsy report rather than reevaluation of the original IF glass slides. Thus, the precise character and distribution of the staining for each immune reactant and in each glomerulus cannot be evaluated. Because the IF findings are reported as glomerular intensity of staining, it is not clear as to how the distribution of the staining for C3 and the staining for other immune reactants compare. In particular, whether there is complete or partial colocalization in individual glomeruli cannot be assessed. Second, the relationship of IgM staining with the presence of sclerosing features also cannot be defined without examining the same glomerulus by light microscopy and IF using serial sections. Finally, although we provide presenting clinical data on our cohort of C3G, our study does not include workup of the AP system, treatment, or follow-up information, which will be the subject of future investigations. Thus, we cannot speak to the true ‘sensitivity’ or ‘specificity’ of the proposed criteria. Nevertheless, using the cases of DDD (diagnosed by EM) as a gold standard or true positive, we have clearly shown that a ‘C3 only’ criterion has far too low sensitivity (50%) and that a more inclusive criterion, allowing for some low-level Ig staining, increases this sensitivity. In conclusion, we performed the first study to assess IF criteria for C3G in a large, well-defined biopsy cohort. By using unbiased hierarchical definitions to find an optimal working definition of C3G for practicing pathologists, we provide a framework for triage of patients who are most likely to benefit from molecular and functional assays of AP dysregulation. An optimal definition of C3G, one that is both descriptive and physiologic, should cast a relatively wide net to maximize opportunities to identify AP abnormalities. The Columbia Renal Pathology Laboratory database was queried for cases diagnosed as MPGN1, 2/DDD, or 3 from the years 1999 to 2012. Detailed pathology reports were retrospectively reviewed. We excluded the following cases: (1) all cases with a clear etiology (such as hepatitis C infection, cryoglobulinemia, and dysproteinemia); (2) cases where complete IF findings were not detailed; (3) cases inadequate for IF on frozen tissue; and (4) cases treated with eculizumab, because of potential confounding IF features.27.Herlitz L.C. Bomback A.S. Markowitz G.S. et al.Pathology after eculizumab in dense deposit disease and C3 GN.J Am Soc Nephrol. 2012; 23: 1229-1237Crossref PubMed Scopus (131) Google Scholar A total of 319 biopsies of primary MPGN types 1–3 were identified, including 23 cases with multiple biopsies. For patients with repeat biopsies, only the first biopsy diagnostic of MPGN was analyzed in the initial criteria study. Three additional patients with initial biopsy diagnosis of postinfectious glomerulonephritis and subsequent biopsy diagnosis of MPGN were included among the repeat biopsy analysis. All biopsies were stained at the time of initial biopsy diagnosis according to standard techniques applied to frozen sections using fluorescein isothiocyanate–conjugated antisera to IgG, IgM, IgA, C3c, C1q, fibrin, albumin, kappa, and lambda light chains (Dako, Carpinteria, CA). IF findings were graded on a scale of 0 to 3 by one of four renal pathologists as follows: 0; trace; 1+; 2+; and 3+. For this study, the glomerular IF findings recorded in the biopsy reports were retrospectively reviewed. Using DDD as the validation group, we proposed hierarchical IF criteria with decreasing stringency for diagnosis of C3G: criterion 1, glomerular deposits of C3 only; criterion 2, C3-dominant deposits and ≤1+ IgM only; and criterion 3, C3-dominant deposits and ≥2 orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. Illustrative examples are shown in Figure 2. These criteria were then applied to cases of primary MPGN1 and MPGN3 to determine the incidence of C3G so defined and the relationship to the Strife and Anders versus Burkholder variants of MPGN3. Cases not meeting the third cutoff were further classified as fulfilling criterion 4: C3-dominant deposits and <2 orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q; criterion 5, C3 co-dominant with IgM (5a) or with IgG (5b); criterion 6, IgM>C3; criterion 7, IgG>C3; and criterion 8, no C3 staining. For those cases defined by IF criteria as C3G, the medical record was reviewed for presenting demographic and clinical features including age, gender, race/ethnicity, duration of proteinuria or renal dysfunction, significant comorbidities (e.g. diabetes and hypertension), and laboratory and serologic findings (including serum creatinine, serum albumin, 24-hour urine protein excretion, urinalysis, and serum C3 and C4 levels). For demographic, clinical, and laboratory findings, continuous variables were expressed as mean values and categorical variables were expressed as prevalence rates. Comparisons were made using analysis of variance (STATA version 11.0, StataCorp, College Station, TX) between three subgroups: MPGN1 versus MPGN2 versus MPGN3 by original diagnostic criteria, and IF criterion 1 versus IF criterion 2 versus IF criterion 3 by the proposed inclusion criteria for C3G detailed above.

Background: The utility of whole-exome sequencing (WES) for the diagnosis and management of adult-onset constitutional disorders has not been adequately studied. Genetic diagnostics may be advantageous in adults with chronic kidney disease (CKD), in whom the cause of kidney failure often remains unknown. Objective: To study the diagnostic utility of WES in a selected referral population of adults with CKD. Design: Observational cohort. Setting: A major academic medical center. Patients: 92 adults with CKD of unknown cause or familial nephropathy or hypertension. Measurements: The diagnostic yield of WES and its potential effect on clinical management. Results: Whole-exome sequencing provided a diagnosis in 22 of 92 patients (24%), including 9 probands with CKD of unknown cause and encompassing 13 distinct genetic disorders. Among these, loss-of-function mutations were identified in PARN in 2 probands with tubulointerstitial fibrosis. PARN mutations have been implicated in a short telomere syndrome characterized by lung, bone marrow, and liver fibrosis; these findings extend the phenotype of PARN mutations to renal fibrosis. In addition, review of the American College of Medical Genetics actionable genes identified a pathogenic BRCA2 mutation in a proband who was diagnosed with breast cancer on follow-up. The results affected clinical management in most identified cases, including initiation of targeted surveillance, familial screening to guide donor selection for transplantation, and changes in therapy. Limitation: The small sample size and recruitment at a tertiary care academic center limit generalizability of findings among the broader CKD population. Conclusion: Whole-exome sequencing identified diagnostic mutations in a substantial number of adults with CKD of many causes. Further study of the utility of WES in the evaluation and care of patients with CKD in additional settings is warranted. Primary Funding Source: New York State Empire Clinical Research Investigator Program, Renal Research Institute, and National Human Genome Research Institute of the National Institutes of Health.

Abstract Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10 −12 ) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10 −14 ), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10 −103 ) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10 −49 ), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10 −93 ), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10 −23 and OR = 3.39, P = 5.2 × 10 −82 , respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Abstract Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods 1 . Here we applied multiple single-cell and single-nucleus assays (&gt;400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Native kidney biopsies are commonly performed in the diagnosis of acute kidney diseases and CKD. Because of the invasive nature of the procedure, bleeding-related complications are not uncommon. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases-sponsored Kidney Precision Medicine Project requires that all participants undergo a kidney biopsy; therefore, the objective of this analysis was to study complication rates of native kidney biopsies performed using automated devices under kidney imaging.This is a systematic review and meta-analysis of the literature published from January 1983 to March 2018. The initial PubMed search yielded 1139 manuscripts. Using predetermined selection criteria, 87 manuscripts were included in the final analysis. A random effects meta-analysis for proportions was used to obtain combined estimates of complication rates. Freeman-Tukey double-arcsine transformations were used to stabilize variance as complications were rare.A total of 118,064 biopsies were included in this study. Patient age ranged from 30 to 79 years, and 45% of patients were women. On the basis of our meta-analysis, pain at the site of biopsy is estimated to occur in 4.3% of biopsied patients, hematomas are estimated to occur in 11%, macroscopic hematuria is estimated to occur in 3.5%, bleeding requiring blood transfusions is estimated to occur in 1.6%, and interventions to stop bleeding are estimated to occur in only 0.3%. Death attributed to native kidney biopsy was a rare event, occurring only in an estimated 0.06% of all biopsies but only 0.03% of outpatient biopsies. Complication rates were higher in hospitalized patients and in those with acute kidney disease. The reported complications varied on the basis of study type and geographic location.Although the native kidney biopsy is an invasive diagnostic procedure, the rates of bleeding complications are low. Albeit rare, death can occur postbiopsy. Complications are more frequently seen after kidney biopsies of hospitalized patients with AKI.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients. Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients. Patient perspectives and involvement in precision medicine researchKidney InternationalVol. 99Issue 3PreviewThe Kidney Precision Medicine Project will advance understanding of chronic kidney disease attributed to diabetes or hypertension and acute kidney injury through a protocol kidney biopsy used for deep phenotyping with state-of-the-art methodology. To guide scientific inquiry toward clinically meaningful benefit, patients are equal partners for priority setting, study design and conduct, and dissemination of findings. Patients from stakeholder organizations, recruitment sites, tissue interrogation sites, and the Central Hub are represented on the Community Engagement Committee. Full-Text PDF

The international deployment of mass vaccinations for coronavirus disease 2019 (COVID-19) has raised new concerns for caregivers who specialize in kidney disease. A number of reports question the ability of transplanted patients on maintenance immunosuppression and patients with kidney failure on dialysis to mount sufficient antibody responses to confer immunity against the virus. At the same time, nephrologists are faced with a small but growing literature of case reports linking COVID-19 vaccines with heightened off-target immune responses leading to the sudden development of de novo or relapsing glomerular diseases.

As mass vaccinations for coronavirus disease 2019 (COVID-19) are being administered worldwide, rare reports of adverse events are emerging. We report a case of minimal change disease presenting with nephrotic syndrome 1 week after a first injection of the COVID-19 vaccine (Pfizer-BioNTech).

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. Funding Travere Therapeutics.

Background The use of mineralocorticoid receptor blockers (MRBs) in patients with chronic kidney disease is growing, but data for efficacy in decreasing proteinuria are limited by a relative paucity of studies, many of which are small and uncontrolled. Study Design We performed a systematic review using the MEDLINE database (inception to November 1, 2006), abstracts from national meetings, and selected reference lists. Setting & Population Adult patients with chronic kidney disease and proteinuria. Selection Criteria for Studies English-language studies investigating the use of MRBs added to long-term angiotensin-converting enzyme (ACE)-inhibitor and/or angiotensin receptor blocker (ARB) therapy in adult patients with proteinuric kidney disease. Intervention MRBs as additive therapy to conventional renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. Outcomes Changes in proteinuria as the primary outcome; rates of hyperkalemia, changes in blood pressure, and changes in glomerular filtration rate as secondary outcomes. Results 15 studies met inclusion criteria for our review; 4 were parallel-group randomized controlled trials, 4 were crossover randomized controlled trials, 2 were pilot studies, and 5 were case series. When MRBs were added to ACE-inhibitor and/or ARB therapy, the reported proteinuria decreases from baseline ranged from 15% to 54%, with most estimates in the 30% to 40% range. Hyperkalemic events were significant in only 1 of 8 randomized controlled trials. MRB therapy was associated with statistically significant decreases in blood pressure and glomerular filtration rate in approximately 40% and 25% of included studies, respectively. Limitations Reported results were insufficient for meta-analysis, with only 2 studies reporting sufficient data to calculate SEs of their published estimates. We were unable to locate studies that showed no effect of MRB treatment over placebo, raising concern for publication bias. Conclusions Although data suggest that adding MRBs to ACE-inhibitor and/or ARB therapy yields significant decreases in proteinuria without adverse effects of hyperkalemia and impaired renal function, routine use of MRBs as additive therapy in patients with chronic kidney disease cannot be recommended yet. However, the findings of this review promote interesting hypotheses for future study. The use of mineralocorticoid receptor blockers (MRBs) in patients with chronic kidney disease is growing, but data for efficacy in decreasing proteinuria are limited by a relative paucity of studies, many of which are small and uncontrolled. We performed a systematic review using the MEDLINE database (inception to November 1, 2006), abstracts from national meetings, and selected reference lists. Adult patients with chronic kidney disease and proteinuria. English-language studies investigating the use of MRBs added to long-term angiotensin-converting enzyme (ACE)-inhibitor and/or angiotensin receptor blocker (ARB) therapy in adult patients with proteinuric kidney disease. MRBs as additive therapy to conventional renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. Changes in proteinuria as the primary outcome; rates of hyperkalemia, changes in blood pressure, and changes in glomerular filtration rate as secondary outcomes. 15 studies met inclusion criteria for our review; 4 were parallel-group randomized controlled trials, 4 were crossover randomized controlled trials, 2 were pilot studies, and 5 were case series. When MRBs were added to ACE-inhibitor and/or ARB therapy, the reported proteinuria decreases from baseline ranged from 15% to 54%, with most estimates in the 30% to 40% range. Hyperkalemic events were significant in only 1 of 8 randomized controlled trials. MRB therapy was associated with statistically significant decreases in blood pressure and glomerular filtration rate in approximately 40% and 25% of included studies, respectively. Reported results were insufficient for meta-analysis, with only 2 studies reporting sufficient data to calculate SEs of their published estimates. We were unable to locate studies that showed no effect of MRB treatment over placebo, raising concern for publication bias. Although data suggest that adding MRBs to ACE-inhibitor and/or ARB therapy yields significant decreases in proteinuria without adverse effects of hyperkalemia and impaired renal function, routine use of MRBs as additive therapy in patients with chronic kidney disease cannot be recommended yet. However, the findings of this review promote interesting hypotheses for future study.

The treatment of lupus nephritis has changed significantly over the past decade in large part because of data from well-conducted randomized clinical trials. The concept of two phases of therapy-induction and maintenance-is widely accepted. The histopathologic classification of lupus nephritis continues to guide therapy, and treatment for all major classes of lupus nephritis has seen some shift in management during this time. New regimens using lower doses and shorter treatment durations of intravenous cyclophosphamide have been advanced to reduce toxicity without sacrificing efficacy of therapy. Mycophenolate mofetil has emerged as a viable alternative to cyclophosphamide for induction therapy of both proliferative and membranous lupus nephritis. Combination induction treatment with multiple agents has also been successful. Large controlled trials using mycophenolate mofetil and azathioprine for maintenance therapy have been performed. Here, we review recent additions to the growing body of literature on how to most effectively treat lupus nephritis with the least amount of toxicity. We discuss new treatment strategies currently being explored in clinical trials.

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t1/2 of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.

