Publications by authors named "Gerald Appel"

131 Publications

Post-COVID-19 vaccination IgA Vasculitis in an Adult.

J Cutan Pathol 2021 Nov 14. Epub 2021 Nov 14.

Department of Dematology, Yale University School of Medicine.

Leukocytoclastic vasculitis has been reported in the setting of COVID-19 infection and post-COVID-19 vaccination. We report a case of post-COVID-19 vaccination IgA vasculitis with IgA immune deposits in the skin and renal involvement; SARS-CoV spike protein immunohistochemical staining was negative. IgA vasculitis with skin and renal involvement is a potential reaction to COVID-19 vaccination. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/cup.14168DOI Listing
November 2021

Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Am J Kidney Dis 2021 Sep 24. Epub 2021 Sep 24.

University of Toronto, Toronto, Canada.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents a myriad of 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 anti-complement therapy trials either planned or underway, the National Kidney Foundation (NKF) facilitated an all-virtual format 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 anti-complement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, subject 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.
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http://dx.doi.org/10.1053/j.ajkd.2021.07.025DOI Listing
September 2021

Anti-neutrophil cytoplasmic antibody associated glomerulonephritis complicating treatment with hydralazine.

Kidney Int 2021 08 20;100(2):440-446. Epub 2021 Apr 20.

Department of Pathology, Columbia University Irving Medical Center, New York, New York, USA.

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.
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http://dx.doi.org/10.1016/j.kint.2021.03.029DOI Listing
August 2021

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome.

Am J Nephrol 2021 31;52(3):180-189. Epub 2021 Mar 31.

Renal Associates PA, San Antonio, Texas, USA.

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome.

Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR.

Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy.

Discussion/conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.
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http://dx.doi.org/10.1159/000513777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220919PMC
March 2021

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

Am J Kidney Dis 2021 09 26;78(3):340-349.e1. Epub 2021 Mar 26.

Departments of Population Health Sciences and Internal Medicine, University of Utah, Salt Lake City, UT.

Rationale & Objective: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope.

Study Design: Individual patient-level meta-analysis.

Setting & Study Populations: Individual data of 1,037 patients from 12 randomized trials.

Selection Criteria For Studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome.

Analytical Approach: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria.

Results: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years.

Limitations: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions.

Conclusions: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.
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http://dx.doi.org/10.1053/j.ajkd.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384669PMC
September 2021

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

Pediatr Nephrol 2021 09 1;36(9):2747-2757. Epub 2021 Mar 1.

Division of Pediatric Nephrology, Brenner Children's Hospital, Wake Forest University, Winston Salem, NC, USA.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging.

Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes.

Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features.

Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
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http://dx.doi.org/10.1007/s00467-021-04990-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524347PMC
September 2021

Familial Fibrillary Glomerulonephritis in Living Related Kidney Transplantation.

Kidney Int Rep 2021 Jan 31;6(1):239-242. Epub 2020 Oct 31.

Department of Medicine, Nephrology, Columbia University Irving Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783556PMC
January 2021

Concurrent Anti-Glomerular Basement Membrane Antibody Disease and Membranous Nephropathy: A Case Series.

Am J Kidney Dis 2021 08 7;78(2):219-225.e1. Epub 2021 Jan 7.

Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY. Electronic address:

Rationale & Objective: 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.

Study Design: Case series.

Setting & Participants: Twelve patients referred to 1 medical center between 2001 and 2019 with anti-GBM disease and MN whose clinical characteristics and course were described.

Results: 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 A receptor (PLAR) 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.

Limitations: Incomplete testing for PLAR in biopsy and serum, limited sample size, and lack of uniform treatment regimen.

Conclusions: 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.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.023DOI Listing
August 2021

The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network.

Clin Kidney J 2020 Aug 5;13(4):597-606. Epub 2019 Aug 5.

Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS).

Methods: FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied.

Results: There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P = 0.02) and mobility (-4.2, P = 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P = 0.009) and anxiety (-2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P  0.03).

Conclusions: PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.
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http://dx.doi.org/10.1093/ckj/sfz092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467600PMC
August 2020

Mycophenolate Mofetil Treatment of C3 Glomerulopathy.

Clin J Am Soc Nephrol 2020 09 19;15(9):1234-1236. Epub 2020 Aug 19.

Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York

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http://dx.doi.org/10.2215/CJN.11740720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480544PMC
September 2020

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

Am J Kidney Dis 2020 09 28;76(3):374-383. Epub 2020 Apr 28.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.

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.
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http://dx.doi.org/10.1053/j.ajkd.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483441PMC
September 2020

How COVID-19 Has Changed the Management of Glomerular Diseases.

Clin J Am Soc Nephrol 2020 06 24;15(6):876-879. Epub 2020 Apr 24.

The Center for Glomerular Diseases, Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York City, New York.

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http://dx.doi.org/10.2215/CJN.04530420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274282PMC
June 2020

Pilot Study of Return of Genetic Results to Patients in Adult Nephrology.

Clin J Am Soc Nephrol 2020 05 16;15(5):651-664. Epub 2020 Apr 16.

Division of Nephrology, Department of Medicine, Columbia University, New York, New York

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, & 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.
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http://dx.doi.org/10.2215/CJN.12481019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269209PMC
May 2020

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Nat Commun 2020 03 30;11(1):1600. Epub 2020 Mar 30.

Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.

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) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10 and OR = 3.39, P = 5.2 × 10, 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.
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http://dx.doi.org/10.1038/s41467-020-15383-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105485PMC
March 2020

Antigens, antibodies, and membranous nephropathy: a decade of progress.

Kidney Int 2020 01;97(1):29-31

Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. Electronic address:

Membranous nephropathy (MN) is either primary or associated with various etiologies, each with unique glomerular antigens. The discovery of the phospholipase A2 receptor (PLA2R) antigen in primary MN revolutionized our understanding of MN and led to major clinical progress. Other recently discovered antigens in MN include the THSD7A antigen and exostosin. Sethi et al. have now identified a new antigen, NELL-1, in primary MN, again decreasing the number of patients whose antigen remains unknown.
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http://dx.doi.org/10.1016/j.kint.2019.10.009DOI Listing
January 2020

Clinicopathologic Assessment of Monoclonal Immunoglobulin-associated Renal Disease in the Kidney Allograft: A Retrospective Study and Review of the Literature.

Transplantation 2020 07;104(7):1341-1349

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.

Background: Monoclonal immunoglobulin (MIg)-associated renal disease (MIgARD) comprises a group of disorders caused by direct deposition of paraproteins in the kidney. Allograft MIgARD is infrequently encountered and poorly characterized.

Methods: First, we assessed our allograft biopsies diagnosed with MIgARD between 2007 and 2018. The cohort included the following 26 patients: proliferative glomerulonephritis with MIg deposits (PGNMID) (n = 13), AL amyloidosis (n = 5), light chain deposition disease (n = 5), light chain proximal tubulopathy (n = 2), and light chain cast nephropathy (n = 1). Second, we conducted a literature review to evaluate the rare non-PGNMID entities. We identified 20 studies describing 29 patients that were added to our cohort (total n = 42).

Results: Part 1: Patients' median age was 55 years; 31% were women, and 19% were blacks. Twelve patients (46%) lost their grafts at a median of 8 months after diagnosis. Compared to non-PGNMID, PGNMID patients had lower frequency of detectable paraproteins (31% versus 92%, P = 0.004) and hematologic neoplasms (23% versus 77%, P = 0.02). Within PGNMID group, 6 patients changed their apparent immunofluorescence phenotype between monotypic and polytypic, while all 3 patients with hematologic neoplasms had substructure on electron microscopy. Part 2: Whereas light chain cast nephropathy occurred the earliest and had the worst graft survival, AL amyloidosis occurred the latest and had the best graft survival.

Conclusions: MIgARD in the kidney allograft is associated with poor prognosis. While posttransplant PGNMID can change its apparent clonality by immunofluorescence supporting oligoclonal immune responses, the presence of deposit substructure is an important indicator of underlying hematologic neoplasm. Non-PGNMID are often associated with hematologic neoplasms and varied prognosis.
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http://dx.doi.org/10.1097/TP.0000000000003010DOI Listing
July 2020

Contributions of Rare Gene Variants to Familial and Sporadic FSGS.

J Am Soc Nephrol 2019 09 15;30(9):1625-1640. Epub 2019 Jul 15.

Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;

Background: Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases.

Methods: To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes.

Results: We validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as "causal" if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include , , and . Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes.

Conclusions: Although our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported "disease-causing" variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.
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http://dx.doi.org/10.1681/ASN.2019020152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727251PMC
September 2019

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.

