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.
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.
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.
Adult-onset nephrotic syndrome (NS) differs from its pediatric counterpart in several important ways. Most importantly, NS in adults is more etiologically heterogeneous compared to children, and thus ...treatment approaches rely heavily on the histological diagnosis provided by renal biopsy. The evidence-based approach to treatment of adult NS has been critically examined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in glomerulonephritis, published in 2012. Here, we examine the strengths and limits of those guidelines and review recent work that expands the evidence-based approach.
IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infections and food antigens, including wheat gluten, have been proposed as potential contributing ...environmental factors. Increased immune reactivity to gluten and/or association with celiac disease, an autoimmune disorder triggered by ingestion of gluten, have been reported in IgA nephropathy. However, studies are inconsistent about this association. We aimed to evaluate the proposed link between IgA nephropathy and celiac disease or immune reactivity to gluten by conducting a comprehensive analysis of associated serologic markers in cohorts of well-characterized patients and controls. Study participants included patients with biopsy-proven IgA nephropathy (n = 99), unaffected controls of similar age, gender, and race (n = 96), and patients with biopsy-proven celiac disease (n = 30). All serum specimens were tested for IgG and IgA antibodies to native gliadin and deamidated gliadin, as well as IgA antibody to transglutaminase 2 (TG2). Anti-TG2 antibody-positive nephropathy patients and unaffected controls were subsequently tested for IgA anti-endomysial antibody and genotyped for celiac disease-associated HLA-DQ2 and -DQ8 alleles. In comparison to unaffected controls, there was not a statistically significant increase in IgA or IgG antibody reactivity to gliadin in individuals with IgA nephropathy. In addition, the levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between IgA nephropathy patients and unaffected controls. Results of the additional anti-endomysial antibody testing and HLA genotyping were corroborative. The data from this case-control study do not reveal any evidence to suggest a significant role for celiac disease or immune reactivity to gluten in IgA nephropathy.
Some living donor kidneys are found to have biopsy evidence of chronic scarring and/or glomerular disease at implantation, but it is unclear if these biopsy findings help predict donor kidney ...recovery or allograft outcomes. Our objective was to identify the prevalence of chronic histological changes and glomerular disease in donor kidneys, and their association with donor and recipient outcomes.
Retrospective cohort study.
Single center, living donor kidney transplants from January 2010 to July 2022.
Chronic histological changes, glomerular disease in donor kidney implantation biopsies.
For donors, single-kidney estimated glomerular filtration rate (eGFR) increase, percent total eGFR loss, ≥40% eGFR decline from predonation baseline, and eGFR<60mL/min/1.73m2 at 6 months after donation; for recipients, death-censored allograft survival.
Biopsies were classified as having possible glomerular disease by pathologist diagnosis or chronic changes based on the percentage of glomerulosclerosis, interstitial fibrosis/tubular atrophy, and vascular disease. We used logistic regression to identify factors associated with the presence of chronic changes, linear regression to identify the association between chronic changes and single-kidney estimated glomerular filtration rate (eGFR) recovery, and time-to-event analyses to identify the relationship between abnormal biopsy findings and allograft outcomes.
Among 1,104 living donor kidneys, 155 (14%) had advanced chronic changes on implantation biopsy, and 12 (1%) had findings suggestive of possible donor glomerular disease. Adjusted logistic regression showed that age (odds ratio OR, 2.44 per 10 years 95% CI, 1.98-3.01), Hispanic ethnicity (OR, 1.87 95% CI, 1.15-3.05), and hypertension (OR, 1.92 95% CI, 1.01-3.64), were associated with higher odds of chronic changes on implantation biopsy. Adjusted linear regression showed no association of advanced chronic changes with single-kidney eGFR increase or relative risk of eGFR<60mL/min/1.73m2. There were no differences in time-to-death-censored allograft failure in unadjusted or adjusted Cox proportional hazards models when comparing kidneys with chronic changes to kidneys without histological abnormalities.
Retrospective, absence of measured GFR.
Approximately 1 in 7 living donor kidneys had chronic changes on implantation biopsy, primarily in the form of moderate vascular disease, and 1% had possible donor glomerular disease. Abnormal implantation biopsy findings were not significantly associated with 6-month donor eGFR outcomes or allograft survival.
Kidney biopsies are the gold standard test to identify the presence or absence of kidney disease. However, kidneys donated by healthy living donors—who are extensively screened for any evidence of kidney disease before donation—occasionally show findings that might be considered “abnormal,” including the presence of scarring in the kidney or findings suggestive of a primary kidney disease. We studied the frequency of abnormal kidney biopsy findings among living donors at our center. We found that about 14% of kidneys had chronic abnormalities and 1% had findings suggesting possible glomerular kidney disease, but the presence of abnormal biopsy findings was not associated with worse outcomes for the donors or their recipients.
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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