The metabolism of high-fructose corn syrup used to sweeten soda drinks may lead to elevations in uric acid levels. Here we determined whether soda drinking is associated with hyperuricemia and, as a potential consequence, reduced kidney function. At baseline, 15,745 patients in the Atherosclerosis Risk in Communities Study completed a dietary questionnaire and had measurements of their serum creatinine and uric acid. After 3 and 9 years of follow-up, multivariate odds ratios from logistic regressions for binary outcome of hyperuricemia and chronic kidney disease (eGFR less than 60 ml/min per 1.73 m2) were evaluated. Compared to participants who drank less, consumption of over one soda per day was associated with increased odds of prevalent hyperuricemia and chronic kidney disease. The odds ratio for chronic kidney disease significantly increased to 2.59 among participants who drank more than one soda per day and had a serum uric acid level over 9.0 mg/dl. In longitudinal analyses, however, drinking more than one soda per day was not associated with hyperuricemia or chronic kidney disease. Neither preexistent hyperuricemia nor development of hyperuricemia modified the lack of association between soda drinking and incident chronic kidney disease. Thus our study shows that high consumption of sugar-sweetened soda was associated with prevalent but not incident hyperuricemia and chronic kidney disease. The metabolism of high-fructose corn syrup used to sweeten soda drinks may lead to elevations in uric acid levels. Here we determined whether soda drinking is associated with hyperuricemia and, as a potential consequence, reduced kidney function. At baseline, 15,745 patients in the Atherosclerosis Risk in Communities Study completed a dietary questionnaire and had measurements of their serum creatinine and uric acid. After 3 and 9 years of follow-up, multivariate odds ratios from logistic regressions for binary outcome of hyperuricemia and chronic kidney disease (eGFR less than 60 ml/min per 1.73 m2) were evaluated. Compared to participants who drank less, consumption of over one soda per day was associated with increased odds of prevalent hyperuricemia and chronic kidney disease. The odds ratio for chronic kidney disease significantly increased to 2.59 among participants who drank more than one soda per day and had a serum uric acid level over 9.0 mg/dl. In longitudinal analyses, however, drinking more than one soda per day was not associated with hyperuricemia or chronic kidney disease. Neither preexistent hyperuricemia nor development of hyperuricemia modified the lack of association between soda drinking and incident chronic kidney disease. Thus our study shows that high consumption of sugar-sweetened soda was associated with prevalent but not incident hyperuricemia and chronic kidney disease. Consumption of high-fructose corn syrup (HFCS) has increased nearly 2000% over the past three decades and has paralleled the epidemics of obesity, metabolic syndrome, and chronic kidney disease (CKD).1.Gross L.S. Li L. Ford E.S. et al.Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment.Am J Clin Nutr. 2004; 79: 774-779PubMed Google Scholar Estimates from the US Department of Agriculture report the average yearly intake of HFCS as an added sweetener to be as high as 62.4 pounds per person. Sweetened beverages such as regular soda account for over 70% of this intake.2.Putnam J.J. Allshouse J.E. Food Consumption, Prices and Expenditures, 1970–1997. Economic Research Service, US Dept of Agriculture, Washington, DC1999Google Scholar The metabolism of fructose, unique to that of other sugars, depletes hepatic adenosine triphosphate, increasing the degradation of nucleotides and promoting the synthesis of uric acid.3.Nakagawa T. Hu H. Zharikov S. et al.A causal role for uric acid in fructose-induced metabolic syndrome.Am J Physiol Renal Physiol. 2006; 290: F625-F631Crossref PubMed Scopus (794) Google Scholar Data from the Third National Health and Nutrition Examination Survey suggested a link between regular, but not diet, soda consumption and the frequency of hyperuricemia,4.Choi J.W. Ford E.S. Gao X. et al.Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey.Arthritis Rheum. 2008; 59: 109-116Crossref PubMed Scopus (287) Google Scholar concerning in the light of recent epidemiological studies in which elevated uric acid levels independently increased the risk for incident kidney disease and progression of established CKD.5.Weiner D.E. Tighiouart H. Elsayed E.F. et al.Uric acid and incident kidney disease in the community.J Am Soc Nephrol. 2008; 19: 1204-1211Crossref PubMed Scopus (318) Google Scholar, 6.Obermayr R.P. Temml C. Gutjahr G. et al.Elevated uric acid increases the risk for kidney disease.J Am Soc Nephrol. 2008; 19: 2407-2413Crossref PubMed Scopus (405) Google Scholar, 7.Chonchol M. Shlipak M.G. Katz R. et al.Relationship of uric acid with progression of kidney disease.Am J Kidney Dis. 2007; 50: 239-247Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 8.Hsu C.Y. Iribarren C. McCulloch C.E. et al.Risk factors for end-stage renal disease: 25-year follow-up.Arch Intern Med. 2009; 169: 342-350Crossref PubMed Scopus (395) Google Scholar In animals, fructose-associated hyperuricemia produces a metabolic syndrome associated with glomerular hypertension, renal hypertrophy, and arteriolopathy of the renal vasculature, with resultant reductions in creatinine clearance and increases in proteinuria.3.Nakagawa T. Hu H. Zharikov S. et al.A causal role for uric acid in fructose-induced metabolic syndrome.Am J Physiol Renal Physiol. 2006; 290: F625-F631Crossref PubMed Scopus (794) Google Scholar, 9.Sanchez-Lozada L.G. Tapia E. Jimenez A. et al.Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats.Am J Physiol Renal Physiol. 2007; 292: F423-F429Crossref PubMed Scopus (238) Google Scholar, 10.Bell R.C. Carlson J.C. Storr K.C. et al.High-fructose feeding of streptozotocin-diabetic rats is associated with increased cataract formation and increased oxidative stress in the kidney.Br J Nutr. 2000; 84: 575-582PubMed Google Scholar, 11.Gersch M.S. Mu W. Cirillo P. et al.Fructose, but not dextrose, accelerates the progression of chronic kidney disease.Am J Physiol Renal Physiol. 2007; 293: F1256-F1261Crossref PubMed Scopus (138) Google Scholar The controversy over the potential dangers of HFCS has been playing out not only in the medical literature12.Anderson G.H. Much ado about high-fructose corn syrup in beverages: the meat of the matter.Am J Clin Nutr. 2007; 86: 1577-1578PubMed Google Scholar, 13.Forshee R.A. Storey M.L. Allison D.B. et al.A critical examination of the evidence relating high fructose corn syrup and weight gain.Crit Rev Food Sci Nutr. 2007; 47: 561-582Crossref PubMed Scopus (99) Google Scholar, 14.Johnson R.J. Segal M.S. Sautin Y. et al.Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease.Am J Clin Nutr. 2007; 86: 899-906PubMed Google Scholar, 15.Neilson E.G. The fructose nation.J Am Soc Nephrol. 2007; 18: 2619-2621Crossref PubMed Scopus (17) Google Scholar, 16.Johnson R.J. Gower T. The Sugar Fix: The High-Fructose Fallout that is Making You Fat and Sick. xvi. Rodale, Emmaus, PA2008: 304Google Scholar, 17.Choi M.E. The not-so-sweet side of fructose.J Am Soc Nephrol. 2009; 20: 457-459Crossref PubMed Scopus (8) Google Scholar but also in the mainstream media, including advertising campaigns funded by the corn-producing industry. Defenders of HFCS point out that this sweetener comprises, approximately, 40–55% fructose (the other components being glucose and polymers of glucose); therefore findings from animal and human studies that use 100% fructose formulations may not apply to HFCS.18.White J.S. Straight talk about high-fructose corn syrup: what it is and what it ain’t.Am J Clin Nutr. 2008; 88: 1716S-1721SCrossref PubMed Scopus (164) Google Scholar Two recent investigations have suggested that sugar-sweetened soda consumption is associated with albuminuria19.Shoham D.A. Durazo-Arvizu R. Kramer H. et al.Sugary soda consumption and albuminuria: results from the National Health and Nutrition Examination Survey, 1999–2004.PLoS ONE. 2008; 3: e3431Crossref PubMed Scopus (76) Google Scholar and elevated serum creatinine,20.Saldana T.M. Basso O. Darden R. et al.Carbonated beverages and chronic kidney disease.Epidemiology. 2007; 18: 501-506Crossref PubMed Scopus (56) Google Scholar yet both focused solely on prevalent disease and neither directly examined whether elevated uric acid levels were responsible for the effects of soda (and HFCS) on the kidney. We therefore investigated whether sugar-sweetened soda consumption is associated with hyperuricemia and kidney disease in both cross-sectional and longitudinal analyses of data from the Atherosclerosis Risk in Communities (ARIC) Study. At the baseline ARIC visit, 15,745 participants provided information about their regular consumption of sugar-sweetened sodas. More than 80% of these participants reported drinking less than one soda per day, whereas approximately 5% drank more than one soda per day (Table 1). Participants in the highest exposure category were more likely to be male, African-American, and current smokers compared with participants who drank less than one soda per day. Participants who completed high school and college were less likely to drink soda on a daily basis. Although there was only a slight difference in mean body mass index among exposure groups, participants with higher soda consumption had significantly greater sodium, animal protein, and total calorie intake. Hypertensive status did not differ among exposure groups, although diabetic participants were most represented in the group with the least amount of sugar-sweetened soda consumption. In this generally healthy cohort, only 4% of diabetics drank more than one regular soda per day, whereas 16% of diabetics drank more than one diet soda per day. The three exposure groups had essentially equal serum creatinine measurements, but uric acid levels were slightly higher in the groups with higher soda consumption.Table 1Baseline characteristics of study population, stratified by sugar-sweetened soda consumption<1 soda per day (n=12,981)1 soda per day (n=1902)>1 soda per day (n=862)Age54.4 (5.8)53.6 (5.7)52.0 (5.5)Female7373 (56.8%)919 (48.3%)398 (46.2%)Race White9882 (76.1%)1004 (52.8%)572 (66.4%) Black3056 (23.5%)895 (47.1%)288 (33.4%) Other43 (0.3%)3 (0.2%)2 (0.2%)Years completed education ≤11 years2804 (21.6%)667 (35.2%)276 (32.1%) 12–16 years5286 (40.8%)738 (38.9%)373 (43.3%) ≥17 years4872 (37.6%)492 (25.9%)212 (24.6%)Current smoking3146 (24.3%)638 (33.6%)333 (38.7%)Current alcohol use7462 (57.6%)861 (45.4%)441 (51.3%)Body mass index (kg/m2)27.6 (5.3)28.1 (5.7)27.9 (5.7)HypertensionaHypertension defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication(s).4479 (34.7%)710 (37.5%)294 (34.3%)DiabetesbDiabetes defined as previous diagnosis of diabetes, use of hypoglycemic medications, or fasting blood glucose ≥126 mg/dl.1604 (12.5%)187 (10.0%)73 (8.5%)Caloric intake (kcal/day)1547.0 (581.0)1748.2 (649.2)2010.5 (744.8)Sodium intake (mg/day)1456.1 (589.8)1537.2 (610.6)1635.0 (673.4)Animal protein intake (g/day)53.3 (23.7)54.4 (23.8)55.9 (25.1)Serum creatinine (mg/dl)1.1 (0.4)1.1 (0.5)1.1 (0.2)Estimated GFR (ml/min per 1.73 m2)cEstimated glomerular filtration rate calculated from serum creatinine by the Modification of Diet in Renal Disease (MDRD) formula with calibration for ARIC creatinine values: eGFR=186 × (serum creatinine-0.24)-1.154 × (age)-0.203 × 1.212 (if black) × 0.742 (if female).91.2 (20.6)94.6 (24.0)94.1 (21.3)Serum uric acid (mg/dl)6.0 (1.5)6.2 (1.6)6.3 (1.6)Abbreviations: ARIC, atherosclerosis risk in communities; GFR, glomerular filtration rate.Categorical data presented as n (%); continuous data presented as mean (s.d.).a Hypertension defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication(s).b Diabetes defined as previous diagnosis of diabetes, use of hypoglycemic medications, or fasting blood glucose ≥126 mg/dl.c Estimated glomerular filtration rate calculated from serum creatinine by the Modification of Diet in Renal Disease (MDRD) formula with calibration for ARIC creatinine values: eGFR=186 × (serum creatinine-0.24)-1.154 × (age)-0.203 × 1.212 (if black) × 0.742 (if female). Open table in a new tab Abbreviations: ARIC, atherosclerosis risk in communities; GFR, glomerular filtration rate. Categorical data presented as n (%); continuous data presented as mean (s.d.). Thirty-seven percent (n=5790) of participants at visit 1 met criteria for hyperuricemia; 24% (n=3718) of participants had baseline uric acids above 7.0 mg/dl. In univariate and multivariate analyses, the odds of hyperuricemia significantly rose with increased daily consumption of sugar-sweetened soda (Table 2). Participants who drank less than one soda per day were the referent in this and all subsequent analyses. The multivariate odds ratio for hyperuricemia was 1.31 (1.12–1.53, P=0.001) for participants who drank more than one soda per day.Table 2Association of sugar-sweetened soda consumption with prevalent hyperuricemia and CKD<1 soda per day Odds ratio (95% CI)1 soda per day Odds ratio (95% CI)>1 soda per day Odds ratio (95% CI)(a) Hyperuricemia, defined by sex-specific cut points (>5.7 mg/dl in women, >7.0 mg/dl in men) Univariate analysis1.00 (referent)1.17 (1.06–1.29)1.20 (1.04–1.38) Parsimonious modelaChange in estimate testing for hyperuricemia suggested that univariate analysis was also the appropriate parsimonious model (i.e., no covariates, when removed from the fully adjusted model, changed the exposure estimates by >10%).1.00 (referent)1.17 (1.06–1.29)1.20 (1.04–1.38) Multivariate modelbMultivariate model for hyperuricemia adjusted for age, sex, animal protein intake, caffeine intake, hypertension, body mass index, renal function, current tobacco and alcohol use, ARIC field center, and race.1.00 (referent)1.12 (1.01–1.25)1.31 (1.12–1.53)(b) Chronic kidney disease, defined by estimated GFR<60 ml/min per 1.73 m2 Univariate analysis1.00 (referent)0.88 (0.65–1.18)1.02 (0.69–1.51) Parsimonious modelcChange in estimate testing for chronic kidney disease suggested a model adjusted only for diabetes, sodium intake, and the composite covariate of ARIC field center, and race.1.00 (referent)1.03 (0.76–1.39)1.22 (0.81–1.83)Multivariate modeldMultivariate model for chronic kidney disease adjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.1.00 (referent)1.14 (0.84–1.55)1.46 (0.96–2.22)Abbreviation: GFR, glomerular filtration rate.a Change in estimate testing for hyperuricemia suggested that univariate analysis was also the appropriate parsimonious model (i.e., no covariates, when removed from the fully adjusted model, changed the exposure estimates by >10%).b Multivariate model for hyperuricemia adjusted for age, sex, animal protein intake, caffeine intake, hypertension, body mass index, renal function, current tobacco and alcohol use, ARIC field center, and race.c Change in estimate testing for chronic kidney disease suggested a model adjusted only for diabetes, sodium intake, and the composite covariate of ARIC field center, and race.d Multivariate model for chronic kidney disease adjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race. Open table in a new tab Abbreviation: GFR, glomerular filtration rate. Of the 15,642 participants with creatinine measurements at visit 1, 479 (3.1%) were identified as having prevalent CKD. The odds of having prevalent CKD were not related to the degree of soda consumption in univariate analysis, but parsimonious and multivariate analyses suggested increased odds of CKD with higher soda use (Table 2). The multivariate odds ratio for prevalent CKD was 1.46 (0.96–2.22, P=0.07) for participants who drank more than one soda per day. Logistic regression for the association of CKD and sugar-sweetened soda consumption, using fully adjusted models stratified by uric acid levels, suggested that the association between soda consumption and kidney function was directly related to uric acid levels (Table 3). The odds ratio for CKD among participants who drank more than one soda per day was 0.76 (0.23–2.45, P=0.6) in those without hyperuricemia and 1.50 (0.95–2.37, P=0.08) in those with hyperuricemia. The prevalence odds ratios for CKD increased with rising uric acid levels, from 0.28 (0.04–2.03, P=0.2) in participants with uric acid <6.0 mg/dl to 2.59 (1.18–5.71, P=0.02) in participants with uric acid levels ≥9.0 mg/dl.Table 3Adjusted odds ratios of prevalent CKD according to sugar-sweetened soda consumption, stratified by uric acid status<1 soda per day Odds ratio (95% CI)aAdjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.1 soda per day Odds ratio (95% CI)aAdjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.>1 soda per day Odds ratio (95% CI)aAdjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.Hyperuricemia, defined by sex-specific cut pointsbHyperuricemia defined as serum uric acid >7.0 mg/dl in men and >5.7 mg/dl in women. Absent1.00 (referent)1.46 (0.81–2.60)0.76 (0.23–2.45) Present1.00 (referent)1.00 (0.69–1.44)1.50 (0.95–2.37)Hyperuricemia, defined as serum uric acid >7.0 mg/dl Absent1.00 (referent)1.17 (0.70–1.79)0.64 (0.26–1.58) Present1.00 (referent)1.15 (0.75–1.74)1.96 (1.18–3.25)Uric acid levels (mg/dl) Uric acid <6.01.00 (referent)1.17 (0.61–2.22)0.28 (0.04–2.03) 6.0 ≤uric acid <7.01.00 (referent)1.08 (0.52–2.24)0.68 (0.21–2.25) 7.0 ≤uric acid <8.01.00 (referent)0.93 (0.42–2.03)1.31 (0.49–3.49) 8.0 ≤uric acid <9.01.00 (referent)0.82 (0.37–1.81)1.72 (0.63–4.67)Uric acid ≥9.01.00 (referent)1.59 (0.82–3.10)2.59 (1.18–5.71)Uric acid levels (mg/dl)cAncillary analyses using a common referent group of participants with uric acid levels <6.0 mg/dl and soda consumption <1 per day. Uric acid <6.01.00 (referent)1.17 (0.61–2.22)0.28 (0.04–2.03) 6.0 ≤uric acid <7.02.34 (1.71–3.20)2.09 (1.03–4.23)1.62 (0.50–5.21) 7.0 ≤uric acid <8.03.21 (2.28–4.53)3.18 (1.50–6.76)4.41 (1.72–11.31) 8.0 ≤uric acid <9.07.60 (5.30–10.89)6.63 (3.06–14.39)11.00 (4.15–29.10) Uric acid ≥9.012.05 (8.25–17.61)20.03 (10.57–37.95)31.32 (15.19–64.58)a Adjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.b Hyperuricemia defined as serum uric acid >7.0 mg/dl in men and >5.7 mg/dl in women.c Ancillary analyses using a common referent group of participants with uric acid levels <6.0 mg/dl and soda consumption <1 per day. Open table in a new tab Over 3 years of follow-up, 15,642 participants had uric acid levels checked at baseline and visit 2. Of the 9451 participants without hyperuricemia at visit 1, 3288 (34.8%) developed hyperuricemia by visit 2. Although univariate analysis suggested that sugar-sweetened soda intake increased the odds of hyperuricemia, both parsimonious and multivariate models revealed no significant association (Table 4). Participants who drank less than one soda per day were again the referent in all longitudinal analyses. The multivariate odds ratio for incident hyperuricemia was 1.17 (0.95–1.43, P=0.1) among participants who drank more than one soda per day. Multivariate linear regression, with uric acid levels as continuous variables and comparing subjects who drank >1 soda per day to the same referent, showed no influence of increased soda consumption on the change in uric acid level from visit 1 to visit 2 (β coefficient -0.025, 95% CI -0.109 to 0.058).Table 4Association of sugar-sweetened soda consumption with incident (a) hyperuricemia and (b) CKD<1 soda per day Odds ratio (95% CI)1 soda per day Odds ratio (95% CI)>1 soda per day Odds ratio (95% CI)(a) Hyperuricemia, defined by sex-specific cut points (>5.7 mg/dl in women, >7.0 mg/dl in men) Univariate analysis1.00 (referent)1.23 (1.07–1.40)1.23 (1.02–1.49) Parsimonious modelaChange in estimate testing for hyperuricemia suggested a model adjusted only for the composite covariate of ARIC field center and race.1.00 (referent)1.09 (0.96–1.25)1.17 (0.97–1.42) Multivariate modelbMultivariate model for hyperuricemia adjusted for age, sex, caffeine intake, animal protein intake, hypertension, body mass index, renal function, current tobacco and alcohol use, ARIC field center, and race.1.00 (referent)1.11 (0.97–1.28)1.17 (0.95–1.43)(b) Chronic kidney disease, defined by estimated GFR<60 ml/min per 1.73 m2 Univariate analysis1.00 (referent)0.70 (0.57–0.87)0.60 (0.43–0.83) Parsimonious modelcChange in estimate testing for chronic kidney disease suggested a model adjusted only for caloric intake and the composite covariate of ARIC field center and race.1.00 (referent)0.77 (0.63–0.96)0.69 (0.49–0.95) Multivariate modeldMultivariate model for chronic kidney disease adjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.1.00 (referent)0.86 (0.69–1.06)0.82 (0.59–1.16)Abbreviation: GFR, glomerular filtration rate.a Change in estimate testing for hyperuricemia suggested a model adjusted only for the composite covariate of ARIC field center and race.b Multivariate model for hyperuricemia adjusted for age, sex, caffeine intake, animal protein intake, hypertension, body mass index, renal function, current tobacco and alcohol use, ARIC field center, and race.c Change in estimate testing for chronic kidney disease suggested a model adjusted only for caloric intake and the composite covariate of ARIC field center and race.d Multivariate model for chronic kidney disease adjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race. Open table in a new tab Abbreviation: GFR, glomerular filtration rate. Over 9 years of follow-up, 15,642 participants had serum creatinine levels checked at baseline, 14,292 had repeat levels at 3 years, and 11,559 had levels checked at 9 years. Of the 14,002 participants without prevalent CKD at visit 1, 1160 (8.3%) met our criteria for incident CKD by visit 2 or 4. Multivariate analysis found no association between sugar-sweetened soda consumption and odds of developing kidney disease (Table 4). The odds ratio for incident kidney disease was 0.82 (0.59–1.16, P=0.3) among participants who drank >1 soda per day. Sensitivity analyses excluding diabetic participants, using a more conservative definition of incident CKD detailed above, and using change in serum creatinine as the outcome did not significantly change these estimates. Multivariate linear regression evaluating the continuous change in estimated glomerular filtration rate (eGFR) from visit 1 to visit 2 (β coefficient -0.442, 95% CI -1.690 to 0.805) and change in eGFR from visit 1 to visit 4 (β coefficient -0.467, 95% CI -1.990 to 1.055) were likewise not significant for participants who consumed >1 soda per day. As with the cross-sectional analyses, we stratified the multivariate logistic models for the association of incident CKD and soda consumption by uric acid levels (Table 5). Neither the presence of hyperuricemia at visit 1 nor the development of hyperuricemia between visits 1 and 2 increased the odds of developing CKD among high-soda consumers in this cohort. Likewise, no degree of change in uric acid levels between visits 1 and 2 seemed to modify the lack of association between soda consumption and incident CKD during the study period. Only participants with uric acid levels of 9.0 mg/dl or higher at visit 1 showed an increased odds of developing CKD if they drank more than one soda per day (OR 3.90, 95% CI 1.55–9.82) compared to participants with similar uric acid elevations who drank less than one soda per day.Table 5Adjusted odds ratios of incident kidney disease according to sugar-sweetened soda consumption, stratified by uric acid status<1 soda per day Odds ratio (95% CI)aAdjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.1 soda per day Odds ratio (95% CI)aAdjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.>1 soda per day Odds ratio (95% CI)aAdjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.HyperuricemiabHyperuricemia defined as serum uric acid >7.0 mg/dl in men and >5.7 mg/dl in women. at visit 1 Absent1.00 (referent)0.68 (0.49–0.96)0.61 (0.35–1.06) Present1.00 (referent)1.03 (0.77–1.38)1.01 (0.65–1.56)Development of hyperuricemiabHyperuricemia defined as serum uric acid >7.0 mg/dl in men and >5.7 mg/dl in women. between visits 1 and 2cAnalysis excludes participants with hyperuricemia at visit 1. Absent1.00 (referent)0.57 (0.35–0.94)0.84 (0.45–1.57) Present1.00 (referent)0.81 (0.50–1.31)0.32 (0.10–1.03)Change in uric acid levels between visits 1 and 2 (mg/dl) Δ Uric acid ≤0.01.00 (referent)1.07 (0.72–1.59)1.34 (0.75–2.39) 0.0 <Δ Uric acid ≤1.01.00 (referent)0.74 (0.51–1.08)0.83 (0.49–1.40) 1.0 <Δ Uric acid ≤2.01.00 (referent)0.74 (0.45–1.21)0.46 (0.18–1.15) 2.0 <Δ Uric acid ≤3.01.00 (referent)0.81 (0.36–1.82)0.31 (0.04–2.43) Δ Uric acid >3.01.00 (referent)1.35 (0.46–4.00)2.47 (0.41–15.07)Uric acid levels at visit 1 (mg/dl) Uric acid <6.01.00 (referent)0.63 (0.43–0.92)0.63 (0.35–1.14) 6.0 ≤Uric acid <7.01.00 (referent)1.00 (0.65–1.53)0.57 (0.26–1.25) 7.0 ≤Uric acid <8.01.00 (referent)1.33 (0.83–2.12)0.74 (0.33–1.68) 8.0 ≤Uric acid <9.01.00 (referent)0.87 (0.44–1.69)0.72 (0.25–2.12) Uric acid ≥9.01.00 (referent)0.57 (0.19–1.73)3.90 (1.55–9.82)Uric acid levels at visit 1 (mg/dl)dAncillary analyses using a common referent group of participants with uric acid levels <6.0 mg/dl and soda consumption <1 per day.Uric acid <6.01.00 (referent)0.63 (0.43–0.92)0.63 (0.35–1.14)6.0 ≤Uric acid <7.01.30 (1.09–1.55)1.32 (0.88–1.98)0.72 (0.33–1.55)7.0 ≤Uric acid <8.01.62 (1.31–1.99)2.00 (1.29–3.09)1.25 (0.57–2.75)8.0 ≤Uric acid <9.02.06 (1.58–2.68)1.84 (0.98–3.44)1.50 (0.53–4.27)Uric acid ≥9.01.87 (1.34–2.62)0.97 (0.34–2.73)5.72 (2.64–12.36)a Adjusted for age, sex, body mass index, sodium intake, caloric intake, hypertension, diabetes, current tobacco and alcohol use, education, ARIC field center, and race.b Hyperuricemia defined as serum uric acid >7.0 mg/dl in men and >5.7 mg/dl in women.c Analysis excludes participants with hyperuricemia at visit 1.d Ancillary analyses using a common referent group of participants with uric acid levels <6.0 mg/dl and soda consumption <1 per day. Open table in a new tab We repeated our analyses substituting diet soda intake as the exposure of interest and using the same three categories of exposure (that is, participants who drank <1 diet soda per day were the referent category). In multivariate models, consumption of >1 diet soda was not associated with prevalent hyperuricemia (OR 1.10, 95% CI 0.98–1.24), prevalent CKD (OR 1.29, 95% CI 0.95–1.74), incident hyperuricemia (OR 0.97, 95% CI 0.83–1.14), or incident CKD (OR 0.80, 95% CI 0.64–1.00) (Supplementary Table S1). Multivariate linear regression comparing subjects who drank >1 diet soda per day to those who drank <1 diet soda per day similarly showed no influence of increased diet soda consumption on the change in uric acid level from visit 1 to visit 2 (β coefficient 0.024, 95% CI -0.039 to 0.087), change in eGFR from visit 1 to visit 2 (β coefficient -0.380, 95% CI -1.313 to 0.553), or change in eGFR from visit 1 to visit 4 (β coefficient -0.184, 95% CI -1.319 to 0.950). Finally, in stratified analysis, subjects with baseline uric acid levels ≥9.0 mg/dl who drank >1 diet soda per day did not have increased odds of either prevalent CKD (OR 0.71, 95% CI 0.28–1.83) or incident CKD (OR 0.44, 95% CI 0.12–1.52). Download .doc (.05 MB) Help with doc files Supplementary Table S1–S3 In this study, increased consumption of regular soft drinks was associated with prevalent hyperuricemia and CKD. Stratified analysis also suggested that the association between such sweetened beverages and kidney function was primarily among participants with elevated uric acid levels. However, in longitudinal analyses, these associations did not h