N Engl J Med 2019 07;381(1):36-46

From the Mayo Clinic, Rochester, MN (F.C.F., S.S., J.C.L., S.B.E., N.L.); Columbia University (G.B.A., P.A.C., J.R.) and the New York University Medical Center (L.B.-L.) - both in New York; the University of British Columbia, Division of Nephrology, Vancouver (S.J.B.), the University Health Network, Toronto General Hospital (C.A.-C., H.N.R., D.C.C.), the Faculty of Community Services, Ryerson University (H.B.), and the Sunnybrook Health Science Centre (M.H.), the Applied Health Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital (D.K.L., B.R.C., P.J.), and the Department of Medicine and Institute of Health Policy, Management, and Evaluation, University of Toronto (B.R.C., P.J.), Toronto, and Centre Hospitalier Universitaire de Québec, Quebec, QC (D.P.) - all in Canada; Ohio State University, Columbus (B.H.R., L.A.H., S.V.P.); Stanford University, Stanford, CA (R.A.L.); the Mayo Clinic, Jacksonville (N.A.), and Florida International University, Miami (D.F.G.) - both in Florida; the University of Washington Medical Center, Seattle (J.A.J.); the University of Michigan Medical Center, Ann Arbor (P.E.G., D.S.G.); the University of Alabama at Birmingham, Birmingham (D.V.R.); Case Western Reserve University (J.R.S.) and the Cleveland Clinic (J.F.S.) - both in Cleveland; Kansas University Medical Center, Kansas City (E.T.M.); Manchester University, Manchester, United Kingdom (P.B.); Washington University School of Medicine, St. Louis (T.L.); the Mayo Clinic, Scottsdale (L.F.T.), and the University of Arizona, Tucson (A.N.S.) - both in Arizona; the University of Mississippi Medical Center, Jackson (L.A.J.); and the Medical College of Wisconsin, Froedtert Hospital, Milwaukee (S.S.B.).

Background: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.

Methods: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.

Results: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06).

Conclusions: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).
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http://dx.doi.org/10.1056/NEJMoa1814427DOI Listing
July 2019

C3 glomerulopathy - understanding a rare complement-driven renal disease.

Nat Rev Nephrol 2019 03;15(3):129-143

Molecular Otolaryngology and Renal Research Laboratories and the Departments of Internal Medicine and Pediatrics (Divisions of Nephrology), Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.
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http://dx.doi.org/10.1038/s41581-018-0107-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876298PMC
March 2019

Diagnostic Utility of Exome Sequencing for Kidney Disease.

N Engl J Med 2019 01 26;380(2):142-151. Epub 2018 Dec 26.

From the Departments of Medicine (E.E.G., M.M., H.M.-R., Y.L., J.Z., J.N., P.K., W.Y.L., A.M., S. Piva, B.H.K., D.C., R.R., D.B., M.D., H.S., X.M., K.M., O.B., J.R., P.C., G.B.A., A.S.B., W.A., D.J.C., R.J.C., G.K.D., M.K.R., S.M., S.S.-C., K.K., A.G.G.) and Pediatrics (N.S.U.), Division of Nephrology, the Departments of Pathology (V.S.A.), Biomedical Informatics (D.A.F., C.W.), and Urology (S.A.), the Institute for Genomic Medicine (S.K., B.C., Z.R., J.B., C.D.M., C.M.M., N.D., D.B.G., A.G.G.) and the Department of Genetics and Development (D.B.G.), Hammer Health Sciences, and the Department of Epidemiology, Mailman School of Public Health (S.M.), Columbia University, New York; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, Innovative Medicines and Early Development (IMED) Biotech Unit, Cambridge, United Kingdom (S.C.-C., S. Petrovski, C.H., J.F., R.M., A.P.); and the Department of Medical Science, Renal Unit, Uppsala University Hospital, Uppsala, Sweden (B.C.F.).

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.).
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http://dx.doi.org/10.1056/NEJMoa1806891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510541PMC
January 2019

Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study.

Kidney Int Rep 2018 Nov 3;3(6):1373-1384. Epub 2018 Aug 3.

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Introduction: 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.

Methods: 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.

Results: 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,  < 0.001), more frequently white (89.7% vs. 78.9%,  = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m,  < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl,  < 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%,  < 0.001).

Conclusion: 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.
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http://dx.doi.org/10.1016/j.ekir.2018.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224619PMC
November 2018

Kidney Transplantation in C3 Glomerulopathy: A Case Series.