C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease. C3 glomerulonephritis (C3GN) and dense deposit disease comprise the two classes of C3 glomerulopathy. Studies from Europe and Asia have aided our understanding of this recently defined disorder, but whether these data apply to a diverse United States patient population remains unclear. We, therefore, reviewed clinical and histopathological data, including generation of a C3 Glomerulopathy Histologic Index to score biopsy activity and chronicity, to determine predictors of progression to end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) in 111 patients (approximately 35% non-white) with C3 glomerulopathy: 87 with C3GN and 24 with dense deposit disease. Complement-associated gene variants and autoantibodies were detected in 24% and 35% of screened patients, respectively. Our C3 Glomerulopathy Histologic Index denoted higher activity in patients with C3GN and higher chronicity in patients with dense deposit disease. Over an average of 72 months of follow-up, remission occurred in 38% of patients with C3GN and 25% of patients with dense deposit disease. Progression to late-stage CKD and ESRD was common, with no differences between C3GN (39%) and dense deposit disease (42%). In multivariable models, the strongest predictors for progression were estimated glomerular filtration rate at diagnosis (clinical variables model) and tubular atrophy/interstitial fibrosis (histopathology variables model). Using our C3 Glomerulopathy Histologic Index, both total activity and total chronicity scores emerged as the strongest predictors of progression. Thus, in a large, diverse American cohort of patients with C3 glomerulopathy, there is a high rate of progression to CKD and ESRD with no differences between C3GN and dense deposit disease. The term “C3 glomerulopathy” (C3G) denotes a glomerulonephritis with isolated or dominant C3 staining that implies an etiology rooted in dysregulation of the alternative complement pathway.1Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (267) Google Scholar This umbrella term encompasses both dense deposit disease (DDD, formerly known as membranoproliferative glomerulonephritis [MPGN] type 2) and C3 glomerulonephritis (C3GN, formerly known as MPGN type 1 or type 3 with isolated C3 staining). A genetic or acquired defect arising from rare genetic variants or autoantibodies that modulate activation of the C3 convertase of the alternative complement pathway can lead to a transformation from low-grade physiologic activity to unrestrained hyperactivity. This loss of alternative pathway control can result in a glomerulonephritis that on immunofluorescence stains only or dominantly for C3, consistent with mediation by deposition of complement proteins rather than immune complexes. The natural history of C3G, a rare disease with a reported incidence between 1 and 3 per million, is slowly being defined, and the heterogeneity among those diagnosed with C3G is striking. The clinical presentation can vary from asymptomatic hematuria and proteinuria with preserved renal function to the full nephrotic syndrome or a rapidly progressive glomerulonephritis.2Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 3Medjeral-Thomas N.R. O'Shaughnessy M.M. O'Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53Crossref PubMed Scopus (146) Google Scholar The most common histologic finding on light microcopy is membranoproliferative glomerulonephritis, although similar C3-dominant staining and deposits (presumably of complement components) in the mesangial, subepithelial, subendothelial, and intramembranous regions of the glomerulus have also been demonstrated in patients with mesangial proliferative or diffuse endocapillary proliferative patterns.4Bomback A.S. Appel G.B. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN.Nat Rev Nephrol. 2012; 8: 634-642Crossref PubMed Scopus (117) Google Scholar, 5D'Agati V.D. Bomback A.S. C3 glomerulopathy: what's in a name?.Kidney Int. 2012; 82: 379-381Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 6Hou J. Markowitz G.S. Bomback A.S. et al.Toward a working definition of C3 glomerulopathy by immunofluorescence.Kidney Int. 2014; 85: 450-456Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Progression to end-stage renal disease (ESRD) has been reported in up to 50% of patients within the first 5 years of diagnosis, with DDD patients reportedly progressing at twice the rate of C3GN patients.2Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 3Medjeral-Thomas N.R. O'Shaughnessy M.M. O'Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53Crossref PubMed Scopus (146) Google Scholar, 7Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274Crossref PubMed Scopus (154) Google Scholar To date, the largest cohorts of C3G have emerged from centers in Japan,8Okuda Y. Ishikura K. Hamada R. et al.Membranoproliferative glomerulonephritis and C3 glomerulonephritis: frequency, clinical features, and outcome in children.Nephrology (Carlton). 2015; 20: 286-292Crossref PubMed Scopus (15) Google Scholar the United Kingdom,3Medjeral-Thomas N.R. O'Shaughnessy M.M. O'Regan J.A. et al.C3 glomerulopathy: clinicopathologic features and predictors of outcome.Clin J Am Soc Nephrol. 2014; 9: 46-53Crossref PubMed Scopus (146) Google Scholar Spain,9Rabasco C. Cavero T. Román E. et al.Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.Kidney Int. 2015; 88: 1153-1160Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Turkey,10Caliskan Y. Torun E.S. Tiryaki T.O. et al.Immunosuppressive treatment in C3 glomerulopathy: is it really effective?.Am J Nephrol. 2017; 46: 96-107Crossref PubMed Scopus (26) Google Scholar Italy,11Iatropoulos P. Noris M. Mele C. et al.Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.Mol Immunol. 2016; 71: 131-142Crossref PubMed Scopus (93) Google Scholar and France.2Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar These reports have helped shape our current understanding of the natural history of C3G, but their generalizability to an ethnically diverse patient population in the United States remains unclear. In addition, these prior cohorts have often focused on either pediatric or adult populations, without taking into account the long disease course of many patients. Here, we present data on 111 pediatric and adult patients with C3G evaluated at the Center for Glomerular Diseases at Columbia University. This represents not only the largest C3G patient cohort in the United States but also the largest single-center experience reported worldwide. The cohort consisted of 111 patients, 87 with C3GN and 24 with DDD (Table 1). Patients with C3GN (mean age 28.3 years) were significantly younger than patients with DDD (mean age 40.0 years), with 36.8% of the C3GN subcohort considered pediatric (under 18 years) at the time of diagnosis versus 12.5% of the DDD subcohort. While whites comprised the majority (65%) of patients, Hispanic, Asian, and African-American patients accounted for 19%, 10%, and 5% of the cohort, respectively. The most common clinical presentation was hematuria and proteinuria with preserved kidney function, although about one-quarter of the patients presented with significant chronic kidney disease (CKD) at the time of diagnosis, as seen in the median and interquartile range of creatinine values at the time of diagnosis across the cohort (1.3 mg/dl, 0.8–2.0 mg/dl). Creatinine values appeared similar between patients with C3GN and DDD, but due to the significant age difference in the subcohorts, the mean estimated glomerular filtration rate (eGFR), by both MDRD and CKD-EPI estimating equations, was higher in C3GN patients than DDD patients. The average proteinuria was 3.9 g/d for the entire cohort, but patients with C3GN were more likely than patients with DDD to present with full nephrotic syndrome.Table 1Baseline clinical data of C3 glomerulopathy cohortCharacteristicC3GN (n = 87)DDD (n = 24)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.Age at diagnosis (yr)28.340.00.03Age groups (%)0.05 <18 years36.812.5 18–50 years47.158.3 >50 years16.129.2Male/female (%)63.2/36.866.7/33.30.8Race/ethnicity (%)0.9 White63.270.8 Hispanic19.516.7 Asian12.68.3 African-American4.64.2Presentation (%)0.05 Hematuria and proteinuria, preserved eGFR40.741.7 Nephrotic syndrome32.616.7 AKI/RPGN8.10 CKD with hematuria and proteinuria18.641.7Antecedent infection (%)18.416.70.8Creatinine at diagnosis (mg/dl)2.02.10.9eGFR at diagnosis (ml/min per 1.73 m2) MDRD (4-variable) formula72.655.30.1 CKD-EPI formula75.758.80.1Proteinuria at diagnosis (mg/g or mg/d)377744100.5Low C3 at diagnosis (%)64.963.60.9Low C4 at diagnosis (%)13.913.61.0Complement factor gene variant (C3, CFH, CFI, CFB, CFHR5, MCP) identified (%)bTesting for complement factor gene variants and autoantibodies was performed on a subset of patients in the cohort (N = 51). More detailed results are available in Supplementary Table S1.21.4 (9 of 42)33.3 (3 of 9)0.5Complement auto-antibody (C3Nef, factor H Ab, factor B Ab) identified (%)bTesting for complement factor gene variants and autoantibodies was performed on a subset of patients in the cohort (N = 51). More detailed results are available in Supplementary Table S1.38.1 (16 of 42)22.2 (2 of 9)0.4Paraprotein detected in serum and/or urine (%)cTesting for paraproteins in serum and/or urine was performed on a subset of patients in the cohort (N = 38).25.0 (6 of 24)57.1 (8 of 14)0.05AKI, acute kidney injury; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; RPGN, rapidly progressive glomerulonephritis.Categorical variables are presented as percentage of total group; continuous variables are presented as mean value.a Testing for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.b Testing for complement factor gene variants and autoantibodies was performed on a subset of patients in the cohort (N = 51). More detailed results are available in Supplementary Table S1.c Testing for paraproteins in serum and/or urine was performed on a subset of patients in the cohort (N = 38). Open table in a new tab AKI, acute kidney injury; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; RPGN, rapidly progressive glomerulonephritis. Categorical variables are presented as percentage of total group; continuous variables are presented as mean value. The prevalence of low complement levels was equal in C3GN and DDD patients, and we did not detect a difference in the rates of complement-associated gene variants or autoantibodies in the subgroup of patients (n = 51) for whom such testing was available (Supplementary Table S1). Pediatric patients demonstrated a significantly higher prevalence of low C3 levels (83.3%) compared with adult patients (56.5%, P = 0.01 for comparison) and demonstrated about twice the rate of detectable genetic variants and/or autoantibodies (24% vs. 13%), although this did not meet statistical significance (P = 0.2 for comparison). Rates of antecedent infections, defined as self-reported infectious illness (viral or bacterial) in the 3 months prior to C3G diagnosis, did not differ between adult (17%) and pediatric (21%) patients. We did, however, find more than twice the prevalence of monoclonal paraproteins (57% vs. 25%) in DDD patients compared with C3GN patients in those tested for dysproteinemias. The median (interquartile range) age in these 14 patients with detectable paraproteins was 53 (43–64) years, and 4 such patients had autoantibodies directed at the alternative complement pathway (2 with C3 nephritic factor and 2 with anti-Factor H). Biopsy materials (glass slides, immunofluorescence images, and electron microscopy scans) were available in 66 of the 111 cases for central re-review at Columbia University Medical Center; in the remaining 45 cases, histopathology data were extracted from the original biopsy reports (Table 2). The most common pattern on light microscopy was MPGN. In both the entire cohort and the subcohort with original biopsy materials re-reviewed, patients with DDD were more likely to have a diffuse sclerosing pattern on light microscopy. There was a trend toward greater likelihood of C3-alone staining (vs. C3-dominant staining) on immunofluorescence in DDD patients versus C3GN patients in both the entire cohort and the subcohort, although this did not reach statistical significance.Table 2Histopathology of entire C3 glomerulopathy cohort (N = 111) and subcohort with biopsy re-read at Columbia University Medical Center (N = 66)(A) Entire cohortC3GN (n = 87)DDD (n = 24)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.Light microscopy pattern (%)0.2 MPGN68.845.8 Mesangial proliferative GN17.529.2 Diffuse endocapillary proliferative GN8.812.5 Diffuse sclerosing GN5.012.5Tubular atrophy/interstitial fibrosis (estimated %)28.423.40.4Cellular or fibrocellular crescents, any identified (%)10.316.70.4Immunofluorescence (%)0.3 C3 alone46.861.9 C3 dominant (with trace or 1+ Ig)53.238.1(B) CUMC subcohortC3GN (n = 46)DDD (n = 20)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables.Light microscopy pattern (%)0.1 MPGN60.935.0 Mesangial proliferative GN17.435.0 Diffuse endocapillary proliferative GN13.015.0 Diffuse sclerosing GN8.715.0Globally sclerotic glomeruli (calculated %)20.332.50.08Segmentally sclerotic glomeruli (calculated %)13.927.10.04Exudative features (%)23.915.00.4Cellular or fibrocellular crescents, any identified (%)17.410.00.4Tubular atrophy/interstitial fibrosis (estimated %)23.531.80.2Immunofluorescence (%)0.2 C3 alone39.155.0 C3 dominant (with trace or 1+ Ig)60.945.0C3GN, C3 glomerulonephritis; CUMC, Columbia University Medical Center; DDD, dense deposit disease; GN, glomerulonephritis; MPGN, membranoproliferative glomerulonephritis.Data presented are percentage of total groups, unless otherwise noted as mean estimated or calculated percentages of sampled glomeruli or tubulointerstitial area.a Testing for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test for continuous variables and Fisher exact test for categorical variables. Open table in a new tab C3GN, C3 glomerulonephritis; CUMC, Columbia University Medical Center; DDD, dense deposit disease; GN, glomerulonephritis; MPGN, membranoproliferative glomerulonephritis. Data presented are percentage of total groups, unless otherwise noted as mean estimated or calculated percentages of sampled glomeruli or tubulointerstitial area. We subsequently used original biopsy material to develop a C3G histologic index for the degree of disease activity and chronicity (Table 3). A semiquantitative scale of 0 to 3 was used for 7 markers of activity, allowing for an activity score of 0 to 21. For a chronicity score, ranging from 0 to 10, we used a semiquantitative scale of 0 to 3 for glomerulosclerosis, tubular atrophy, and interstitial fibrosis, and a scale of 0 to 1 for severity of arteriosclerosis. There were no statistically significant differences detected in any of the parameters of activity between C3GN and DDD patients (Table 4), although there was a trend for higher total activity among patients with C3GN (average activity score 9.1 out of 21) versus patients with DDD (7.6). Patients with DDD demonstrated greater chronicity scores in all parameters evaluated compared with patients with C3GN, with total chronicity score averaging 6.0 (out of 10) compared with 4.1 (P = 0.02).Table 3C3 glomerulopathy histopathology indexComponentDefinitionScore(A) Activity score, 0–21Mesangial hypercellularity% glomeruli with >3 mesangial cells per mesangial area0 = none1 = 1%–25%2 = 26%–50%3 = >50%Endocapillary proliferation% glomeruli with an increased number of cells within glomerular capillary lumina, causing luminal narrowing0 = none1 = 1%–25%2 = 26%–50%3 = >50%Membranoproliferative morphology% glomeruli with GBM duplication with or without endocapillary proliferation0 = none1 = 1%–25%2 = 26%–50%3 = >50%Leukocyte infiltration% glomeruli with glomerular capillary infiltration by ≥3 neutrophils and/or macrophages0 = none1 = 1%–25%2 = 26%–50%3 = >50%Crescent formation% glomeruli with cellular and/or fibrocellular crescents0 = none1 = 1%–10%2 = 11%–25%3 = >25%Fibrinoid necrosis% glomeruli with presence of ≥2 of fibrin, karyorrhexis, and GBM rupture0 = none1 = 1%–10%2 = 11%–25%3 = >25%Interstitial inflammation% cortical tubulointerstitial area with inflammation in non-fibrotic cortex0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%(B) Chronicity score, 0–10Glomerulosclerosis% glomeruli with global and segmental sclerosis0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%Tubular atrophy% cortical tubulointerstitial area involved with tubular atrophy0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%Interstitial fibrosis% cortical tubulointerstitial area involved with interstitial fibrosis0 = <10%1 = 10%–25%2 = 26%–50%3 = >50%Arterio- and arteriolosclerosisIntimal thickening ≥ thickness of media0 = absent1 = presentGBM, glomerular basement membrane. Open table in a new tab Table 4C3 glomerulopathy (C3G) histopathology index values in the C3G cohortComponentC3GN (n = 46)DDD (n = 20)P valueaTesting for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test.(A) Activity scorebFor mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, and leukocyte infiltration, we used a scale of 0 = none, 1 = 1-25%, 2 = 26-50%, and 3 = >50% involvement of sampled glomeruli. For crescent formation and fibrinoid necrosis, we used a scale of 0 = none, 1 = 1-10%, 2 = 11-25%, and 3 = >25% involvement of sampled glomeruli. For interstitial inflammation, we used a scale of 0 = <10%, 1 = 10-25%, 2 = 26-50%, and 3 = >50% based on percentage of involved cortical tubulointerstitial area.Mesangial hypercellularity (0–3)2.72.30.06Endocapillary proliferation (0–3)1.71.30.2Membranoproliferative morphology (0–3)1.91.50.2Leukocyte infiltration (0–3)1.61.30.3Crescent formation (0–3)0.30.60.3Fibrinoid necrosis (0–3)0.20.10.7Interstitial inflammation (0–3)0.80.60.2Total Activity Score (0-21)9.17.60.1(B) Chronicity scorecGlomerulosclerosis, tubular atrophy, and interstitial fibrosis were assigned a score of 0 to 3 based on the percentage involvement (0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%). For vascular disease, we assigned 0 if intimal thickening was < thickness of media and 1 if intimal thickening was ≥ thickness of media.Global and segmental glomerulosclerosis (0–3)1.42.20.02Tubular atrophy (0–3)1.31.70.09Interstitial fibrosis (0–3)1.31.70.09Arterio- and arteriolosclerosis (0–1)0.20.50.03Total chronicity score (0–10)4.16.00.02C3GN, C3 glomerulonephritis; DDD, dense deposit disease.a Testing for differences was performed using a 2-sample Wilcoxon rank-sum (Mann-Whitney) test.b For mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, and leukocyte infiltration, we used a scale of 0 = none, 1 = 1-25%, 2 = 26-50%, and 3 = >50% involvement of sampled glomeruli. For crescent formation and fibrinoid necrosis, we used a scale of 0 = none, 1 = 1-10%, 2 = 11-25%, and 3 = >25% involvement of sampled glomeruli. For interstitial inflammation, we used a scale of 0 = <10%, 1 = 10-25%, 2 = 26-50%, and 3 = >50% based on percentage of involved cortical tubulointerstitial area.c Glomerulosclerosis, tubular atrophy, and interstitial fibrosis were assigned a score of 0 to 3 based on the percentage involvement (0 = <10%, 1 = 10-25%, 2 = 26-50%, 3 = >50%). For vascular disease, we assigned 0 if intimal thickening was < thickness of media and 1 if intimal thickening was ≥ thickness of media. Open table in a new tab GBM, glomerular basement membrane. C3GN, C3 glomerulonephritis; DDD, dense deposit disease. The mean duration of follow-up was 69 months for C3GN patients and 83 months for DDD patients (P = 0.4). More than 75% of patients were treated with blockers of the renin-angiotensin-aldosterone system (RAAS). Eighty of the 111 patients were treated with at least 1 course of immunosuppression (Table 5), and there was no difference in this regard between C3GN and DDD patients (74% vs. 67% treated with immunosuppression). However, patients with C3GN vs. DDD were more likely to be treated with mycophenolate mofetil (44% vs. 17%, P = 0.02) and demonstrated a nonsignificant trend toward greater utilization of corticosteroids (70% vs. 50%, P = 0.09). Seven of the patients in the cohort received eculizumab at some point in their disease course, of which 4 progressed to ESRD and 2 progressed to CKD stage 5. Complete or partial remission occurred more often in C3GN patients (38%) vs. DDD patients (25%), although this was not statistically significant (P = 0.2, Figure 1). Likewise, a higher rate of complete remission was seen in C3GN (15%) versus DDD (8%), but this was not statistically significant (P = 0.4). Nineteen of the 42 C3G patients treated with mycophenolate mofetil (MMF) achieved complete or partial remission, of which 18 received concomitant treatment with corticosteroids. Among those patients treated with MMF, we did not detect any clear predictors of response to treatment. C3 levels were similar among responders and nonresponders, with approximately half demonstrating depressed C3 levels at initiation of treatment. Fifteen of the 42 MMF-treated patients demonstrated elevated levels of serum membrane attack complex (C5b-9): 10 nonresponders versus 5 responders. Testing for C3 nephritic factor was positive in 4 of 14 nonresponders and 4 of 9 responders. Only 3 patients in this MMF subcohort had detectable genetic variants.Table 5Treatment and outcome data of C3 glomerulopathy cohortParameterC3GN (n = 87)DDD (n = 24)P valueaTesting for differences was performed using Fisher exact test for treatment history and univariate Cox proportional hazards model for outcomes of interest.(A) TreatmentRAAS blockade: ACE-I, ARB, MRB75.679.20.8Steroids70.150.00.09Mycophenolate mofetil43.716.70.02Calcineurin inhibitor8.10.00.3Eculizumab4.612.50.2Rituximab8.10.00.3Cyclophosphamide4.68.30.6Other immunosuppression3.512.50.1Any immunosuppression73.666.70.5(B) OutcomesDuration of follow-up (months)69.183.20.4Remission (complete + partial)37.925.00.2Remission (complete)14.98.30.4Doubling of creatinine (eGFR > 15 ml/min per 1.73 m2)9.28.30.7Progression to CKD 5 (eGFR < 15 ml/min per 1.73 m2)9.20.0–Pre-emptive transplantation9.28.31.0ESRD11.520.80.3Death0.04.2–Combined outcome (doubling of creatinine, progression to CKD stage 5, ESRD, transplantation, death)39.141.70.7ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MRB, mineralocorticoid receptor blocker; RAAS, renin-angiotensin system.Data presented are percentage of total groups with the exception of duration of follow-up, given as mean months.a Testing for differences was performed using Fisher exact test for treatment history and univariate Cox proportional hazards model for outcomes of interest. Open table in a new tab ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; C3GN, C3 glomerulonephritis; CKD, chronic kidney disease; DDD, dense deposit disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MRB, mineralocorticoid receptor blocker; RAAS, renin-angiotensin system. Data presented are percentage of total groups with the exception of duration of follow-up, given as mean months. Progression to late-stage CKD and ESRD requiring dialysis and transplantation was common in the cohort (Table 5), with no detectable differences between those with C3GN (39.1%) and DDD (41.7%) for our primary outcome of doubling of creatinine, progression to CKD stage 5, ESRD, transplantation, or death (Figure 2). In univariate analyses, we did detect a trend toward faster progression to this combined outcome in older patients compared with younger patients (Figure 3), but this distinction was mitigated in a multivariate model that adjusted for sex, race and/or ethnicity, presenting renal function and proteinuria, complement levels, presence of complement-associated gene variants and/or autoantibodies, and utilization of immunosuppression (Table 6). In this clinical variables–only model, the sole predictor of progression to late-stage CKD, ESRD, or death was kidney function at the time of presentation. In the second multivariate model based on histopathology variables only, the strongest predictor for our combined outcome was degree of tubular atrophy and/or interstitial fibrosis (each 10% increase in fibrosis imparting approximately twice the risk for progression). In this model, we additionally found that the presence of C3-only staining on immunofluorescence, as opposed to C3-dominant staining with trace to 1+ Ig, was associated with higher risk of progression (hazard ratio 5.09, 95% confidence interval 1.49–17.35, P = 0.009). There was also a trend, not reaching statistical significance, for higher risk associated with the presence of cellular or fibrocellular crescents.Figure 3In univariate analysis, progression to end-stage renal disease, advanced chronic kidney disease (doubling creatinine or chronic kidney disease stage 5), or death was faster among adult patients diagnosed with C3 glomerulopathy than among pediatric patients. Survival analysis excludes 3 patients for whom time to outcome was unable to be verified (N = 108).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 6Predictors of progression to primary outcome in C3 glomerulopathy using 3 multivariate modelsPredictorHazard ratio (95% CI)P value(A) Clinical variables modelFemale1.44 (0.53–3.92)0.5Age Less than 18 years1.00 (reference)N/A 18-50 years0.91 (0.28–3.03)0.9 Over 50 years1.19 (0.30–4.81)0.8Race/ethnicity White1.00 (reference)N/A Hispanic1.29 (0.48–3.47)0.6 Asian4.01 (0.81–19.77)0.09 African-American3.24 (0.33–32.00)0.3eGFR via CKD-EPI equation (per 10 ml/min per 1.73 m2)0.69 (0.57–0.83)<0.001Proteinuria at diagnosis (per 1 g/d)1.03 (0.93–

Adrenocorticotropic hormone (ACTH) has shown efficacy as primary and secondary therapy for nephrotic syndrome due to membranous nephropathy. The data on using ACTH to treat idiopathic FSGS are limited. This report describes our experience using ACTH for nephrotic syndrome due to idiopathic FSGS in the United States.Twenty-four patients with nephrotic syndrome from idiopathic FSGS were treated with ACTH gel at two academic medical centers between 2009 and 2012, either as part of investigator-initiated pilot studies (n=16) or by prescription for treatment-resistant FSGS (n=8). The primary outcome was remission of proteinuria. The median dose of ACTH was 80 units injected subcutaneously twice weekly. Treatment durations were not uniform.Twenty-two patients had received immunosuppression (mean, 2.2 medications) before ACTH therapy. Six patients had steroid-dependent and 15 had steroid-resistant FSGS. At the time of ACTH initiation, the median serum creatinine (interquartile range) was 2.0 (1.1-2.7) mg/dl, estimated GFR was 36 (28-78) ml/min per 1.73 m(2), and urine protein-to-creatinine ratio was 4595 (2200-8020) mg/g. At the end of ACTH therapy, 7 of 24 patients (29%) experienced remission (n=2 complete remissions, n=5 partial remissions). All remitters had steroid-resistant (n=5) or steroid-dependent (n=2) FSGS. Two responders relapsed during the follow-up period (mean ± SD, 70±31 weeks). Adverse events occurred in 21 of 24 patients, including one episode of new-onset diabetes that resolved after stopping ACTH and two episodes of AKI.Response to ACTH treatment among steroid-resistant or steroid-dependent patients with FSGS is low, but ACTH gel may be a viable treatment option for some patients with resistant nephrotic syndrome due to idiopathic FSGS. Further research is necessary to determine which patients will respond to therapy.

The potential of medications to cause kidney injury is well known. Although nephrotoxicity is most commonly associated with injury in the tubulointerstitial compartment as either acute tubular necrosis or acute interstitial nephritis, a growing body of literature has also highlighted the potential for drug-induced glomerular lesions. This review surveys the three primary patterns of drug-induced glomerular diseases stratified by the cell type at which the glomerular lesion is focused: visceral epithelial cell (or podoctye) injury, endothelial cell injury, and mesangial cell injury. A number of commonly prescribed medications, including IFNs, bisphosphonates, nonsteroidal anti-inflammatory drugs, antiplatelet agents, and antiangiogenesis drugs, that are both prescribed and available over the counter, have been implicated in these iatrogenic forms of glomerular disease. Recognition of these drug-induced etiologies of glomerular disease and rapid discontinuation of the offending agent are critical to maximizing the likelihood of renal function recovery.

Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death.Multicenter prospective cohort study.Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded.Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year.Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events.The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year.Current follow-up can only detect large differences in ESKD and death outcomes.Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

C3 glomerulopathy is a form of complement-mediated GN. Immunosuppressive therapy may be beneficial in the treatment of C3 glomerulopathy. Mycophenolate mofetil is an attractive treatment option given its role in the treatment of other complement-mediated diseases and the results of the Spanish Group for the Study of Glomerular Diseases C3 Study. Here, we study the outcomes of patients with C3 glomerulopathy treated with steroids and mycophenolate mofetil.We conducted a retrospective chart review of patients in the C3 glomerulopathy registry at Columbia University and identified patients treated with mycophenolate mofetil for at least 3 months and follow-up for at least 1 year. We studied clinical, histologic, and genetic data for the whole group and compared data for those who achieved complete or partial remission (responders) with those who did not achieve remission (nonresponders). We compared remission with mycophenolate mofetil with remission with other immunosuppressive regimens.We identified 30 patients who met inclusion criteria. Median age was 25 years old (interquartile range, 18-36), median creatinine was 1.07 mg/dl (interquartile range, 0.79-1.69), and median proteinuria was 3200 mg/g creatinine (interquartile range, 1720-6759). The median follow-up time was 32 months (interquartile range, 21-68). Twenty (67%) patients were classified as responders. There were no significant differences in baseline characteristics between responders and nonresponders, although initial proteinuria was lower (median 2468 mg/g creatinine) in responders compared with nonresponders (median 5000 mg/g creatinine) and soluble membrane attack complex levels were higher in responders compared with nonresponders. For those tapered off mycophenolate mofetil, relapse rate was 50%. Genome-wide analysis on complement genes was done, and in 12 patients, we found 18 variants predicted to be damaging. None of these variants were previously reported to be pathogenic. Mycophenolate mofetil with steroids outperformed other immunosuppressive regimens.Among patients who tolerated mycophenolate mofetil, combination therapy with steroids induced remission in 67% of this cohort. Heavier proteinuria at the start of therapy and lower soluble membrane attack complex levels were associated with treatment resistance.

Objective This study aimed to evaluate the safety of avacopan, an orally administered C5a receptor inhibitor, for the treatment of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis in addition to standard‐of‐care (SOC) treatment with glucocorticoids with cyclophosphamide or rituximab. Methods In this randomized 12‐week study, twice daily avacopan (10 mg or 30 mg) plus SOC was assessed versus SOC only in patients with newly diagnosed/relapsing ANCA‐associated vasculitis. Efficacy measurements included 50% or greater reduction in Birmingham Vasculitis Activity Score (BVAS) at day 85, rapid reduction (day 29) of BVAS to a score of 0 that was sustained through day 85, change in Vasculitis Damage Index (VDI), renal response (improvement in estimated glomerular filtration rate [eGFR], hematuria, and albuminuria), and health‐related quality of life (HRQoL). Results Forty‐two patients were randomized (n = 13 SOC, n = 13 avacopan 10 mg, and n = 16 avacopan 30 mg). Serious adverse events occurred in 15% and 17% of patients receiving SOC only and patients receiving avacopan with SOC, respectively. In the intent‐to‐treat population, BVAS response was high across arms (11 of 13 SOC, 11 of 12 avacopan 10 mg, and 12 of 15 avacopan 30 mg); increases in mean VDI were greater with SOC only than with avacopan plus SOC (0.3 versus 0.1). Avacopan 30 mg was numerically superior to placebo and avacopan 10 mg in early remission (15%, 8%, and 20% for SOC only, avacopan 10 mg, and avacopan 30 mg, respectively), improved eGFR (+2.0 ml/min/1.73m 2 , +1.3 ml/min/1.73m 2 , and +6.2 ml/min/1.73m 2 , respectively), renal response (17%, 40%, and 63%, respectively), and measures of HRQoL. Conclusion Avacopan in addition to SOC for ANCA‐associated vasculitis was well tolerated, and at the higher study dose, it appeared to improve time to remission (ClinicalTrials.gov identifier NCT02222155).

Complement 3 glomerulopathy (C3G) is a rare kidney disease characterized by dysregulation of the alternative pathway (AP) of the complement system. About 50% of patients with C3G progress to kidney failure within 10 years of diagnosis. Currently, there are no approved therapeutic agents for C3G. Iptacopan is an oral, first-in-class, potent, and selective inhibitor of factor B, a key component of the AP. In a Phase II study, treatment with iptacopan was associated with a reduction in proteinuria and C3 deposit scores in C3G patients with native and transplanted kidneys, respectively.APPEAR-C3G (NCT04817618) is a randomized, double-blind, and placebo-controlled Phase III study to evaluate the efficacy and safety of iptacopan in C3G patients, enrolling 68 adults with biopsy-confirmed C3G, reduced C3 (<77 mg/dl), proteinuria ≥1.0 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplantation, progressive crescentic glomerulonephritis (GN), monoclonal gammopathy of undetermined significance, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg twice daily for all patients for 6 months. The primary objective is to evaluate the efficacy of iptacopan versus placebo on proteinuria reduction urine protein:creatinine ratio (UPCR) (24 h urine). Key secondary endpoints will assess kidney function measured by eGFR, histological disease total activity score, and fatigue.This study aims to demonstrate the clinical benefits of AP inhibition with iptacopan in C3G.

ABSTRACT A refined understanding of the role of complement in the pathogenesis of glomerular and other kidney diseases has, over the past two decades, been matched by the development of novel, complement-targeting therapies. As we increasingly recognize the important role that complement activation across all three pathways—classical, lectin and alternative—plays in glomerular lesions both rare (e.g. C3 glomerulopathy) and common (e.g. immunoglobulin A nephropathy), we can identify avenues for precise, targeted approaches to modifying the natural history of these kidney diseases. In this review, we survey the evidence on using complement inhibition from the earliest, small-scale studies focusing on C5-targeting agents to more recent, large, multicenter, randomized trials utilizing complement blockade higher up in the complement pathway at the level of C3. We conclude by examining where the field of complement targeting therapy may be headed in light of these studies.

<h3>Rationale & Objective</h3> Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. <h3>Study Design</h3> Observational cohort study from July 1, 2021, to January 1, 2023. <h3>Setting & Participants</h3> A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. <h3>Exposure</h3> COVID-19 and COVID-19 vaccination. <h3>Outcome</h3> Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. <h3>Analytical Approach</h3> Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. <h3>Results</h3> Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was−1.40mL/min/1.73m² (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was−4.26mL/min/1.73m² (± 3.02 SD), which was not significantly different (<i>P</i>=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (−1.34mL/min/1.73m²±0.15 SD vs−2.16mL/min/1.73m²±1.74 SD; <i>P</i>=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. <h3>Limitations</h3> Infrequent or short follow-up. <h3>Conclusions</h3> Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. <h3>Plain-Language Summary</h3> In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.

Despite the growing burden of chronic kidney disease (CKD), there are no algorithms (to our knowledge) to quantify the effect of concurrent risk factors on the development of incident disease.A combined cohort (N = 14 155) of 2 community-based studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, was formed among men and women 45 years or older with an estimated glomerular filtration rate (GFR) exceeding 60 mL/min/1.73 m(2) at baseline. The primary outcome was the development of a GFR less than 60 mL/min/1.73 m(2) during a follow-up period of up to 9 years. Three prediction algorithms derived from the development data set were evaluated in the validation data set.The 3 prediction algorithms were continuous and categorical best-fitting models with 10 predictors and a simplified categorical model with 8 predictors. All showed discrimination with area under the receiver operating characteristic curve in a range of 0.69 to 0.70. In the simplified model, age, anemia, female sex, hypertension, diabetes mellitus, peripheral vascular disease, and history of congestive heart failure or cardiovascular disease were associated with the development of a GFR less than 60 mL/min/1.73 m(2). A numeric score of at least 3 using the simplified algorithm captured approximately 70% of incident cases (sensitivity) and accurately predicted a 17% risk of developing CKD (positive predictive value).An algorithm containing commonly understood variables helps to stratify middle-aged and older individuals at high risk for future CKD. The model can be used to guide population-level prevention efforts and to initiate discussions between practitioners and patients about risk for kidney disease.

Purpose: A synthetic adrenocorticotropin (ACTH) analog has shown efficacy in Europe as primary and secondary therapy for nephrotic syndrome, but there is no published experience using the natural, highly purified ACTH gel formulation, available in the United States, for nephrotic syndrome. We therefore investigated the use of ACTH gel for nephrotic syndrome in the United States. Patients and methods: Twenty-one patients with nephrotic syndrome treated with ACTH gel outside of research settings in the United States, with initiation of therapy by December 31, 2009, allowing a minimum 6 months follow-up. We defined complete remission as stable renal function with proteinuria falling to <500 mg/day, and partial remission as stable renal function with >50% reduction in proteinuria from 500 to 3500 mg/day. Results: Twenty-one patients with nephrotic syndrome were treated: 11 with idiopathic membranous nephropathy (iMN), 4 with membranoproliferative glomerulonephritis (MPGN), 1 with focal segmental glomerulosclerosis (FSGS), 1 with minimal change disease (MCD), 1 with immunoglobulin A (IgA) nephropathy, 1 with class V systemic lupus erythematosus (SLE) glomerulonephritis, 1 with monoclonal diffuse proliferative glomerulonephritis, and 1 with unbiopsied nephrotic syndrome. ACTH was used as primary therapy for 3 patients; the remaining patients had previously failed a mean 2.3 immunosuppressive regimens. Eleven patients achieved a complete or partial remission, with 4 (19%) in complete remission. Of the 11 patients who achieved remission, 9 had iMN, 1 had FSGS, and 1 had IgA nephropathy. Of the 11 patients with iMN, 3 (27%) achieved complete remission and 6 (55%) achieved partial remission despite having previously failed a mean 2.4 therapies. Five patients reported steroid-like adverse effects, but there were no severe infections. The limitations were retrospective data analysis with short-term follow-up. Conclusion: ACTH gel may be a viable treatment option for resistant nephrotic syndrome due to membranous nephropathy. Short-term data suggest that remission rates may approach 80%. Keywords: nephrotic syndrome, membranous nephropathy, chronic kidney disease

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Adrenocorticotropic hormone (ACTH) has shown promising results in glomerular diseases resistant to conventional therapies, but the reported data have solely been from retrospective, observational studies. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; In this prospective, open-label study (NCT01129284), 15 subjects with resistant glomerular diseases were treated with ACTH gel (80 units subcutaneously twice weekly) for 6 months. Resistant membranous nephropathy (MN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS) were defined as failure to achieve sustained remission of proteinuria off immunosuppressive therapy with at least 2 treatment regimens; resistant IgA nephropathy was defined as &gt;1 g/g urine protein:creatinine ratio despite maximally tolerated RAAS blockade. Remission was defined as stable or improved renal function with ≥50% reduction in proteinuria to &lt;0.5 g/g (complete remission) or 0.5–3.5 g/g (partial remission). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The study included 5 subjects with resistant idiopathic MN, 5 subjects with resistant MCD (n = 2)/FSGS (n = 3), and 5 subjects with resistant IgA nephropathy. Two resistant MN subjects achieved partial remission on ACTH therapy, although 3 achieved immunologic remission of disease (PLA&lt;sub&gt;2&lt;/sub&gt;R antibody disappeared by 4 months of therapy). One subject with resistant FSGS achieved complete remission on ACTH; one subject with resistant MCD achieved partial remission but relapsed within 4 weeks of stopping ACTH. Two subjects with resistant IgA nephropathy demonstrated &gt;50% reductions in proteinuria while on ACTH, with proteinuria consistently &lt;1 g/g by 6 months. Three of 15 subjects reported significant steroid-like adverse effects with ACTH, including weight gain and hyperglycemia, prompting early termination of therapy without any clinical response. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; ACTH gel is a promising treatment for resistant glomerular diseases and should be studied further in controlled trials against currently available therapies for resistant disease.

The treatment of membranous nephropathy (MN) remains controversial. Rituximab, which selectively targets B cells, has emerged as a possible alternative treatment option with limited toxicity.The available data on rituximab therapy for MN were reviewed using the MEDLINE database (inception to August 1, 2008), Google Scholar, and selected reference lists. English-language studies investigating the use of rituximab in idiopathic and secondary MN, in native and transplanted kidneys, were included. Study design, subject number, clinical characteristics (diagnosis, previous and concomitant treatment courses, baseline proteinuria, baseline renal function), rituximab protocol, follow-up period, achievement of complete or partial remission, changes in proteinuria and renal function, and adverse effects of therapy were extracted.Twenty-one articles were included for review; all were either case reports or case series without controls. More than half of the published cases (50 of 85) came from one center where rituximab was used as primary immunosuppression for idiopathic MN. The available data suggest that rituximab, dosed either as 375 mg/m(2) once weekly for 4 wk or as 1 g on days 1 and 15, achieves a 15 to 20% rate of complete remission and a 35 to 40% rate of partial remission. The drug was well tolerated with minimal adverse events.Although rituximab may prove to be a better treatment option for MN than alkylating agents or calcineurin inhibitors, the current literature only supports using the drug in research protocols. Whether, when, how, and why to use rituximab in MN remains to be determined.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune glomerulonephritis (GN) is the most common finding in very elderly patients biopsied for acute kidney injury. Appropriate treatment strategies in this age group are currently undefined since it is unclear whether the benefits of immunosuppression exceed the risks. We retrospectively evaluated a cohort of 78 cases of biopsy-proven pauci-immune GN in individuals aged >80 years of whom 72% were p-ANCA and 20% were c-ANCA positive. The patients treated with immunosuppression had a significantly lower incidence of end-stage renal disease (ESRD) 1 year after biopsy (36%) compared with untreated patients (73%; P=0.03). Only peak serum creatinine before biopsy and the use of immunosuppression influenced progression to ESRD. There was no significant difference in the 1-year mortality rates between these groups (46 vs 64%; P=0.3). However, when follow-up was extended beyond 2 years, immunosuppression was associated with a lower risk of death (HR 0.33, 95% CI 0.11-0.97) and death or ESRD (HR 0.16, 95% CI 0.06-0.42) in multivariable models.

C3 glomerulopathy (C3G), a form of glomerulonephritis associated with dysregulation of the alternative complement pathway, occurs either as dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). Few studies have reported outcomes of patients with C3G after transplantation since its formal classification and the advent of complement-targeting therapies such as eculizumab.Case series of C3G.We reviewed laboratory testing, native and allograft biopsy reports, and clinical charts of the 19 patients (12, C3GN; and 7, DDD) from our C3G registry who underwent transplantation between 1999 and 2016.During a median follow-up of 76 months, 16 patients had recurrent disease (10 of 12, C3GN; and 6 of 7, DDD), with median time to recurrence of 14 months in C3GN versus 15 months in DDD. Graft failure was more frequent in patients with DDD (6 of 7) than in patients with C3GN (3 of 12), occurred at a median time of 42 months posttransplantation, and was attributed to recurrent disease in half the failures. A rare genetic variant or autoantibody associated with alternative complement pathway abnormalities was detected in 9 of 10 screened patients. Treatment of 7 patients (8 allografts) with eculizumab was associated with variable clinical outcomes.Incomplete testing for complement pathway abnormalities and genetic defects, incomplete records of HLA antigen matching, lack of centralized biopsy review, and limited sample size.In a case series of C3G transplant recipients, the proportion of disease recurrence was high in both C3GN and DDD, although graft loss appeared to occur more frequently in DDD. In a small subset of study patients, eculizumab therapy was not consistently followed by salutary outcomes.

Podocyte injury is the initiating step in the pathway toward clinically evident forms of nephrotic syndrome known as podocytopathies, represented as either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). There are hallmark differences in the histologic appearances of MCD and FSGS, which in turn represent distinct pathogenic models after initial podocyte injury (eg, no change in podocyte number in MCD vs podocyte detachment and death in FSGS). However, MCD and FSGS also share a number of common causes, supporting the theory that these diseases lie along a shared podocytopathy spectrum. In this installment of AJKD's Core Curriculum in Nephrology, we demonstrate how the podocytopathies can be classified according to pathogenesis and treatment response as an alternative to histologic description. Using case examples, we show how these alternative classification schemes can assist not only diagnosis, but also long-term management of podocytopathies.

HIV-associated kidney disease is evolving rapidly. Few North American studies have addressed modern trends and none has applied the 2018 Kidney Disease Improving Global Outcomes (KDIGO) pathologic classification. Therefore we performed a retrospective clinical-pathologic analysis of all HIV-positive patients with kidney biopsy interpreted at Columbia University from 2010-2018 using the KDIGO classification. The biopsy cohort of 437 HIV-positive patients had median age 53 years, including 66% males, 80% on anti-retroviral therapy, 57% with hypertension, 31% with diabetes, 27% with hepatitis C and 6% with hepatitis B co-infections. Race, known in 308 patients, included 58% black, 25% white and 17% Hispanic. Pathologic diagnoses were surprisingly diverse. Immune complex glomerulonephritis (ICGN) and diabetic nephropathy each outnumbered HIV-associated nephropathy, followed by tenofovir nephrotoxicity, FSGS- not otherwise specified (NOS) and global sclerosis (NOS). HIV-associated nephropathy was the most common disease in patients not on anti-retroviral therapy, and 94% were black. The association of FSGS (NOS) with black race (68%) and anti-retroviral therapy use (77%) suggests some cases may represent attenuated HIV-associated nephropathy. The most common ICGNs were IgA nephropathy and membranous glomerulopathy, both associating with anti-retroviral therapy (over 90%), followed by hepatitis C-associated proliferative ICGN. Among the 16 cases of uncharacterized ICGN lacking identifiable etiology, 69% were not on anti-retroviral therapy, possibly representing true HIV-associated immune complex kidney disease. Dual diseases occurred in 17% of patients, underscoring lesion complexity. Thus, anti-retroviral therapy has shifted the landscape of HIV-associated kidney disease toward diverse ICGN, diabetic nephropathy, and non-collapsing glomerulosclerosis, but has not eradicated HIV-associated nephropathy.

The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown.We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2.The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected.Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.

Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment. Membranous glomerulopathy (MGN) is characterized by global subepithelial immune deposits that stain most intensely by immunofluorescence for IgG. Here we describe the clinical and pathologic findings in a cohort of patients with MGN in which, by definition, only segmental immune deposits are present. This rare variant, termed segmental MGN (sMGN), is poorly characterized. We retrospectively identified all patients with sMGN diagnosed at Columbia University from January 2010 to October 2018, excluding those with systemic lupus erythematosus. Data on presenting features, pathologic findings, and outcomes were collected. Fifty cases of sMGN were identified, representing 2.5% of MGN. In 21 of 50 biopsies, there was an alternative, predominant disease process. The remaining 29 patients with isolated sMGN had a median creatinine of 0.97 mg/dl, median 24-hour urine protein 3.1 g/day, and 32% had nephrotic syndrome. Staining for NELL-1 (a protein kinase C binding protein) was positive in five of 17 cases. Staining for PLA2R, THSD7A, and exostosin 1 (autoantigens in primary MGN) was negative in all biopsies evaluated. Ultrastructural evaluation revealed predominantly early stage sMGN (stage 1 or 1-2 in 14/29). Follow-up was available for 21 of the 29 patients with isolated sMGN (median 12 months), including seven who received immunosuppression (primarily glucocorticoids). During follow-up, 86% had stable/improved kidney function and 45% achieved complete while 15% achieved partial remission. Among the 15 patients with isolated sMGN without full nephrotic syndrome, only two received immunosuppression; nonetheless, 50% achieved complete while 21% achieved partial remission. Thus, sMGN is a rare PLA2R-negative variant of MGN with 29% NELL-1 positivity and favorable prognosis, even in the absence of immunosuppressive treatment.

Background and objectives Kidney biopsy is the current gold standard to diagnose membranous nephropathy. Approximately 70%–80% of patients with primary membranous nephropathy have circulating anti-phospholipase A2 receptor antibodies. We previously demonstrated that in proteinuric patients with preserved eGFR and absence of associated conditions ( e.g., autoimmunity, malignancy, infection, drugs, and paraproteinemia), a positive anti-phospholipase A2 receptor antibody test by ELISA and immunofluorescence assay confirms the diagnosis of membranous nephropathy noninvasively. These data have not been externally validated. Design, setting, participants, &amp; measurements The clinical and pathologic characteristics of patients with a positive anti-phospholipase A2 receptor antibody test at the Mayo Clinic, the University Hospital Vall D’Hebron (Barcelona), and the Columbia University Medical Center (New York) were retrospectively reviewed. Biopsy findings and presence or absence of a potential associated condition were assessed. Results From a total of 276 patients with positive anti-phospholipase A2 receptor serology, previously reported patients ( n =33), kidney transplant recipients ( n =9), pediatric patients ( n =2), and patients without kidney biopsy ( n =69) were excluded. Among the 163 remaining patients, associated conditions were identified in 47 patients, and 15 patients had diabetes mellitus. All 101 patients of the final cohort had a primary diagnosis of membranous nephropathy on kidney biopsy. In the 79 patients with eGFR≥60 ml/min per 1.73 m 2 , none of the biopsy findings altered diagnosis or management. Among the 22 patients with decreased eGFR, additional findings included superimposed acute interstitial nephritis ( n =1). Conclusions In patients with preserved eGFR and absence of associated conditions or diabetes, a positive anti-phospholipase A2 receptor test by either ELISA &gt;20 RU/ml or a positive immunofluorescence assay confirms the diagnosis of membranous nephropathy, precluding the requirement for a kidney biopsy.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on 'disease manifestations' (ie, signs, symptoms and patient-reported outcomes) and on 'disease outcomes' (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

Image-based machine learning tools hold great promise for clinical applications in pathology research. However, the ideal end-users of these computational tools (e.g., pathologists and biological scientists) often lack the programming experience required for the setup and use of these tools which often rely on the use of command line interfaces.We have developed Histo-Cloud, a tool for segmentation of whole slide images (WSIs) that has an easy-to-use graphical user interface. This tool runs a state-of-the-art convolutional neural network (CNN) for segmentation of WSIs in the cloud and allows the extraction of features from segmented regions for further analysis.By segmenting glomeruli, interstitial fibrosis and tubular atrophy, and vascular structures from renal and non-renal WSIs, we demonstrate the scalability, best practices for transfer learning, and effects of dataset variability. Finally, we demonstrate an application for animal model research, analyzing glomerular features in three murine models.Histo-Cloud is open source, accessible over the internet, and adaptable for segmentation of any histological structure regardless of stain.