Am J Kidney Dis 2019 03 7;73(3):316-323. Epub 2018 Nov 7.

Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.

Rationale & Objective: 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.

Study Design: Case series of C3G.

Setting & Participants: 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.

Results: 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.

Limitations: Incomplete testing for complement pathway abnormalities and genetic defects, incomplete records of HLA antigen matching, lack of centralized biopsy review, and limited sample size.

Conclusions: 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.
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http://dx.doi.org/10.1053/j.ajkd.2018.09.002DOI Listing
March 2019

Effects of bardoxolone methyl on body weight, waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease.

J Diabetes Complications 2018 Dec 13;32(12):1113-1117. Epub 2018 Sep 13.

Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, DK-2820, Gentofte, Denmark. Electronic address:

Aims: Obesity is associated with progression of chronic kidney disease (CKD). Treatment with bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with bardoxolone methyl.

Methods: Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to <30 mL/min/1.73 m) were randomized 1:1 to receive once-daily oral dose of bardoxolone methyl (20 mg) or placebo.

Results: BEACON enrolled 2185 patients. Patients randomized to bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (-5.7 kg; 95% CI: -6.0 to -5.3 kg; p < 0.001). In patients randomized to bardoxolone methyl, rate and magnitude of body weight loss were proportional to baseline BMI. Bardoxolone methyl resulted in significant reductions in waist circumference and improved glycemic control.

Conclusions: Bardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.
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http://dx.doi.org/10.1016/j.jdiacomp.2018.09.005DOI Listing
December 2018

C3 Glomerulopathy: A New Disease Comes of Age.

Authors:
Gerald B Appel

Mayo Clin Proc 2018 08;93(8):968-969

Columbia University Medical Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.mayocp.2018.06.014DOI Listing
August 2018

modifies -induced kidney disease risk.

Proc Natl Acad Sci U S A 2018 03 12;115(13):3446-3451. Epub 2018 Mar 12.

Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215;

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with We performed an admixture mapping study to identify genetic modifiers of -associated kidney disease. Individuals with two risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the locus correlates with lower levels of expression. In cell-based experiments, the disease-associated alleles (known as G1 and G2) lead to increased abundance of mRNA but to decreased levels of protein. gene expression inversely correlates with G1 and G2 -mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both and , which interact in a functionally important manner. UBD appears to mitigate -mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in and expression appear to modify the -associated kidney phenotype.
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http://dx.doi.org/10.1073/pnas.1716113115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879665PMC
March 2018

Treatment of Rapidly Progressive Glomerulonephritis in the Elderly.

Blood Purif 2018 26;45(1-3):208-212. Epub 2018 Jan 26.

As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.
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http://dx.doi.org/10.1159/000485367DOI Listing
February 2019

Mycophenolate Mofetil in Combination with Steroids for Treatment of C3 Glomerulopathy: A Case Series.

Clin J Am Soc Nephrol 2018 03 11;13(3):406-413. Epub 2018 Jan 11.

Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York; and.

Background And Objectives: 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.

Design, Setting, Participants, & Measurements: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.2215/CJN.09080817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967675PMC
March 2018

C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy.

Kidney Int 2018 04 6;93(4):977-985. Epub 2018 Jan 6.

Department of Medicine, Division of Nephrology, Columbia University College of Physicians and Surgeons, New York, New York, USA.

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.
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http://dx.doi.org/10.1016/j.kint.2017.10.022DOI Listing
April 2018

Whole-Exome Sequencing in Adults With Chronic Kidney Disease: A Pilot Study.

Ann Intern Med 2018 01 5;168(2):100-109. Epub 2017 Dec 5.

From Columbia University, New York, New York; VU University Medical Center, Amsterdam, the Netherlands; Nephrology Associates, Newark, Delaware; Krysiewicza Children's Hospital, Poznań, Poland; Poznań University of Medical Sciences and Center for Medical Genetics GENESIS, Poznań, Poland; IRCCS Giannina Gaslini Children's Hospital, Genova, Italy; IRCCS San Raffaele Scientific Institute, Milan, Italy; New York University School of Medicine, New York, New York; University of Texas Southwestern Medical Center, Dallas, Texas; and French Institute of Health and Medical Research (INSERM) U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, and Necker Hospital, Paris, France.

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.
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http://dx.doi.org/10.7326/M17-1319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947852PMC
January 2018
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