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultra-rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Dysregulation of the alternative complement pathway is implicated in the pathophysiology of IC-MPGN; and currently, there are no approved targeted treatments. Iptacopan is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the alternative pathway (AP).This randomized, double-blind, placebo-controlled phase 3 study (APPARENT; NCT05755386) will evaluate the efficacy and safety of iptacopan in patients with idiopathic (primary) IC-MPGN, enrolling up to 68 patients (minimum of 10 adolescents) aged 12 to 60 years with biopsy-confirmed IC-MPGN, proteinuria ≥1 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplant, progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily (bid) or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg bid for all patients for 6 months. The primary objective of the study is to evaluate the efficacy of iptacopan versus placebo in proteinuria reduction measured as urine protein-to-creatinine ratio (UPCR) (24-h urine) at 6 months. Key secondary end points will assess kidney function measured by eGFR, patients who achieve a proteinuria-eGFR composite end point, and patient-reported fatigue.This study will provide evidence toward the efficacy and safety of iptacopan in idiopathic (primary) IC-MPGN.

Chronic kidney disease and cardiovascular disease share many risk factors. Injury to the vascular endothelium, measured by elevated levels of serum C-reactive protein (CRP), may play a role in kidney and cardiovascular disease. We therefore examined the association of CRP with microalbuminuria, a marker of early kidney injury. We conducted a cross-sectional analysis of a nationally representative, population-based survey. Weighted multiple logistic regression was used to study the association between CRP and microalbuminuria, adjusting for well-known risk factors. CRP was analyzed by a continuous variable and two categorized variables using quartiles and clinically recommended cutpoints. CRP concentration was positively associated with microalbuminuria. In the multivariate model, a one unit (in milligrams per liter) increase in CRP concentration was associated with a 2% increased odds of microalbuminuria (odds ratio 1.02, 95% confidence interval [CI] 1.01 to 1.02, p=0.0003). When CRP concentrations were stratified by clinically recommended cutpoints, compared with persons with CRP concentrations<1 mg/dl, persons with CRP concentrations between 1 and 3 mg/L and >3 mg/L were 1.15 times (95% CI 0.94 to 1.42) and 1.33 times (95% CI 1.08 to 1.65) more likely to have microalbuminuria, respectively. In subgroup analyses, the strength of association was comparable or stronger. In conclusion, elevated CRP levels were associated with microalbuminuria in a large, nationally representative data set. Vascular inflammation, as measured by CRP, may be a common contributor to early heart and kidney disease.

J Clin Hypertens (Greenwich). Determining which demographic and medical variables predict the development of hypertension could help clinicians stratify risk in both prehypertensive and nonhypertensive persons. Subject‐level data from 2 community‐based biracial cohorts were combined to ascertain the relationship between baseline characteristics and incident hypertension. Hypertension, defined as diastolic blood pressure ≥90 mm Hg, systolic blood pressure ≥140 mm Hg, or reported use of medication known to treat hypertension, was assessed prospectively at 3, 6, and 9 years. Internal validation was performed by the split‐sample method with a 2:1 ratio for training and testing samples, respectively. A scoring algorithm was developed by converting the multivariable regression coefficients to integer values. Age, level of systolic or diastolic blood pressure, smoking, family history of hypertension, diabetes mellitus, high body mass index, female sex, and lack of exercise were associated with the development of hypertension in the training sample. Regression models showed moderate to high capabilities of discrimination between hypertension vs nonhypertension (area under the receiver operating characteristic curve 0.75–0.78) in the testing sample at 3, 6, and 9 years of follow‐up. This risk calculator may aide health care providers in guiding discussions with patients about the risk for progression to hypertension. J Clin Hypertens (Greenwich). 2010;12:800‐808. © 2010 WileyPeriodicals, Inc.

Often, patients with chronic kidney disease are reported to be unaware of it. We prospectively evaluated the association between awareness of kidney disease to end-stage renal disease and mortality.We utilized 2000-2009 data from the National Kidney Foundation's Kidney Early Evaluation Program. Mortality was determined by cross reference to the Social Security Administration Death Master File and development of end stage by cross reference with the United States Renal Data System.Of 109,285 participants, 28,244 (26%) had chronic kidney disease defined by albuminuria or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). Only 9% (n=2660) reported being aware of kidney disease. Compared with those who were not aware, participants aware of chronic kidney disease had lower eGFR (49 vs 62 mL/min/1.73 m(2)) and a higher prevalence of albuminuria (52% vs. 46%), diabetes (47% vs 42%), cardiovascular disease (43% vs 28%), and cancer (23% vs 14%). Over 8.5 years of follow-up, aware participants compared with those unaware had a lower rate of survival for end stage (83% and 96%) and mortality (78% vs 81%), P <.001. After adjustment for demographics, socioeconomic factors, comorbidity, and severity of kidney disease, aware participants continued to demonstrate an increased risk for end-stage renal disease (hazard ratio 1.37; 95% confidence interval, 1.07-1.75; P <.0123) and mortality (hazard ratio 1.27; 95% confidence interval, 1.07-1.52; P <.0077) relative to unaware participants with chronic kidney disease.Among patients identified as having chronic kidney disease at a health screening, only a small proportion had been made aware of their diagnosis previously by clinicians. This subgroup was at a disproportionately high risk for mortality and end-stage renal disease.

<h3>Background</h3> Uninsured adults in the United States have poor access to health care services and worse health outcomes than insured adults. Little is known about the association between lack of insurance and chronic kidney disease (CKD) progression to end-stage renal disease (ESRD) or death in patients at high risk of kidney disease. We used 2000-2011 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) to examine this association. <h3>Methods</h3> The study population included KEEP participants younger than 65 years. Outcomes were time to ESRD (chronic kidney failure treated by renal replacement therapy) and time to death. Incident ESRD was ascertained by linkage to the US Renal Data System, and vital status, by linkage to the Social Security Administration Death Master File. We used Cox proportional hazard regression to examine the association between insurance and risk of death or ESRD after adjusting for demographic variables. <h3>Results</h3> Of 86,588 participants, 27.8% had no form of insurance, 10.3% had public insurance, and 61.9% had private insurance; 15.0% had CKD (defined as estimated glomerular filtration rate <60 mL/min/1.73 m² or urine albumin-creatinine ratio ≥30 mg/g), 63.3% had hypertension, and 27.7% had diabetes. Of participants with CKD, 29.3% had no health insurance. Participants without insurance were younger, more likely to be Hispanic and to have 12 or fewer years of education, and less likely to have seen a physician in the past year. After adjustment for demographic characteristics, uninsured KEEP participants were 82% more likely than privately insured participants to die (HR, 1.82; 95% CI, 1.56-2.12; <i>P</i> < 0.001) and 72% more likely to develop ESRD (HR, 1.72; 95% CI, 1.33-2.22; <i>P</i> < 0.001). The association between insurance and outcomes varied by CKD stage. <h3>Conclusions</h3> Lack of insurance is an independent risk factor for early death and ESRD in this population at high risk of kidney disease. Considering the high morbidity and mortality and increasing cost associated with ESRD, access to appropriate health insurance coverage is warranted.

Patients with IgA nephropathy typically present with hematuria and subnephrotic proteinuria. Nephrotic syndrome is uncommon in IgA nephropathy, and when present, it is usually associated with severe histologic features, such as endocapillary proliferation, segmental sclerosis, and crescent formation. Rarely, patients with IgA nephropathy present with nephrotic syndrome and only mild mesangial disease. This study sought to better characterize these patients.A retrospective review of cases of IgA nephropathy diagnosed from 2004 to 2011 identified patients with nephrotic range proteinuria and histologically mild IgA nephropathy. Specifically, using the Oxford Classification of IgA Nephropathy, we identified cases that lacked endocapillary proliferation or segmental sclerosis.The cohort consisted of 17 patients, including 10 men and 15 adults. The median serum creatinine was 0.9 mg/dl (range=0.7-3.1), median 24-hour urine protein was 8.0 g/d (3.0-18.0 g), and 14 patients were fully nephrotic, whereas the remaining 3 patients fulfilled two of three criteria for nephrotic syndrome. Biopsies revealed IgA-dominant or codominant deposits accompanied by mesangial proliferation in 14 patients (82.4%). Electron microscopy showed mesangial deposits and extensive foot process effacement (median=90%). Initial treatment consisted of corticosteroids, although many patients required additional agents to maintain remission status. Over a median follow-up of 20 months (2.2-82 months), 14 patients experienced a complete response, and 3 patients showed a partial response, with a median response time of 2 months (0.5-27 months). At least one relapse of nephrotic syndrome occurred in nine patients (53%). All patients exhibited stable or improved renal function over the follow-up period.The findings in this cohort and previous studies suggest that rare cases of mild IgA nephropathy with nephrotic range proteinuria exhibit a clinical presentation, biopsy findings, treatment response, and outcome more typical of IgA nephropathy with superimposed minimal change disease. This study favors the view that such cases represent a dual glomerulopathy.

BackgroundApproximately 50% of patients with fibrillary glomerulonephritis (GN) progress to end-stage renal disease (ESRD) within 2 years of diagnosis, and no standard therapy exists. The data on rituximab therapy for fibrillary GN are limited and have inconsistent outcomes. Here, we report the largest case series to date using rituximab for fibrillary GN.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. This review focuses on mechanisms involved in the pathogenesis of MN and approaches to treatment of this disease.Our understanding of the pathogenesis of primary MN has advanced greatly with the identification of M-type phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A as target antigens whose antibodies serve as biomarkers of this disease. Additional research, including investigations into the roles of complement and melanocortin receptors on the podocyte, may further improve our understanding of how best to treat this condition. Immunosuppressive therapies, including corticosteroids alternating with alkylating agents, and calcineurin inhibitors are partially successful in reducing proteinuria in MN, but their use may be associated with significant adverse effects and a high relapse rate. Novel interventions, including targeting B cells with rituximab as well as treatment with adrenocorticotropic hormone (ACTH), are being investigated. Key Messages: The understanding of treatment targets and availability of new biomarkers has facilitated diagnosis and improved risk stratification for MN and may also be useful for individualizing treatment with a wider range of therapeutic options for patients with MN. Considerable evidence supports the use of B-cell depletion as initial therapy in nephrotic patients with MN. ACTH should be considered for patients who do not respond to traditional therapies such as alkylating agents and calcineurin inhibitors.

More than one half of all patients with SLE will have clinically evident kidney disease, generally termed lupus nephritis (LN), at some point during their disease course. The diagnosis and management of LN have improved remarkably over the last three decades enhanced by (1) a refined and reproducible classification scheme for the diverse glomerulopathies associated with SLE, (2) a number of epidemiologic studies highlighting LN subgroups at increased risk for poor outcomes, and in contrast to other glomerular diseases, (3) a consistent record for well performed randomized trials evaluating induction and maintenance therapies (1). Still, there remain subgroups of patients with LN that remain poorly categorized, and these pockets of disease can confound the diagnosing renal pathologist and treating clinical nephrologist. In 2002, Dube et al. (2) and Hertig et al. (3) described small series of patients with SLE, nephrotic syndrome, and biopsy findings of minimal change disease (MCD) or FSGS. Eight of 18 patients in these reports had mesangial deposits, including seven of 11 with MCD and one of seven with FSGS, consistent with concurrent mesangial LN (class 1 or 2). The patients with MCD universally showed rapid remission of nephrotic syndrome with steroid therapy; the response to steroids was inconsistent in patients with FSGS lesions. In 2005, Kraft et al. (4) reported eight additional patients with SLE, nephrotic syndrome, and light microscopic findings of MCD (i.e., normal appearing), FSGS, or mesangial proliferative GN. Kraft et al. (4) argued that the “development of nephrotic-range proteinuria in patients with SLE without peripheral immune aggregate deposition or endocapillary proliferation on renal biopsy is more likely a manifestation of SLE than the coexistence of idiopathic minimal-change glomerulopathy and SLE” (4). The term lupus podocytopathy thus arose to describe these lesions as part of the LN spectrum. In this issue of the Clinical Journal of the American Society of Nephrology, Hu et al. (5) present 50 patients who they have classified as having lupus podocytopathy, culled from a 14-year biopsy registry (2000–2013) and representing 1.3% of all LN biopsies read at Nanjing University during this time period. Thirteen patients had normal light microscopy findings, 28 showed mesangial proliferative changes, and nine had FSGS lesions; 47 of the 50 patients had mesangial immune deposits as confirmed by immunofluorescence and electron microscopy. All of the patients had full nephrotic syndrome with ≥50% (and in most patients, >70%) foot process effacement. This series emerges as the largest cohort of lupus podocytopathy and provides representative data on clinical presentations, treatment responses, and relapse rates in patients with this entity. For example, the remission rate with immunosuppression of 94% is not altogether surprising on the basis of prior series, but the median time to remission of 4 weeks adds a new layer of important, clinically relevant information. Importantly, response and relapse rates differed among the histologic subtypes: all of the patients with MCD and 27 of the 28 patients with mesangial proliferative changes responded, whereas nonresponders were disproportionately high in the FSGS subgroup. Similarly, AKI was over-represented in the FSGS group (78%) compared with the MCD and mesangial proliferative groups (23% and 25%, respectively). As with podocytopathies not associated with SLE, relapse rates were high (56%) and did not differ by histologic pattern. A finding that emerges in this series, as in prior reports, is that, in the setting of SLE and lupus podocytopathy, morphologic findings of FSGS are associated with a distinctly more dismal prognosis. Specifically, patients with FSGS compared with those with MCD or mesangial proliferative changes had higher rates of hypertension and AKI on clinical presentation and more severe tubulointerstitial involvement on biopsy. In follow-up, the patients with FSGS not only were less likely to respond to therapy, but when responses did occur, the remissions happened at a median of 8 weeks (compared with 4 weeks for the other subgroups). In contrast, the strikingly similar clinical presentation, remission rates, rapidity of remission, and relapse rates in the MCD and mesangial proliferative subgroups argue against significant differences between these subtypes. These observations raise the question of whether it is appropriate to use the same umbrella term of lupus podocytopathy for all three of these patterns of glomerular injury. One of the limitations of the series by Hu et al. (5) is that their results may not apply to non-Asians, and this nongeneralizability could have its biggest effect in the patients with FSGS patterns. For example, a black patient with SLE and FSGS could have lupus podocytopathy but, just as plausibly, could have SLE with concomitant apolipoprotein L1 (APOL1) nephropathy (6). Hu et al. (5) propose criteria for diagnosing lupus podocytopathy on the basis of clinical presentation and hallmark biopsy findings on light microscopy, immunofluorescence microscopy, and electron microscopy. The commonly used International Society of Nephrology/Renal Pathology Society classification of LN does not include lupus podocytopathy. In our practice, we use fairly simple criteria to diagnose lupus podocytopathy: (1) clinical presentation of full nephrotic syndrome in a patient with SLE, (2) diffuse and severe foot process effacement, and (3) the absence of subendothelial or subepithelial immune deposits (Table 1). Mesangial deposits and mesangial proliferation are not part of the criteria; if these findings are present, then the additional diagnosis of mesangial proliferative LN (LN class 2) is merited. If mesangial deposits are not accompanied by mesangial proliferation, the diagnosis of minimal mesangial LN (LN class 1) is rendered. In this manner, we separate the classic forms of immune complex–mediated LN from lupus podocytopathy, with a willingness to diagnose both in the appropriate situation, and we avoid the need for a mesangial proliferative category of lupus podocytopathy. We also subdivide lupus podocytopathy into patients who would otherwise meet criteria for MCD or FSGS, including the morphologic subtypes of FSGS (collapsing, tip lesion, etc.). The criteria proposed by Hu et al. (5) are similar to what we propose, with the exception of our preference to separate out the findings of mesangial LN (LN class 1 or 2), thus eliminating the mesangial proliferative pattern of lupus podocytopathy. The differences are small.Table 1: Proposed criteria for diagnosis of lupus podocytopathyThe report from Hu et al. (5) is an important contribution that brings us closer to recognizing and understanding the entity of lupus podocytopathy. The process of developing consensus diagnostic criteria should be straightforward. At present, data supporting an association between MCD and FSGS with SLE are limited to the observation that these entities seem to be more common in SLE and are often present in the setting of a lupus flare; a goal for the future will be to connect these entities in more than an observational manner. Another important question is whether lupus podocytopathy will be added to the next revision of the classification of LN (7). For now, and in significant part because of the contribution of the work by Hu et al. (5), we have reached the point that lupus podocytopathy should be considered a distinct and recognizable disease entity. Disclosures None. Acknowledgments This work was supported by National Institutes of Health-National Institute on Minority Health and Health Disparities grant R01-MD009223.

The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients.Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment.A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001).This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

A renewed interest in the role of complement in the pathogenesis of glomerular diseases has improved our understanding of their basic, underlying physiology. All 3 complement pathways-classical, lectin, and alternative-have been implicated in glomerular lesions both rare (e.g., dense deposit disease) and common (e.g., IgA nephropathy). Here we review the basic function of these pathways and highlight, with a disease-specific focus, how activation can lead to glomerular injury. We end by exploring the promise of complement-targeted therapies as disease-specific interventions for glomerular diseases.

Background and objectives In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this “stand-alone” kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis. Design, setting, participants, &amp; measurements Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed. Results Five characteristic features of lupus nephritis were identified: “full-house” staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98. Conclusions In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis.

Collapsing focal segmental glomerulosclerosis (cFSGS) in the native kidney is associated with heavy proteinuria and accelerated renal failure. However, cFSGS in the renal allograft is less well characterized. Here we report clinico-pathologic features and APOL1 donor risk genotypes in 38 patients with de novo post-kidney transplant cFSGS. Recipients were 34% female and 26% African American. Concurrent viral infections and acute vaso-occlusion (including thrombotic microangiopathy, cortical necrosis, atheroembolization, and cardiac arrest with contralateral graft thrombosis) were present in 13% and 29% of recipients, respectively. Notably, 61% of patients had concurrent acute rejection and 47% received grafts from African American donors, of which 53% carried APOL1 high-risk genotypes. These frequencies of acute rejection and grafts from African American donors were significantly higher than in our general transplant population (35% and 16%, respectively). Patients had a median serum creatinine of 5.4 mg/dl, urine protein/creatinine 3.5 g/g, and 18% had nephrotic syndrome. Graft failure occurred in 63% of patients at an average of eighteen months post-index biopsy. By univariate analysis, donor APOL1 high-risk genotypes, post-transplant time, nephrotic syndrome, and chronic histologic changes were associated with inferior graft survival while acute vaso-occlusion was associated with superior graft survival. Donor APOL1 high-risk genotypes independently predicted poor outcome. Compared to native kidney cFSGS, post-transplant cFSGS had more acute vaso-occlusion but less proteinuria. Thus, de novo cFSGS is associated with variable proteinuria and poor prognosis with potential predisposing factors of African American donor, acute rejection, viral infection and acute vaso-occlusion. Additionally, donor APOL1 high-risk genotypes are associated with higher incidence and worse graft survival.

Morbid obesity, defined as body mass index (BMI) ≥40 kg/m², affects approximately 8% of United States adults and is a recognized risk factor for chronic kidney disease (CKD). We present the first focused biopsy-based study exploring the range of kidney diseases in this population. Among 3263 native kidney biopsies interpreted at Columbia University in 2017, we identified 248 biopsies from morbidly obese patients. In this cohort with median age of 53.5 years, 56% were female and median BMI was 44.0 kg/m². Diabetes and hypertension were present in 47% and 81% of patients, respectively. Median estimated glomerular filtration rate (eGFR) was 30 ml/min/1.73 m², and most patients had nephrotic range proteinuria. Obesity related glomerulopathy (ORG), defined as focal segmental glomerulosclerosis with glomerulomegaly or glomerulomegaly alone, was detected in 73 patients, including 29 with ORG alone and 44 with ORG plus another kidney disease. In contrast, 167 patients had other kidney diseases alone, without ORG, most commonly (in descending order) diabetic nephropathy, acute tubular necrosis, hypertensive nephrosclerosis, IgA nephropathy, membranous nephropathy, and lupus nephritis. In 49% of patients, kidney biopsy yielded a diagnosis predicted to change patient management. The strongest predictor of non-ORG lesions was eGFR <30 ml/min per 1.73 m², and presentation with nephrotic syndrome or acute kidney injury (with or without background CKD) was more common in non-ORG than ORG. The findings reveal an unexpectedly broad spectrum of kidney pathology beyond metabolic syndrome-associated disorders and highlight the importance of kidney biopsy to guide management and prognosis in the morbidly obese population.

Background and objectives Actionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best practices for return of results and clinical application of actionable genetic findings for kidney patients. Design, setting, participants, &amp; measurements We developed a return of results workflow in collaborations with clinicians for the retrospective recontact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings. Results Using this workflow, we attempted to recontact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings, encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully recontacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients’ nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for patients requiring extranephrologic referrals. Conclusions Developing the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_16_12481019.mp3

BACKGROUNDAssessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1, MCP-1) for predicting long-term kidney outcomes after cardiac surgery.METHODSWe measured EGF and MCP-1 in postoperative urine samples from 865 adults who underwent cardiac surgery at 2 sites in Canada and the United States and assessed EGF and MCP-1's associations with the composite outcome of CKD incidence or progression. We used single-cell RNA-Seq (scRNA-Seq) of AKI patient biopsies to perform transcriptomic analysis of programs corregulated with the associated genes.RESULTSOver a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Postoperatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73-0.95 and 1.10, 95% CI 1.00-1.21, respectively). Intrarenal scRNA-Seq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.CONCLUSIONUrinary EGF and MCP-1 were each independently associated with CKD after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes, and provide an opportunity for novel interventions in cardiac surgery.TRIAL REGISTRATIONClinicalTrials.gov NCT00774137.FUNDINGThe NIH funded the TRIBE-AKI Consortium and Kidney Precision Medicine Project. Yale O'Brien Kidney Center, American Heart Association, Patterson Trust Fund, Dr. Adam Linton Chair in Kidney Health Analytics, Canadian Institutes of Health Research, ICES, Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine & Dentistry, Western University, Lawson Health Research Institute, Chan Zuckerberg Initiative Human Cell Atlas Kidney Seed Network.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

Background and objectives C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, &amp; measurements To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

In the setting of an IgG-dominant immune complex-mediated glomerulonephritis, there are multiple pathological findings that strongly suggest the diagnosis of lupus nephritis (LN) including (i) 'full-house' immunofluorescence staining for IgG, IgM, IgA, C3 and C1; (ii) extraglomerular immune deposits; (iii) combined mesangial, subendothelial and subepithelial immune deposits and (iv) the presence of endothelial tubuloreticular inclusions. We report four female adult patients with renal biopsy findings which are highly suggestive of LN but without extrarenal signs, symptoms or serologies of systemic lupus erythematosus at the time of biopsy or over a mean follow-up period of 3 years. Despite aggressive therapy, outcomes were poor in this small cohort. We refer to these cases as renal-limited 'lupus-like' nephritis.

Background A recent cross-sectional analysis of Kidney Early Evaluation Program (KEEP) participants suggested that obesity is a heterogeneous disease state in African Americans and whites with chronic kidney disease (CKD). Study Design In longitudinal analyses spanning 8 years of follow-up, we examined whether race and body mass index (BMI) influence end-stage renal disease (ESRD) and mortality rates in participants with CKD stages 3-4. Setting & Participants KEEP participants were included in this analysis if they met the following criteria: (1) estimated glomerular filtration rate (eGFR) of 15-59 mL/min/1.73 m2, (2) white or African American race, and (3) no previous dialysis or transplantation. Outcomes & Measurements Survival analyses were performed for the outcomes of ESRD, death, and combined outcome of ESRD or death. Results Of 14,631 participants with CKD stages 3-4, 28% were African American and 72% were white. African American participants had higher rates of obesity and hypertension, with a higher baseline mean eGFR, higher prevalence of albuminuria, and greater degree of anemia compared with whites. In multivariable models, African American race increased the risk of ESRD (HR, 1.66; 95% CI, 1.26-2.07), but not death (HR, 0.89; 95% CI, 0.76-1.03). In these models, male sex, hypertension, diabetes, lower baseline eGFR, and albuminuria were predictive of higher rates of ESRD; age, male sex, diabetes, lower baseline eGFR, and albuminuria were predictive of overall mortality. There was no significant interaction between race and BMI in the adjusted model for outcomes of ESRD (P = 0.7) or death (P = 0.3). Limitations Baseline values used in the analysis are from a cross-sectional data set. Dyslipidemia and secondary hyperparathyroidism were not accounted for in the analysis. Conclusions African American race was associated with a higher incidence of ESRD, but not mortality. Although obesity may be a heterogeneous disease state in African Americans and whites with CKD, there does not appear to be a significant interaction between race and BMI in progression to ESRD or death. A recent cross-sectional analysis of Kidney Early Evaluation Program (KEEP) participants suggested that obesity is a heterogeneous disease state in African Americans and whites with chronic kidney disease (CKD). In longitudinal analyses spanning 8 years of follow-up, we examined whether race and body mass index (BMI) influence end-stage renal disease (ESRD) and mortality rates in participants with CKD stages 3-4. KEEP participants were included in this analysis if they met the following criteria: (1) estimated glomerular filtration rate (eGFR) of 15-59 mL/min/1.73 m2, (2) white or African American race, and (3) no previous dialysis or transplantation. Survival analyses were performed for the outcomes of ESRD, death, and combined outcome of ESRD or death. Of 14,631 participants with CKD stages 3-4, 28% were African American and 72% were white. African American participants had higher rates of obesity and hypertension, with a higher baseline mean eGFR, higher prevalence of albuminuria, and greater degree of anemia compared with whites. In multivariable models, African American race increased the risk of ESRD (HR, 1.66; 95% CI, 1.26-2.07), but not death (HR, 0.89; 95% CI, 0.76-1.03). In these models, male sex, hypertension, diabetes, lower baseline eGFR, and albuminuria were predictive of higher rates of ESRD; age, male sex, diabetes, lower baseline eGFR, and albuminuria were predictive of overall mortality. There was no significant interaction between race and BMI in the adjusted model for outcomes of ESRD (P = 0.7) or death (P = 0.3). Baseline values used in the analysis are from a cross-sectional data set. Dyslipidemia and secondary hyperparathyroidism were not accounted for in the analysis. African American race was associated with a higher incidence of ESRD, but not mortality. Although obesity may be a heterogeneous disease state in African Americans and whites with CKD, there does not appear to be a significant interaction between race and BMI in progression to ESRD or death.

Data are scant regarding access to health care in patients with chronic kidney disease (CKD). We performed descriptive analyses using data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP), a nationwide health screening program for adults at high risk of CKD.From 2000-2010, a total of 122,502 adults without end-stage renal disease completed KEEP screenings; 27,927 (22.8%) met criteria for CKD (10,082, stages 1-2; 16,684, stage 3; and 1,161, stages 4-5). CKD awareness, self-rated health status, frequency of physician visits, difficulty obtaining medical care, types of caregivers, insurance status, and medication coverage and estimated costs were assessed.Participants with CKD were more likely to report fair/poor health status than those without CKD. Health care utilization increased at later CKD stages; ~95% of participants at stages 3-5 had visited a physician during the preceding year compared with 83.7% of participants without CKD. More Hispanic and African American than white participants at all CKD stages reported not having a physician. Approximately 40% of participants younger than 65 years reported fair/poor health status at stages 4-5 compared with ~30% who were 65 years and older. Younger participants at all stages were more likely to report extreme or somewhat/moderate difficulty obtaining medical care. Comorbid conditions (diabetes, hypertension, and prior cardiovascular events) were associated with increased utilization of care. Utilization of nephrology care was poor at all CKD stages; <6% of participants at stage 3 and <30% at stages 4-5 reported ever seeing a nephrologist.Lack of health insurance and perceived difficulty obtaining medical care with lower health care utilization, both of which are consistent with inadequate access to health care, are more likely for KEEP participants who are younger than 65 years, nonwhite, and without previously diagnosed comorbid conditions. Nephrology care is infrequent in elderly participants with advanced CKD who are nonwhite, have comorbid disease, and have high-risk states for cardiovascular disease.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p &lt; 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant.

In systemic lupus erythematosus, nephrotic-range proteinuria typically signals the presence of a proliferative lupus nephritis (class III/IV) and/or membranous lupus nephritis (class V, with or without concomitant class III or IV lesions). However, in rare instances, systemic lupus erythematosus patients with nephrotic syndrome have kidney biopsy findings of normal glomeruli or focal segmental glomerulosclerosis lesions, with or without mesangial proliferation, on light microscopy; the absence of subepithelial or subendothelial deposits on immunofluorescence and electron microscopy; and diffuse foot process effacement on electron microscopy. This pattern, termed lupus podocytopathy, is a unique form of lupus nephritis that mimics minimal change disease or primary focal segmental glomerulosclerosis and represents approximately 1% of lupus nephritis biopsies. Here we review the clinical features, histological manifestations, diagnostic criteria and classification, pathogenesis, treatment, and prognosis of lupus podocytopathy.

A 26-year-old woman contacted our office asking for an urgent call back. She had a history of steroid-dependent and frequently relapsing minimal change disease, and calls like this usually meant her home dipsticks had turned positive. Instead, she reported that she had just tested positive for the 2019 novel coronavirus (SARS-CoV-2 or COVID-19). She had a low-grade fever, myalgias, and a reduced sense of smell, but fortunately no cough or shortness of breath. She was worried about her dipsticks, however, which were still negative. What was usually a reassuring do-it-yourself test now frightened her. “Does that mean the rituximab is still in my system?” she asked, referring to the infusion she had done about 4 months earlier. As COVID-19 infections spread across the world, nephrologists and their patients face difficult decisions regarding management of glomerular diseases. Our Center for Glomerular Diseases has fielded countless questions in the last few weeks, not just from patients but from other nephrologists about the most appropriate way to handle immunosuppression in the current climate. Should lupus nephritis patients reduce their mycophenolate mofetil doses or stop the drug altogether? Should membranous nephropathy patients with rising titers of antibodies to the phospholipase A2 receptor (PLA2R) proceed with their scheduled rituximab infusions? Should severe ANCA-associated GN patients in the midst of an intravenous course of cyclophosphamide switch over to oral cyclophosphamide to avoid trips into the infusion center? Of course, there are no perfect, or even evidence-based, answers to these and other inquiries. Here, we offer some insight as to how our center in New York City, currently the world’s hottest spot for COVID-19 infections, has adapted the management of our glomerular disease patients to reduce complications of potential COVID-19 disease (Table 1). We also speculate on how our practice will be altered in the future, even at a time when, hopefully, COVID-19 infections are a thing of the past. Table 1. - Concise guidelines for management of glomerular disease patients during the COVID-19 pandemic (opinion-based) Component Recommendations Immunosuppression Discontinue antimetabolites for patients with confirmed or suspected infection Consider discontinuation of antimetabolites for patients in sustained remission >12 mo Favor short-acting, reversible agents over long-acting infusions Avoid therapy initiation for marginal criteria or nonstandard indications Avoid therapy initiation for minimally symptomatic patients with stable eGFR Convert intravenous infusions to oral formulation when possible (e.g., cyclophosphamide) and utilize home infusion services in lieu of hospital- or clinic-based infusion suites For patients in clinical trials with potential patient benefit, continue study drug by sending medication to their home if an oral or subcutaneous agent, or dosing in a COVID-19–compliant infusion center if an intravenous agent Diagnosis and monitoring Reserve biopsies for critical decision-making needs Consider empirical treatment, without biopsy, for conditions with high pretest probability diagnoses (e.g., RPGN with positive ANCA serologies) Limit blood draws to safety laboratories performed at commercial (i.e., non–hospital-based) laboratories Utilize home urine dipsticks for proteinuria monitoring Utilize commercially shipped collection kits for 24-h urine collections that can be done at home and shipped back Postpone protocol biopsies Supportive care Continue ACE inhibitors or ARBs in the absence of clear contraindications at this point Continue prophylactic antibiotics (e.g., TMP-SMX) Encourage social distancing Encourage use of masks while outside of the house Complete recommended vaccinations for influenza and pneumococcus (PCV13 and PPSV23) to prevent secondary or coinfection Office management Change all appointments to telemedicine video visits Allow office staff to manage phones and patient messages from home Develop a standard script of recommendations for patients calling with questions about possible COVID-19 exposure based on CDC guidelines Use telemedicine video visits rather than telephone calls for patients concerned about COVID-19 infectious symptoms to best triage respiratory status ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; TMP-SMX, trimethoprim-sulfamethoxazole; PCV, pneumococcal conjugate vaccine; PPSV, pneumococcal polysaccharide vaccine; RPGN, rapidly progressive glomerulonephritis; CDC, Centers for Disease Control and Prevention. While considering the impact of immunosuppression on COVID-19 outcomes, nephrologists must simultaneously account for the potential impact on kidney outcomes from withholding immunosuppression. Therefore, we are still advising that patients who are at high risk of progression to ESKD without immediate therapy begin standard of care immunosuppression regimens. These patients are principally those with rapidly progressive glomerulonephritides due to lupus, ANCA, and anti–glomerular basement membrane-associated disease. In addition, patients with severe forms of nephrotic syndrome that are already manifesting reductions in kidney function, or complications related to proteinuria and hypoalbuminemia (e.g., deep venous thrombosis and anasarca), fit this criterion. In contrast, we have advised many of our patients who otherwise would be treated with immunosuppression to postpone treatment until their local transmission rates of COVID-19 are low enough that social distancing measures are no longer recommended. These include the following: (1) membranous nephropathy patients with nephrotic syndrome and/or rising anti-PLA2R antibody titers, but without complications and with preserved eGFR, (2) minimal change disease or FSGS patients with preserved eGFR, and (3) IgA nephropathy patients with endocapillary hypercellularity and/or low crescentic burden on kidney biopsy with preserved eGFR. In addition, for diseases without a validated standard of care regimen, such as immune complex or complement-mediated forms of membranoproliferative GN, we are not advocating immunosuppressive therapy at this time regardless of clinical parameters. Glomerular disease patients who started immunosuppressive therapy prior to the COVID-19 pandemic require a risk-benefit assessment regarding continuation of immunosuppression, which should account for the potential impact of modifying or stopping treatment, as well as patient access to therapies. Patients in the midst of an intravenous induction regimen (e.g., EuroLupus dosing of intravenous cyclophosphamide for lupus nephritis) can be changed to an equivalent oral induction regimen if one exists (e.g., use of oral cyclophosphamide or high-dose mycophenolate mofetil for lupus nephritis) to potentiate stay-at-home adherence and avoid exposure to health care settings. Likewise, many patients who would receive pulse methylprednisolone intravenous treatments can be treated with high-dose oral prednisone or oral methylprednisolone. We have leveraged home infusion services to maintain necessary infusions while minimizing (without eliminating) social contact. Alterations to maintenance immunosuppression regimens should be individualized according to disease status and drug class. For example, stable patients on chronic immunosuppression should lower their doses to the safest level that will maintain remission; for many of our patients, this translates to a 50% drop in cumulative dose. If disease remission already extends >12 months, we consider immediate cessation of antimetabolites like mycophenolate mofetil or azathioprine, and we are not dosing maintenance rituximab infusions. Patients in sustained remission on maintenance steroids can, if on a low and alternate-day dose, discontinue these agents; otherwise, we begin a taper with dose adjustments every 2 weeks. We do not adjust the dose of calcineurin inhibitors in line with recommendations from our kidney transplant colleagues, who have recently reported that COVID-19–infected allograft recipients maintained on calcineurin inhibitors alone, with the antimetabolite held, have similar hospital-based outcomes compared with non–immune suppressed COVID-19–infected patients (1). As many glomerular disease patients are young without significant comorbidities, suspected or confirmed cases of COVID-19 infection can often be managed at home without the need for hospitalization. For such patients, we recommend discontinuation of antimetabolites as part of their management and ask for continued communication on their clinical course with our office. Patients with glomerular diseases who require hospitalization for COVID-19 respiratory illnesses should, in addition to holding their antimetabolites, be started on stress doses of corticosteroids if on a long-term steroid regimen. If hydroxychloroquine and azithromycin are started on patients with nephrotic-range proteinuria, close monitoring of calcium levels is required, and it is mandatory to confirm that a baseline electrocardiogram has a normal QTc interval. Our Center for Glomerular Diseases averages about 3000 annual office visits for glomerular disease care. Since mid-March 2020, we have moved the entirety of our clinic to telemedicine encounters using video visits. Telemedicine video visits with our physicians and support staff have been helpful to answer patients’ questions, allay their concerns, and maintain contact with them during home sequestration. Patients can monitor their BPs, daily weights, and symptoms of glomerular disease and relate these in real time to our staff. For example, peripheral edema can be easily visualized with cell phone and tablet cameras. Laboratory surveillance is a critical component of managing glomerular disease patients. We have limited this surveillance to primarily focus on safety laboratories that can be drawn at a commercial laboratory (i.e., not a hospital-based laboratory) that is enforcing social distancing among its clients. As an alternative, for some patients we have been able to use laboratory services that provide home testing visits. We have always relied on the use of urine dipsticks for home monitoring of disease status and include a review of dipstick results in our telemedicine visits. Importantly, if a patient contacts our office with symptoms suggestive of COVID-19 infection, such as cough, fever, and/or myalgias, a video visit potentiates better assessment of dyspnea and respiratory effort than a phone call for triaging whether the patient should be seen at an emergency room for oxygen therapy and potential hospital admission. New enrollment into clinical trials has been paused during the COVID-19 crisis, but glomerular disease patients enrolled in therapeutic clinical trials that offer the prospect of direct benefit to participants should continue on the study drug. Many single-arm but also randomized clinical trials, particularly in phases 2 and 3, allow participants access to novel or unapproved therapies and thus have the prospect of benefit. The Food and Drug Administration has provided guidance (2) on conducting clinical trials during the pandemic, which includes sending study drugs to participants if oral or subcutaneous agents, or dosing study drugs in an outpatient infusion center with appropriate protocols for safe infusion therapy if an intravenous agent. The American College of Rheumatology has provided recommendations (3) for facilities providing infusion therapy during the COVID-19 crisis (Table 2). Visits that do not require study drug administration can be converted to telemedicine encounters. Study laboratories that are required for safety monitoring can be performed at commercial laboratories, at which time outcome-associated laboratories that are standard (e.g., creatinine and proteinuria) can also be collected. Some clinical trials have provided subjects with mailing kits for biosamples procured at local laboratories, so that these specimens can still be processed at a central study laboratory. Table 2. - Infusion suite strategies to reduce risk of COVID-19 infection (adapted from American College of Rheumatology guidance document) Strategy Postpone all nonessential infusions Adjust schedule so that waiting rooms and infusion suites allow for social distancing with chairs at least 2 m apart Provide face masks for all patients and staff to wear within the facility Frequently clean and decontaminate all equipment and surfaces in patient areas with appropriate contact time for disinfectant Verbally inform patients and post signs about appropriate social distancing and hygiene procedures Recommend remote check-in (e.g., over the phone from outside the facility) to minimize waiting time Screen staff with temperature checks at beginning and end of shift Screen patients by phone prior to their visit about infectious symptoms and exposure to individuals with known COVID-19 infection Kidney biopsies fit the definition of “elective procedures,” which have been cancelled in many institutions at this time. We still are performing kidney biopsies in settings where we expect that findings are crucial for the immediate management of patients (e.g., rapidly progressive GN). Patients with apparent primary nephrotic syndrome and preserved eGFR should not undergo biopsies at this time; they can be managed empirically with calcineurin inhibitors with a biopsy to follow at a safer date. The use of anti-PLA2R antibody testing to diagnose primary membranous nephropathy can be helpful in this situation (4). Protocol biopsies to assess the efficacy of immunosuppression and activity versus chronicity of disease, as well as research biopsies for clinical trials or observational studies, should be cancelled. As we reduce our glomerular disease patients’ exposure to immunosuppression, we often need to adjust our conservative therapies, particularly renin-angiotensin-aldosterone system blocking agents and diuretics. Despite recent controversies regarding the possible impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 transmission, we adhere to the recommendations made by experts across various disciplines (cardiology, nephrology, and hypertension) not to discontinue these drugs (5–67). Therefore, we keep our patients on these agents and, if proteinuria is heavy in patients being weaned off immunosuppression, consider either increasing the dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blockers or, alternatively, keeping the dose unchanged but adding a mineralocorticoid receptor blocker (e.g., eplerenone). For patients already on chronic hydroxychloroquine therapy, we are continuing the drug but not altering the dose; in the event of a drug shortage, we will need to consider dose reductions for these patients. We are not starting any patients on this drug prophylactically and are seeing cases of COVID-19 infection in lupus patients on maintenance hydroxychloroquine. We anticipate that our management of glomerular disease patients will be altered by our current COVID-19–influenced practices even when the current pandemic has resolved. We have seen significantly lower rates of rapidly progressive GN in our hospitalized patients and disease relapses in our clinic patients since widespread adoption of social distancing. We have heard similar reports from our colleagues in other disciplines (e.g., fewer myocardial infarctions seen by cardiologists). This seemingly quiescent disease state supports the hypothesis that environmental exposures, including but not limited to infections, may be a major trigger of glomerular disease onset and relapse. While we do not foresee advocating formal social distancing for immunosuppressed patients outside of a pandemic window, we will repeatedly reinforce patient education on measures to reduce infectious exposures such as strict avoidance of sick contacts, frequent handwashing, avoiding touching of the face, and, whenever possible, staying at least 2 m away from other individuals. We also foresee wide adoption of telemedicine encounters to reduce time in healthcare settings for many of our glomerular disease patients, especially in follow-up visits when these patients are often on their highest doses of immunosuppressants. Most importantly, given forecasts of a possible second wave of COVID-19 infections after the current pandemic has abated, as well as broader speculation that we are now firmly entrenched in an era of viral pandemics, we will need to consider the degree to which we are immunosuppressing all of our glomerular disease patients regardless of current infection rates. Fortunately, the field of glomerular diseases has been moving in this direction well before the emergence of COVID-19. For example, the Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis study showed noninferior outcomes in Anti-Neutrophil Cytoplasm Antibody-associated GN with a reduced dose of corticosteroids compared with a standard dose of corticosteroids (8), the Supportive versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy and Therapeutic Evaluation of Steroids in IgA Nephropathy Global trials argued against use of high dose corticosteroids for IgA nephropathy (9,10), and the Membranous Nephropathy Trial of Rituximab study found better long-term outcomes with just one or two dosing intervals of rituximab compared with year-long therapy with cyclosporine (11). But we likely will need to go even further than these trials and begin to question, for each glomerular disease, how much immunosuppression is needed to induce a remission and whether long-term maintenance therapy is required to sustain this remission. In other words, the debates on risks versus benefits of immunosuppression that we are forced to have now in the face of widespread COVID-19 infections should continue past this year, when our world, and our patients, will be very different because of what we are experiencing now. Disclosures Dr. Ahmad, Dr. Ahn, Dr. Appel, Dr. Bomback, Dr. Canetta, and Dr. Radhakrishnan have nothing to disclose. Funding Dr. Bomback and Dr. Canetta are supported, in part, by National Institutes of Health grant UM1DK100876.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.

Acute kidney injury (AKI) induces a broad range of clinically significant perturbations in kidney morphology and function. Insights into the molecular and cellular basis governing a clinical-pathologic course are limited by the availability of molecular maps of healthy and injured kidney cells. The Kidney Precision Medicine Project (KPMP) and the Human Biomolecular Atlas Project (HuBMAP) have generated a comprehensive molecular atlas of the kidney from more than 400,000 cells that define healthy and injured cell types and states in AKI and chronic kidney disease. 1 de Boer I.H. Alpers C.E. Azeloglu E.U. et al. Rationale and design of the Kidney Precision Medicine Project. Kidney Int. 2021; 99: 498-510 Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar ,2 Tuttle K.R. Bebiak J. Brown K. et al. Patient perspectives and involvement in precision medicine research. Kidney Int. 2021; 99: 511-514 Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Using the atlas as a resource to perform deep interrogation of a biopsy from a patient participant with AKI, we applied single-cell analysis and detailed morphologic and pathway analysis to gain molecular insights into cellular diversity, injury states, and outcome. In this issueKidney InternationalVol. 101Issue 6PreviewIn this issue of Kidney International, we are pleased to introduce a new article series called Next Generation Clinical Pathologic Conference (CPC). These articles will merge the traditional CPC with molecular medicine for a fresh approach to decipher mechanisms of kidney disease. In cooperation with the National Institutes of Health–sponsored Kidney Precision Medicine Project, biopsies from patients with chronic kidney disease (CKD) or acute kidney injury (AKI) that have been interrogated with cutting-edge molecular technologies will be reviewed and correlated with clinical and histopathologic findings. Full-Text PDF

The renin-angiotensin-aldosterone system (RAAS), an important regulator of blood pressure as well as fluid and electrolyte balance, plays an important role in the pathophysiology of cardiovascular and kidney diseases. Blockade of the RAAS with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-II (ANG-II) receptor blockers (ARBs) lowers blood pressure, decreases morbidity and mortality in patients with chronic heart failure, and decreases proteinuria and the rate of decline in renal function in patients with chronic kidney disease. Although these drugs are highly effective and are widely used in the management of cardiovascular and kidney diseases, current treatment regimens with ACEIs and ARBs may not completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes. With the growing appreciation of the role of aldosterone in the pathogenesis of cardiorenal diseases and the recent approval of the direct renin inhibitor (DRI), aliskiren, additional combination strategies have emerged that may offer novel ways to more fully suppress the RAAS. This review examines what is presently known about ACEI/ARB combination therapy and explores alternative combination strategies that include DRIs and mineralocorticoid receptor blockers (MRBs).

Obesity and obesity-associated kidney injuries have played an important role in the rising prevalence of chronic kidney disease (CKD). The link between obesity and kidney disease begins with obesity’s well-known associations with diabetes and hypertension, the two leading etiologies of CKD. However, a growing body of evidence suggests that elevated aldosterone levels and expanded extracellular volume are key components of obesity-induced renal disease via aldosterone’s non-epithelial effects on the kidney. Highlighting these blood pressure- and diabetes-independent mechanisms of kidney injury in obesity allows an exploration of whether mineralocorticoid receptor blockade, coupled with weight loss and salt restriction, is an optimal treatment for overweight CKD patients.

Women with gestational diabetes mellitus (GDM) maintain a higher risk for recurrent GDM and overt diabetes. Overt diabetes is a risk factor for development of chronic kidney disease (CKD), but GDM alone, without subsequent development of overt diabetes, may also pose a risk for CKD.This cross-sectional analysis included Kidney Early Evaluation Program (KEEP) participants from 2000 to 2009. Patient characteristics and kidney function among three categories (GDM alone, overt diabetes, and no history of diabetes) were compared. The prevalence of microalbuminuria, macroalbuminuria, and CKD stages 1-2 and 3-5 was assessed using logistic regression.Of 37,716 KEEP female participants, 571 (1.5%) had GDM alone and 12,100 (32.1%) had overt diabetes. Women with GDM had a higher rate of microalbuminuria but not macroalbuminuria than their nondiabetic peers (10.0 vs. 7.7%) that was substantially lower than the 13.6% prevalence in diabetic women. In multivariate analysis, women with GDM alone, compared with nondiabetic women, demonstrated increased odds of CKD stages 1-2 (multivariate odds ratio 1.54 [95% CI 1.16-2.05]) similar to the odds for women with overt diabetes (1.68 [1.55-1.82]). In stratified analyses, age, race, BMI, and hypertension modified the odds for CKD stages 1-2 but not CKD stages 3-5 among women with GDM.Women with GDM alone have a higher prevalence of microalbuminuria than women without any history of diabetes, translating to higher rates of CKD stages 1-2. These results suggest that GDM, even in the absence of subsequent overt diabetes, may increase the risk for future cardiovascular and kidney disease.

Whereas early classifications of membranoproliferative glomerulonephritis (MPGN) were based on morphologic features, the modern approach is directed at immunofluorescence findings. Glomerular deposits of C3 alone, without immunoglobulin, are the hallmark of alternative complement pathway dysregulation through inherited or acquired defects. These immunoglobulin-negative forms are referred to as C3 glomerulopathy, which encompasses both dense deposit disease and C3 glomerulonephritis. Distinguishing C3 glomerulopathy from immunoglobulin-mediated MPGN is opening the way to better diagnostic, prognostic, and treatment algorithms. Whereas early classifications of membranoproliferative glomerulonephritis (MPGN) were based on morphologic features, the modern approach is directed at immunofluorescence findings. Glomerular deposits of C3 alone, without immunoglobulin, are the hallmark of alternative complement pathway dysregulation through inherited or acquired defects. These immunoglobulin-negative forms are referred to as C3 glomerulopathy, which encompasses both dense deposit disease and C3 glomerulonephritis. Distinguishing C3 glomerulopathy from immunoglobulin-mediated MPGN is opening the way to better diagnostic, prognostic, and treatment algorithms. Among glomerular diseases, none has undergone greater conceptual metamorphosis over the past five years than membranoproliferative glomerulonephritis (MPGN). In the 1970s, before there was knowledge of pathogenesis, MPGN was categorized on the basis of histologic and ultrastructural findings.1.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type 1 MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (38) Google Scholar, 2.Habib R. Gubler M.C. Loirat C. et al.Dense deposit disease: a variant of membranoproliferative glomerulonephritis.Kidney Int. 1975; 7: 204-215Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 3.Strife C.F. McEnery P.T. McAdams A.J. et al.Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.Clin Nephrol. 1977; 7: 65-72PubMed Google Scholar The membranoproliferative pattern of glomerular injury is defined as mesangial interposition and duplication of glomerular basement membranes, typically associated with peripheral capillary wall immune deposits. Over the next two decades, many secondary forms with clear etiologic associations (such as related to cryoglobulinemia, dysproteinemia, autoimmune disease, and infections) were differentiated from the primary idiopathic form. But the pathologic classification of primary MPGN remained problematic because it was based largely on the ultrastructural appearance and location of deposits, devoid of pathogenetic context. Subendothelial and mesangial deposits predominated in type I MPGN, where the membranoproliferative pattern was typically well developed.1.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type 1 MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (38) Google Scholar Highly electron-dense intramembranous and mesangial deposits were the hallmark of type II, also known as dense deposit disease (DDD).2.Habib R. Gubler M.C. Loirat C. et al.Dense deposit disease: a variant of membranoproliferative glomerulonephritis.Kidney Int. 1975; 7: 204-215Abstract Full Text PDF PubMed Scopus (155) Google Scholar In type III, deposits could be subendothelial and subepithelial (Burkholder subtype) or produce complex intramembranous, subendothelial, and subepithelial formations with fraying of the lamina densa (Strife and Anders subtype).3.Strife C.F. McEnery P.T. McAdams A.J. et al.Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.Clin Nephrol. 1977; 7: 65-72PubMed Google Scholar Even within the same biopsy or a given glomerulus, pathologists may observe overlapping features between these subtypes, defying easy classification. While hypocomplementemia was a well-recognized clinical feature of all these entities, with the exception of C3 nephritic factor, causation was largely unknown. Over the next two decades, increasing attention was paid to the composition of the deposits detected by immunofluorescence. Type I was typically characterized by deposits of immunoglobulin as well as complement components; type II was distinguished by deposits of C3 only; the type III Burkholder variant typically had deposits of immunoglobulin and complement; whereas the type III Strife and Anders variant could manifest C3 either alone or in combination with immunoglobulins. As long as the pathogenesis of these forms remained obscure, the classification was cumbersome to use and perplexing to clinicians and pathologists alike. In the past decade, our understanding of the role of complement in the pathogenesis of MPGN has illuminated the field and led to a paradigm shift in classification (Figure 1). First, the observation that a number of patients with intramembranous dense deposits lack an MPGN pattern altogether caused the designation MPGN II to be discarded in favor of DDD. Second, pathologists began emphasizing in their reports the presence of isolated deposits of C3 in examples of MPGN type I and type III. A major breakthrough was the discovery of genetic mutations or deficiencies in complement-regulatory proteins in patients with isolated C3 deposits.4.Appel G.B. Cook H.T. Hageman G. et al.Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.J Am Soc Nephrol. 2005; 16: 1392-1403Crossref PubMed Scopus (296) Google Scholar,5.Servais A. Fremeaux-Bacchi V. Lequintrec M. et al.Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.J Med Genet. 2007; 44: 193-199Crossref PubMed Scopus (226) Google Scholar Thereafter, ‘C3 glomerulopathy’ assumed center stage as a newly recognized subgroup encompassing DDD and those examples of type I and type III (now termed ‘C3 glomerulonephritis’; C3GN) in which immunofluorescence reveals isolated deposits of C3, underscoring the pathogenetic importance of dysregulation of the alternative complement pathway. Thus, the modern approach to classification distinguishes those forms of MPGN with deposits of C3 only (known as C3 glomerulopathy and including both DDD and C3GN) from MPGN with deposits of immunoglobulin and complement.6.Sethi S. Fervenza F.C. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification.Semin Nephrol. 2011; 31: 341-348Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The reports from Servais et al.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar and Sethi et al.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar in this issue of Kidney International highlight the strengths and weaknesses of the term ‘C3 glomerulopathy.’ As validation of the classification, defective control of the alternative complement pathway was detectable in 71% of patients in the French cohort7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar (which included cases of C3GN, DDD, and MPGN type I) and 100% of those in the American cohort8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar (which included cases of C3GN only). This defect can be due to mutations in complement proteins (such as C3, factor B, factor H, and factor I) or due to acquired autoantibodies that either stabilize the C3 convertase of the alternative pathway (e.g., C3 nephritic factors) or target the inhibitory complement factors (e.g., factor H autoantibodies). These abnormalities promote excessive activation of the alternative complement pathway in the fluid phase, with deposition of complement debris, including breakdown products of C3b and components of the terminal complement cascade, in the glomerular capillary wall. A reclassification of MPGN into immunoglobulin-mediated disease (prompting a work-up for infectious, autoimmune, or dysproteinemia-associated etiologies) vs. complement-mediated disease (prompting a work-up of the alternative pathway) should lead to better diagnostic and treatment algorithms and, ideally, improved outcomes in these diseases. For example, 9 of the 12 patients with C3GN in the American cohort were initially misclassified as having MPGN type I (n=4), MPGN type III (n=1), and postinfectious glomerulonephritis (n=4). The demonstration by Sethi et al.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar that the proteomic profile of C3GN by mass spectrometry is similar to that of DDD (with predominance of C3 and distal complement pathway components) further supports the emerging view that the presence of C3 alone is the major hallmark of alternative complement pathway dysregulation in C3 glomerulopathy, independent of histologic and ultrastructural features. However, the pitfall of lumping diseases into a single descriptor or category is an implied assumption of homogeneity. As compared with atypical hemolytic uremic syndrome, which is also strongly associated with dysregulated alternative complement pathway activity, C3 glomerulopathy manifests a much broader spectrum of clinical presentation, histopathology, genetic abnormalities, complement activity, and prognosis. Servais et al., looking only at the adult patients in their cohort, found worse 10–year renal survival in patients with DDD than in patients with MPGN type I and C3GN;7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Sethi et al., in their smaller cohort, also report worse outcomes in DDD than in C3GN and suggest that C3GN may be a less aggressive entity.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar One possible explanation is the much higher rate of C3 nephritic factor (C3NeF) positivity in DDD (86.4% in the French cohort, in accordance with the approximately 80% rate described in other cohorts)9.Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274Crossref PubMed Scopus (140) Google Scholar than in C3GN (45.3% in the French cohort and 50% in the American cohort).7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar,8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Yet even this discrepancy is open to question, as Servais et al. report a fluctuation of the C3NeF activity in one-third of their patients during follow-up and a normal range of serum C3 levels in approximately 40% of C3NeF-positive patients, suggesting that the C3NeF-stabilized C3 convertase may be subject to regulation by other factors.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar The authors hypothesize that complement-regulatory membrane cofactor protein (MCP) variants may explain this heterogeneity of disease in C3 glomerulopathy.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar However, they are not able to show a functional role of their proposed at-risk MCP haplotype, and the P-values reported for the selected single-nucleotide polymorphisms in the MCP gene are not robust enough to denote significance, particularly without replication in an independent cohort.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar One of the most intriguing findings to emerge from the French cohort is the identification of alternative complement pathway dysregulation in more than half of the 48 patients with MPGN type I.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar In fact, a C3NeF was identified as frequently in MPGN type I as in C3GN. The terminology ‘C3 glomerulopathy’ is intended for immunoglobulin-negative diseases, to highlight the underlying alternative pathway dysregulation as opposed to activation of the classical pathway by antigen–antibody immune complexes. How, then, should we classify the MPGN type I patients described here with genetic abnormalities in factor H (n=5) or factor I (n=3) or with positive C3NeF activity (n=18)? One possible explanation is that these patients were previously misclassified as MPGN type I, akin to some patients in the American C3GN cohort, and that the immunoglobulin staining was trace and inconsequential; the lack of central review of all biopsies in this study, as the authors themselves acknowledge, is therefore a major limitation.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Small amounts of immunoglobulin may become trapped in areas of sclerosis or accumulate in podocyte protein resorption droplets, confounding immunofluorescence interpretation. However, if we are to accept that these cases truly have immunoglobulin deposits alongside serologic evidence of alternative pathway dysregulation, should we now consider these as yet another subtype of C3 glomerulopathy? These findings suggest more commonality between MPGN type I and C3 glomerulopathies than previously recognized and raise the question of whether patients with dysregulated alternative complement pathway may not also develop disease-causing immune deposits containing immunoglobulin and complement in the course of antigen-driven immune responses. Such observations are consistent with the predisposition to immune complex-mediated lupus nephritis in MRL-lpr mice with genetic deletion of complement factor H10.Bao L. Haas M. Quigg R.J. Complement factor H deficiency accelerates development of lupus nephritis.J Am Soc Nephrol. 2011; 22: 285-295Crossref PubMed Scopus (80) Google Scholar and the increased susceptibility to IgA nephropathy in people with mutations in the complement factor H locus on human chromosome 1q32.11.Gharavi A.G. Kiryluk K. Choi M. et al.Genome-wide association study identifies susceptibility loci for IgA nephropathy.Nat Genet. 2011; 43: 321-327Crossref PubMed Scopus (378) Google Scholar C3NeF has also been identified in some patients with postinfectious glomerulonephritis.12.Fremeaux-Bacchi V. Weiss L. Demouchy C. et al.Hypocomplementaemia of poststreptococcal acute glomerulonephritis is associated with C3 nephritic factor [C3NeF] IgG autoantibody activity.Nephrol Dial Transplant. 1994; 9: 1747-1750PubMed Google Scholar Because patients with complement-regulatory disorders are not protected from development of other immune-mediated glomerulonephritides, future studies will be needed to explore the potential contribution of alternative pathway complement dysregulation beyond C3 glomerulopathy. Screening tests of alternative complement pathway activity may help clear up some of this confusion and provide much-needed physiologic information supporting the diagnosis of C3 glomerulopathy. Sethi et al. used three different screening tests of the alternative pathway in their cohort of C3GN: a hemolytic assay, an alternative pathway functional assay, and levels of serum membrane attack complex.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar In such a small cohort, in which most patients showed remarkable stability of disease despite varied treatment regimens, it is impossible to discern whether these markers of alternative pathway activity are linked to outcomes. Such testing would likely have been far more informative in the larger French cohort but was not performed.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Instead, levels of C3 and C4 were used as baseline markers of complement activity, which by themselves are substandard in these complex diseases; not surprisingly, neither low C3 (<600mg/l) nor very low C3 (<200mg/l) levels were predictive of renal outcomes.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Wider access to the types of genetic and complement testing described in both studies should allow more etiology-specific diagnosis. Another provocative finding is the identification of both C3NeF and a genetic defect in the complement pathway in a proportion of patients in the French cohort: among 24 patients with an identified mutation in a complement gene, 13 also had detectable C3NeF.7.Servais A. Noël L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Why is there coexistence of inherited and acquired abnormalities of the alternative complement pathway in such cases? These numbers are difficult to ascribe to coincidence and raise the question of whether increased activity of the alternative complement pathway on a genetic basis might promote autoimmune phenomena by unbridled activation (and perhaps conformational change) of the C3 convertase. These findings suggest a two-hit disease model in some people. Larger cohorts are needed to evaluate the prevalence of this phenomenon and the implications for evidence-based treatment.

Aldosterone levels increase in 30%–40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This “aldosterone breakthrough” may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2, and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m2; baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade.

Besides its epithelial effect on sodium retention and potassium excretion in the distal tubule, aldosterone promotes inflammation and fibrosis in the heart, kidneys, and blood vessels. As glomerular filtration rate falls, aldosterone is inappropriately elevated relative to extracellular fluid expansion. In addition, studies in CKD patients on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or direct renin inhibitors have shown that aldosterone levels paradoxically rise in approximately 30% to 40% of patients on these renin-angiotensin system-blocking drugs. Hence, there is interest in using mineralocorticoid receptor blockers that directly target the inflammatory and fibrotic effects of aldosterone in CKD patients. This interest, however, is tempered by a number of unresolved issues, including the safety of using such drugs in advanced CKD and ESRD populations, and the potential for differences in drug efficacy according to race and ethnicity of patient populations. A better understanding of mineralocorticoid receptor blocker pharmacology should help inform future research directions and clinical practice decisions as to how best to use these agents in CKD. Besides its epithelial effect on sodium retention and potassium excretion in the distal tubule, aldosterone promotes inflammation and fibrosis in the heart, kidneys, and blood vessels. As glomerular filtration rate falls, aldosterone is inappropriately elevated relative to extracellular fluid expansion. In addition, studies in CKD patients on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or direct renin inhibitors have shown that aldosterone levels paradoxically rise in approximately 30% to 40% of patients on these renin-angiotensin system-blocking drugs. Hence, there is interest in using mineralocorticoid receptor blockers that directly target the inflammatory and fibrotic effects of aldosterone in CKD patients. This interest, however, is tempered by a number of unresolved issues, including the safety of using such drugs in advanced CKD and ESRD populations, and the potential for differences in drug efficacy according to race and ethnicity of patient populations. A better understanding of mineralocorticoid receptor blocker pharmacology should help inform future research directions and clinical practice decisions as to how best to use these agents in CKD.

Summary: Acute kidney injury (AKI) currently is diagnosed by a temporal trend of a single blood analyte: serum creatinine. This measurement is neither sensitive nor specific to kidney injury or its protean forms. Newer biomarkers, neutrophil gelatinase-associated lipocalin (NGAL, Lipocalin 2, Siderocalin), or kidney injury molecule-1 (KIM-1, Hepatitis A Virus Cellular Receptor 1), accelerate the diagnosis of AKI as well as prospectively distinguish rapidly reversible from prolonged causes of serum creatinine increase. Nonetheless, these biomarkers lack the capacity to subfractionate AKI further (eg, sepsis versus ischemia versus nephrotoxicity from medications, enzymes, or metals) or inform us about the primary and secondary sites of injury. It also is unknown whether all nephrons are injured in AKI, whether all cells in a nephron are affected, and whether injury responses can be stimulus-specific or cell type-specific or both. In this review, we summarize fully agnostic tissue interrogation approaches that may help to redefine AKI in cellular and molecular terms, including single-cell and single-nuclei RNA sequencing technology. These approaches will empower a shift in the current paradigm of AKI diagnosis, classification, and staging, and provide the renal community with a significant advance toward precision medicine in the analysis AKI. Summary: Acute kidney injury (AKI) currently is diagnosed by a temporal trend of a single blood analyte: serum creatinine. This measurement is neither sensitive nor specific to kidney injury or its protean forms. Newer biomarkers, neutrophil gelatinase-associated lipocalin (NGAL, Lipocalin 2, Siderocalin), or kidney injury molecule-1 (KIM-1, Hepatitis A Virus Cellular Receptor 1), accelerate the diagnosis of AKI as well as prospectively distinguish rapidly reversible from prolonged causes of serum creatinine increase. Nonetheless, these biomarkers lack the capacity to subfractionate AKI further (eg, sepsis versus ischemia versus nephrotoxicity from medications, enzymes, or metals) or inform us about the primary and secondary sites of injury. It also is unknown whether all nephrons are injured in AKI, whether all cells in a nephron are affected, and whether injury responses can be stimulus-specific or cell type-specific or both. In this review, we summarize fully agnostic tissue interrogation approaches that may help to redefine AKI in cellular and molecular terms, including single-cell and single-nuclei RNA sequencing technology. These approaches will empower a shift in the current paradigm of AKI diagnosis, classification, and staging, and provide the renal community with a significant advance toward precision medicine in the analysis AKI.

Rationale & Objectives Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. Study Design Multicenter case series. Setting & Participants We included 77 patients from 5 North American and European medical centers with post–kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. Findings Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. Limitations Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. Conclusions De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney. Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood. Multicenter case series. We included 77 patients from 5 North American and European medical centers with post–kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls. Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence. Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies. De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.

Anti-glomerular basement membrane (GBM) disease is a rapidly progressive glomerulonephritis which, in some instances, occurs concurrently with other diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rarely, it also occurs with membranous nephropathy (MN). We report a series of such patients, characterizing their long-term follow up.Case series.Twelve patients referred to 1 medical center between 2001 and 2019 with anti-GBM disease and MN whose clinical characteristics and course were described.Patients' ages ranged from 20 to 81 years old, and all presented with severe acute kidney injury requiring dialysis on presentation or shortly thereafter. Only 1 patient had pulmonary findings on presentation. The predominant pathology was crescentic and necrotizing glomerulonephritis with linear staining for immunoglobulin G along the GBM associated with epimembranous electron-dense immune-type deposits. All 11 patients who were tested had significant titers of anti-GBM antibodies, but only 1 of the 5 tested for phospholipase A2 receptor (PLA2R) on biopsy was positive. Eight patients received therapy with cyclophosphamide, prednisone, and plasmapheresis; 2 patients with prednisone and plasmapheresis; and 2 with rituximab-based regimens. Progression to a requirement for kidney replacement therapy occurred in all 12 patients, but 2 patients later recovered kidney function. Recurrence of anti-GBM disease did not occur for any of the patients studied.Incomplete testing for PLA2R in biopsy and serum, limited sample size, and lack of uniform treatment regimen.In this case series, the presentation of concurrent anti-GBM disease and MN was characterized by rapidly progressive glomerulonephritis and poor kidney outcomes. These findings suggest possible value from earlier diagnosis and the need for identification of more effective treatment regimens.

Hydralazine, a widely used therapy for hypertension and heart failure, can elicit autoimmune disease, including anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN). We identified 80 cases of ANCA-GN complicating treatment with hydralazine, accounting for 4.3% (80/1858 biopsies) of ANCA-GN diagnosed between 2006 and 2019. Over three-fourths of patients were on hydralazine for at least one year, with mean daily dose of approximately 250 mg/day. ANCA testing revealed p-ANCA/myeloperoxidase-ANCA seropositivity in 98%, including 39% with dual p-ANCA/myeloperoxidase-ANCA and cANCA/anti-protinase 3-ANCA positivity, often accompanied by anti-nuclear antibody (89%), anti-histone antibody (98%), and hypocomplementemia (58%). Kidney biopsy revealed necrotizing and crescentic glomerulonephritis, similar to primary ANCA-GN, but significantly less frequently pauci-immune (77 vs. 100%) and more commonly associated with mesangial hypercellularity (30 vs. 5%), electron dense deposits (62 vs. 20%), and endothelial tubuloreticular inclusions (11 vs. 0%); all significant differences. On follow-up, 42 of 51 patients received induction immunosuppression: 19 reached the combined end-points of kidney failure or death and 32 had mean creatinine of 1.49 mg/dL at last follow-up. Thus, hydralazine-associated ANCA-GN often exhibits overlapping clinical and pathologic features of mild immune complex glomerulonephritis resembling lupus nephritis. With discontinuation of hydralazine and immunosuppression, outcomes are similar to primary ANCA-GN.

Complement 3 Glomerulopathy (C3G) is a rare kidney disorder comprising C3 Glomerulonephritis and Dense Deposit Disease. C3G is caused by dysregulation of the alternative complement pathway, often leading to increased levels of terminal fragments of C5 pathway, including C5a. C3G patients can present with proteinuria, hematuria, renal insufficiency, and/or hypertension, and commonly experience end-stage renal disease (ESRD) within 10 years after diagnosis.

Significance Statement Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. Background Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. Methods We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). Results We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. Conclusions We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

<h3>Background</h3> Diabetes is a leading cause of chronic kidney disease (CKD). Whether reclassification of CKD stages based on glomerular filtration rate estimated using the CKD Epidemiology Collaboration (CKD-EPI) equation versus the Modification of Diet in Renal Disease (MDRD) Study equation modifies estimates of prevalent risk factors across stages is unknown. <h3>Methods</h3> This is a cross-sectional analysis of data from the Kidney Early Evaluation Program (KEEP), a community-based health screening program targeting individuals 18 years and older with diabetes, hypertension, or a family history of diabetes, hypertension, or kidney disease. Of 109,055 participants, 68.2% were women and 31.8% were African American. Mean age was 55.3 ± 0.05 years. Clinical, demographic, and laboratory data were collected from August 2000 through December 2009. Glomerular filtration rate was estimated using the CKD-EPI and MDRD Study equations. <h3>Results</h3> CKD was present in 25.6% and 23.5% of the study population using the MDRD Study and CKD-EPI equations, respectively. Diabetes was present in 42.4% and 43.8% of participants with CKD, respectively. Prevalent risk factors for diabetes included obesity (body mass index >30 kg/m²), 44.0%; hypertension, 80.5%; cardiovascular disease, 23.2%; family history of diabetes, 55.9%; and dyslipidemia, 43.0%. In a logistic regression model after adjusting for age and other risk factors, odds for diabetes increased significantly compared with no CKD with each CKD stage based on the CKD-EPI equation and similarly with stages based on the MDRD Study equation. Using a CKD-EPI–adjusted model, ORs were: stage 1, 2.08 (95% CI, 1.90-2.27); stage 2, 1.86 (95% CI, 1.72-2.02); stage 3, 1.23 (95% CI, 1.17-1.30); stage 4, 1.69 (95% CI, 1.42-2.03); and stage 5, 2.46 (95% CI, 1.46-4.14). <h3>Conclusions</h3> Using the CKD-EPI equation led to a lower prevalence of CKD but to similar diabetes prevalence rates associated with CKD across all stages compared with the MDRD Study equation. Diabetes and other CKD risk factor prevalence was increased compared with the non-CKD population.

Idiopathic membranous nephropathy (i-MN) is a leading cause of nephrotic syndrome in adults and results in end-stage renal disease in approximately one third of patients. There are few large, long-term US studies evaluating clinical and histologic prognostic factors in i-MN.We describe 132 patients with biopsy-proven i-MN who were followed for a mean period of 68 months at our tertiary referral center from 1977 to 2009, and we analyzed clinical and histologic features that predicted renal outcomes.The presence of hypertension and treating physician's decision to institute immunosuppression were negative predictors of attaining complete or partial remission. Among clinical variables, impaired renal function (eGFR <60 ml/min/1.73 m(2)) at time of presentation was the only variable at presentation associated with an increased risk of reaching end-stage renal disease. The use of statins and RAAS blockers were protective. The choice of corticosteroids as the initial immunosuppressive agent by referring physicians decreased over time but even in the most recent era (2000-2008) was significant (33%).Renal function at presentation and non-white race were the main predictors of a worse renal outcome. Corticosteroid therapy is still being adopted as first-line therapy in a significant number of patients in this era. The development of guidelines may help clarify the treatment strategies of i-MN.

Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular mortality, but little is known about the association between physician utilization and cardiovascular disease risk-factor control in patients with CKD. We used 2005-2010 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) to examine this association at first and subsequent screenings.Control of risk factors was defined as control of blood pressure, glycemia, and cholesterol levels. We used multinomial logistic regression to examine the association between participant characteristics and seeing a nephrologist after adjusting for kidney function and paired t tests or McNemar tests to compare characteristics at first and second screenings.Of 90,009 participants, 61.3% had a primary care physician only, 2.9% had seen a nephrologist, and 15.3% had seen another specialist. The presence of 3 risk factors (hypertension, diabetes, and hypercholesterolemia) increased from 26.8% in participants with CKD stages 1-2 to 31.9% in those with stages 4-5. Target levels of all risk factors were achieved in 7.2% of participants without a physician, 8.3% of those with a primary care physician only, 9.9% of those with a nephrologist, and 10.3% of those with another specialist. Of up to 7,025 participants who met at least one criterion for nephrology consultation at first screening, only 12.3% reported seeing a nephrologist. Insurance coverage was associated strongly with seeing a nephrologist. Of participants who met criteria for nephrology consultation, 406 (5.8%) returned for a second screening, of whom 19.7% saw a nephrologist. The percentage of participants with all risk factors controlled was higher at the second screening (20.9% vs 13.3%).Control of cardiovascular risk factors is poor in the KEEP population. The percentage of participants seeing a nephrologist is low, although better after the first screening. Identifying communication barriers between nephrologists and primary care physicians may be a new focus for KEEP.

Mineralocorticoid receptor antagonists (MRAs) that block aldosterone's effects on both epithelial and non-epithelial receptors have become a mainstay of therapy for chronic heart failure. Given that cardiovascular events remain the leading cause of death for patients with end-stage renal disease (ESRD), the question of whether these MRAs can be employed in dialysis patients arises. This review summarizes the rationale for blocking aldosterone in patients with chronic and end-stage kidney disease and surveys the data on both the efficacy and safety of using MRAs in the ESRD population. A small but growing body of literature suggests that use of MRAs by ESRD patients is associated with lower blood pressure, reduced left ventricular (LV) mass, and improved LV ejection fraction. Recently, a large randomized trial found an overall 3-year mortality rate of 6.4% in ESRD patients on spironolactone 25 mg daily vs. 19.7% in ESRD patients on no MRA therapy (p = 0.002), without a significantly increased risk of hyperkalemia.

The overall kidney survival among lupus nephritis patients has improved with currently used induction immunosuppression regimens of corticosteroids and either cyclophosphamide or mycophenolate mofetil; however, there still remains a significant number of lupus nephritis patients who do not achieve remission with these regimens. Investigators have looked at other immunosuppressive regimens for lupus nephritis, and there has been interest in the use of calcineurin inhibitors in this regard. Calcineurin inhibitors are potentially an attractive option because of their established ability to inhibit T cell function, attenuate proteinuria through non-immunologic means, and their safety in pregnancy and lactation. In this review, we discuss the findings and limitations of selected trials that evaluated the use of calcineurin inhibitors in the treatment of lupus nephritis, either with corticosteroids alone or as a component of multitarget therapy when combined with mycophenolate mofetil. There may be a role for calcineurin inhibitors among patients with heavy proteinuria, as well as younger patients with refractory lupus nephritis. The multitarget therapy trials reveal higher rates of remission compared with mycophenolate mofetil alone and cyclophosphamide; however, some trials highlight the possibility of more infectious adverse events. We discuss the need for further study of calcineurin inhibitors in more diverse patient populations and the need for trials with longer follow-up with "hard" endpoints beyond proteinuria reduction, such as worsening CKD or repeat protocol biopsies, given the calcineurin inhibitors ability to reduce proteinuria non-immunologically and thus increased rate of relapse when the drug is tapered. While there may indeed be a space for calcineurin inhibitors to help increase remission rates in lupus nephritis patients, more work is needed to help address the questions the studies available to date have yet to answer.

C3 glomerulopathy (C3G) is a rare set of kidney diseases with 2 patterns: C3 glomerulonephritis (C3GN) and dense deposit disease. Pathogenesis of both diseases is due to complement dysregulation in the alternative pathway. Acquired or genetic alterations of the regulatory proteins of the complement pathway result in C3G. Although the disease is characterized by low C3 levels in serum and C3-dominant staining by immunofluorescence on biopsy, other disease entities such as infection-related glomerulonephritis and masked monoclonal deposits can present similarly. Both the C3GN and dense deposit disease variants of C3G are progressive and recur in transplanted kidneys. Although no direct treatment is available, complement blockers are either available or in the clinical trial phase. This review will survey the pathogenesis of C3GN and current treatment options.

Minimal change disease (MCD) is defined by the absence of visible glomerular lesions on light microscopy and effacement of foot processes on electron microscopy. MCD is the main cause of nephrotic syndrome (NS) in children (75-90%)1Eddy A.A. Symons J.M. Nephrotic syndrome in childhood.Lancet. 2003; 362: 629-639Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar, with most cases responding to corticosteroid treatment; kidney biopsy is thus typically not performed in children with nephrotic syndrome unless steroid resistance is observed. However, MCD only explains 10-15% of NS in adults2Floege J. Amann K. Primary glomerulonephritides.Lancet. 2016; 387: 2036-2048Abstract Full Text Full Text PDF PubMed Google Scholar, who demonstrate higher incidence of steroid resistance or dependence and poorer kidney survival. In contrast to MCD, focal segmental glomerulosclerosis (FSGS) shows segmental solidification of the glomerular tuft. Its prevalence and incidence are difficult to approximate, but FSGS seems to be increasing worldwide and is a major contributor to end-stage kidney disease (ESKD)3Rosenberg Avi Z. Kopp Jeffrey B. Focal Segmental Glomerulosclerosis.Clinical Journal of the American Society of Nephrology. 2017; 12: 502-517Crossref PubMed Scopus (0) Google Scholar. Plasma factors, adaptive changes, genetic predisposition, infections, and drugs, among others, have been linked to the development of various forms of FSGS. Treatment guidance and prognostic insights in FSGS rely on integration of findings from clinical history, kidney biopsy, laboratory values, and, increasingly, genetic testing. Both MCD and FSGS are histological lesions in the broad spectrum of podocytopathies. However, in these morphologic descriptions the podocyte injury can be caused by multiple pathological pathways4Wooin Ahn, Andrew S. Bomback. Approach to Diagnosis and Management of Primary Glomerular Diseases Due to Podocytopathies in Adults: Core Curriculum 2020. American Journal of Kidney Disease 2020;75(6):955-964.Google Scholar (Figure 1). Moving forward from histological description to an etiologic classification would offer clear benefits, not only at the diagnostic level, but especially in therapeutic management and long-term prognosis improvement. The development of biomarkers with high sensitivity and specificity to discriminate the different pathogeneses of podocytopathies therefore remains a holy grail. Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases like atypical hemolytic uremic syndrome or C3 glomerulopathy, with clear therapeutic implications. However, in MCD and FSGS, complement-level data from studies analyzing plasma, urine, and kidney biopsies, both in patients and animal models5Han R. Hu S. Qin W. et al.C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis.JCI Insight. 2019; 4e122912Crossref Scopus (3) Google Scholar,6Trachtman H. Laskowski J. Lee C. et al.Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.Am J Physiol Renal Physiol. 2021; 321: F505-f516Crossref Scopus (11) Google Scholar, is limited and can be confounded by other phenotypic variation (infections, drugs, etc). In this issue, Cambier et al.7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar analyzed urinary terminal complement components - membrane attack complex (MAC, C5b-9), cytolytic effectors of innate and adaptative immunity, and C5a, a potent anaphylatoxin and chemotactic agent - as potential biomarkers for different podocytopathies. Fifty-six subjects with biopsy proven MCD (n=15) or FSGS (n=41) and proteinuria > 1 g/g creatinine were recruited in 4 Canadian hospitals from 2006 to 2023. Compared to FSGS, MCD patients were younger at the time of urinary sampling (33±22 vs 48±19 years, p=0.02), with higher eGFR (99±32 vs 53±37 mL/min/1.73m2Floege J. Amann K. Primary glomerulonephritides.Lancet. 2016; 387: 2036-2048Abstract Full Text Full Text PDF PubMed Google Scholar, p<0.001), lower albuminemia (22±9 vs 31±10 g/L, p=0.002), and lower proteinuria (3.1 vs 5.1 g/g, p=0.40). FSGS patients were classified as primary disease in up to 58% of cases (24/41); 2 were drug-induced, 1 genetic, 1 maladaptive (previous different GN), and 13 uncertain cause. All MCD subjects achieved complete remission with preserved kidney function, while only 25/41 (60.9%) FSGS subjects experienced partial remission (with frequent relapses) and 15/41 developed kidney failure. Kidney biopsies were reviewed by a blinded nephropathologist within a median of 2 (0-18) months from urinary sampling. Five subjects with glomeruli showing only adhesions but no evidence of segmental sclerosis were classified as a “potential FSGS.” In addition, histology also evaluated interstitial fibrosis and tubular atrophy (IFTA), arteriosclerosis and arteriolar hyalinosis (scaled 0 to 3+), and foot process effacement (FPE) by EM (diffuse ≥ 75% versus segmental < 75%). In the analysis of complement factors, FSGS subjects presented higher urinary MAC (C5b-9) levels (8.7 μg/mmol of creatinine) than MCD cases (0.8 μg/mmol of creatinine; p <0.001). Likewise, higher levels of MAC were found in primary FSGS (12.5 μg/mmol of creatinine) compared to those considered secondary or of undetermined cause (4.8 μg/mmol of creatinine), although the difference was not statistically significant (p=0.09). Urinary MAC threshold > 2 μg/mmol of creatinine in the entire cohort was 73% sensitive and 93% specific for FSGS, increasing its sensitivity up to 93% in cases with proteinuria ≥ 3g/g creatinine. FSGS patients also showed significantly higher urinary levels of C5a (1.26 μg/mmol of creatinine) compared to MCD patients (0.06 μg/mmol of creatinine; p<0.001), with high sensitivity and specificity. Cambier et al.7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar propose these results support a role of complement activation in the pathogenesis of FSGS and, consequently, a potential therapeutic intervention. The search for pathophysiological mechanisms and new therapeutic targets in diseases without specific treatments is undoubtedly a crucial driving force for investigations like theirs. However, enthusiasm should not outweigh caution. First, in the present cohort, the FSGS population is significantly older, and many patients already had advanced chronic kidney disease (CKD: 5 patients stage G3a; 15 patients stage G3b; 7 patients stage G4; and 3 patients stage G5) compared to MCD subjects. Additionally, in the FSGS group, several patients had borderline or normal albuminemia, proteinuria less than 3 g/g creatinine, and higher histological chronicity findings (IFTA, arteriosclerosis and arteriolar hyalinosis) than MCD patients (11/15 showed no chronic changes). Furthermore, the patients with secondary FSGS had higher urinary complement component levels than MCD cases. Do terminal complement components in the urine reflect the activity of FSGS lesions or are they just reflective of the severity and chronicity of kidney injury? To reduce these confounding factors, investigations like this should aim to study populations with FSGS and MCD balanced by age and kidney function. In this observational study7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar, the authors reported no urinary complement activation in MCD subjects. However, previous studies6Trachtman H. Laskowski J. Lee C. et al.Natural antibody and complement activation characterize patients with idiopathic nephrotic syndrome.Am J Physiol Renal Physiol. 2021; 321: F505-f516Crossref Scopus (11) Google Scholar showed an increase in blood and urinary C4a levels in patients with nephrotic syndrome compared to healthy controls (with no differences between patients with MCD and FSGS). Urinary C5b-9 levels were higher in patients with nephrotic syndrome (part of NEPTUNE cohort) and trended higher in 15 pediatric patients with idiopathic nephrotic syndrome (validation cohort). These prior studies8Yoshiki Morita, Hiroshi Ikeguchi Jiro Nakamura, et al. Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol 2000;11(4):700-707.Google Scholar suggest that the degree of urinary complement fragments could be a nonspecific result of plasma complement proteins spilling into the urinary space and may be influenced by impairment of kidney function, level of proteinuria, and metabolic acidosis. Complement activation frequently occurs in physiological situations, is not harmful in all conditions, and is most frequently self-limiting. A study of a larger cohort of patients, with inclusion of patients with different clinical presentations (steroid-resistant and steroid-responsive nephrotic syndrome) and degrees of kidney damage, alongside inclusion of a control group, would allow a better assessment of the potential role of complement activation in the podocytopathies. Because glomerular diseases are dynamic processes, the time between biopsy and urinary complement components collection should be as short as possible when evaluating the possible correlation between histology and biomarkers. Finally, a prospective study of the evolution of complement-level biomarkers, reflecting the patient's clinical parameters and treatments received, could allow greater opportunities to evaluate a biomarker's ability to predict outcome. The search for new biomarkers in podocytopathies is crucial and will offer better pathophysiological knowledge of these entities and improvements in the diagnostic process that, hopefully, allow the development of novel therapeutic targets to improve kidney outcomes. The work by Cambier et al.7Alexandra Cambier, Natacha Patey, Virginie Royal et al. Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease: a Prospective study. Kidney International Reports – In press.Google Scholar is a valuable contribution to this field in promoting the hypothesis that complement is implicated in FSGS development. Nevertheless, more studies are necessary in a broader population of podocytopathy patients, at varying time points of the disease course, before we can move beyond interesting studies like this towards therapeutic trials of complement-targeting therapies. Download .pdf (.09 MB) Help with pdf files A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change DiseaseKidney International ReportsPreviewMinimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown. Full-Text PDF Open Access

<h2>Abstract</h2> C3 glomerulopathy is a rare disease caused by fluid phase dysregulation of the alternative complement pathway. Currently, treatment depends on clinical and histological severity and includes nephroprotection, unspecific immunosuppression and terminal complement blockers (C5), without having an etiological treatment approved. C3 glomerulopathy has high recurrence rates after kidney transplantation with a high risk of graft loss. Fortunately, new molecules are being developed that specifically target the proximal alternative complement pathway, such as iptacopan, a factor B inhibitor which showed promising results in native kidneys and cases of transplant recurrence in a phase-II clinical trial. We present two "real world" cases of C3 glomerulopathy recurrence in kidney allograft treated with iptacopan, with initial excellent clinical response and safety profile, especially with early introduction. We also present follow-up biopsies that showed no C3 deposition during factor B inhibition. Our cases suggest that proximal blockade of the alternative complement pathway can be effective and safe in the treatment of C3 glomerulopathy recurrence in kidney transplantation, bringing other questions such as dual blockade (e.g., in C3 and C5), the optimal patient profile to benefit from factor B inhibition or treatment duration and its potential use in other forms of membranoproliferative glomerulonephritis (e.g., immune-complex mediated).

For some hypertensive patients, conventional blockade of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers does not adequately protect against target organ damage. This may be particularly true for hypertensive patients with obesity, a condition often associated with elevated aldosterone levels.We conducted a pre-post study of fixed, low-dose spironolactone (12.5 mg/d), added to chronic ACE inhibitor-based antihypertension regimens, in obese subjects with essential hypertension and preexistent target organ damage. Outcomes of interest were changes in blood pressure (office, 24-h, and nocturnal), urinary albumin excretion, and potassium.21 subjects with mean age 57.3 +/- 7.1 years, BMI 32.4 +/- 3.4 kg/m2 and 12.0 +/- 7.0 years of antihypertensive therapy were enrolled. The mean aldosterone level before spironolactone treatment was 10.1 +/- 7.3 ng/dl, and over 40% of subjects had baseline levels greater than mean population levels. During 4 weeks of low-dose spironolactone, mean office (110.6 +/- 7.8 to 105.0 +/- 8.1 mmHg, p = 0.004), 24-hour ambulatory (100.6 +/- 9.4 to 95.5 +/- 7.1 mmHg, p = 0.03) and nocturnal (95.3 +/- 11.5 to 87.5 +/- 8.2, p = 0.004) blood pressures all declined significantly. Log urine albumin : creatinine ratios also significantly dropped during spironolactone treatment (p = 0.002); in multivariate analysis, this decline did not appear to be due to changes in blood pressure but was influenced by concomitant changes in estimated glomerular filtration rate. Both the reductions in blood pressure and albumin excretion reversed after withdrawal of spironolactone. Serum potassium levels were essentially unchanged by low-dose spironolactone (p = 0.9).A fixed, low-dose of spironolactone, added to chronic ACE inhibitor therapy, reduced blood pressure and urinary albumin excretion in obese subjects with hypertension and preexistent target organ damage. A relative hyperaldosteronism due to aldosterone escape and/or obesity may explain the beneficial effects of spironolactone therapy in this study.

Sodium loading, and subsequent volume expansion, suppresses aldosterone levels in individuals with normal renal function. We hypothesised that loss of renal function impairs this volume-aldosterone relationship.With multifrequency bioimpedance spectroscopy, we measured total body water (TBW), extracellular volume (ECV), and intracellular volume in five haemodialysis patients at varied states of hydration and in five healthy volunteers during low-, normal-, and high-salt diets. Serum aldosterone, potassium, and C-reactive protein were measured simultaneously. Scatterplots and general estimating equations were used to examine the relationship among these variables.In healthy volunteers with salt loading, and in haemodialysis subjects with increased inter-dialytic weight gain, expansion of ECV led to reciprocal declines in serum aldosterone concentrations. The relationship was more profound in healthy volunteers (p<0.001) than in haemodialysis subjects (p=0.1). Notably, haemodialysis subjects posted consistently higher levels of ECV (median 49.6% TBW, IQR 43.9-51.8% compared to 41.1%, 39.9-42.8% in volunteers) and serum aldosterone (median 26.7 ng/dl, IQR 19.8-29.6 compared to 12.4 ng/dl, 8.8-16.0 in volunteers). Serum potassium did not appear to influence aldosterone concentration (p=0.9).The shift of the volume-aldosterone curve in haemodialysis subjects suggests that end-stage kidney disease is a state of high volume and inappropriately high aldosterone. These data have important clinical implications, as dialysis patients may benefit from both volume reduction and mineralocorticoid receptor blockade.