Search

Background and Objectives: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients., Design, Setting, Participants, & Measurements: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors., Results: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m 2 ; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival., Conclusions: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival., Design, Setting, Participants, & Measurements: Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan-Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score-adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy., Results: In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score-adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P =0.01; month 8: hazard ratio, 0.30; P =0.002)., Conclusions: Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018&#95;02&#95;20&#95;CJASNPodcast&#95;18&#95;3&#95;T.mp3., (Copyright © 2018 by the American Society of Nephrology.)

Background and Objectives: For many women pregnancy is the first contact with health services, thus providing an opportunity to identify renal disease. This study compares causes and long-term renal outcomes of biopsy-proven renal disease identified during pregnancy or within 1 year postpartum, with nonpregnant women., Design, Setting, Participants, & Measurements: Native renal biopsies (1997-2012), in women of childbearing age (16 to <50 years), from 21 hospitals were studied. The pregnancy-related diagnosis group included those women with abnormal urinalysis/raised creatinine identified during pregnancy or within 1 year postpartum. Pregnancy-related and control biopsies were matched for age and ethnicity (black versus nonblack)., Results: One hundred and seventy-three pregnancy-related biopsies (19 antenatal, 154 postpregnancy) were identified and matched with 1000 controls. FSGS was more common in pregnancy-related biopsies (32.4%) than controls (9.7%) ( P <0.001) but there were no differences in Columbia classification. Women with a pregnancy-related diagnosis were younger (32.1 versus 34.2 years; P =0.004) and more likely to be black (26.0% versus 13.3%; P <0.001) than controls, although there were no differences in ethnicities in women with FSGS. The pregnancy-related group (excluding antenatal biopsies) was more likely to have a decline in Chronic Kidney Disease Epidemiology Collaboration eGFR in the follow-up period than the control group (odds ratio, 1.67; 95% confidence interval, 1.03 to 2.71; P =0.04), and this decline appeared to be more rapid (-1.33 versus -0.56 ml/min per 1.73 m 2 per year, respectively; P =0.045). However, there were no differences between groups in those who required RRT or who died., Conclusions: Pregnancy is an opportunity to detect kidney disease. FSGS is more common in women who have been pregnant than in controls, and disease identified in pregnancy or within 1 year postpartum is more likely to show a subsequent decline in renal function. Further work is required to determine whether pregnancy initiates, exacerbates, or reveals renal disease., (Copyright © 2017 by the American Society of Nephrology.)

Background and Objectives: Dent disease is a rare X-linked disorder characterized by low molecular weight proteinuria and often considered a renal tubular disease. However, glomerulosclerosis was recently reported in several patients. Thus, Dent disease renal histopathologic features were characterized and assessed, and their association with kidney function was assessed., Design, Setting, Participants, & Measurements: Clinical renal pathology reports and slides (where available) were collected from 30 boys and men in eight countries who had undergone clinical renal biopsy between 1995 and 2014., Results: Median (25th, 75th percentiles) age at biopsy was 7.5 (5, 19) years with an eGFR of 69 (44, 94) ml/min per 1.73 m 2 and a 24-hour urine protein of 2000 (1325, 2936) mg. A repeat biopsy for steroid-resistant proteinuria was performed in 13% (four of 30) of the patients. Prominent histologic findings included focal global glomerulosclerosis in 83% (25 of 30; affecting 16%±19% glomeruli), mild segmental foot process effacement in 57% (13 of 23), focal interstitial fibrosis in 60% (18 of 30), interstitial lymphocytic infiltration in 53% (16 of 30), and tubular damage in 70% (21 of 30). Higher percentages of globally sclerotic glomeruli, foot process effacement, and interstitial inflammation were associated with lower eGFR at biopsy, whereas foot process effacement was associated with steeper annual eGFR decline., Conclusions: These associations suggest a potential role for glomerular pathology, specifically involving the podocyte, in disease progression, which deserves further study. Furthermore, Dent disease should be suspected in boys and men who have unexplained proteinuria with focal global glomerulosclerosis and segmental foot process effacement on renal biopsy., (Copyright © 2016 by the American Society of Nephrology.)

Background and Objectives: Idiopathic collapsing FSGS has historically been associated with poor renal outcomes. Minimal clinical data exist on the efficacy of immunosuppressive therapy. Our study sought to provide a comprehensive description of renal survival in patients with collapsing and not otherwise specified FSGS after controlling for factors affecting renal prognosis., Design, Setting, Participants, & Measurements: We performed a retrospective analysis of an inception cohort study of patients diagnosed between 1989 and 2012. All potential patients with collapsing FSGS fulfilling the inclusion criteria were identified and compared with patients with not otherwise specified FSGS (approximately 1:2 ratio) on the basis of biopsy report and record availability. Time to ESRD was analyzed using Cox proportional hazards models., Results: In total, 187 patients were studied (61 collapsing and 126 not otherwise specified), with a mean follow-up of 96 months. At baseline, patients with collapsing FSGS had higher median proteinuria (12.2 [5.6-14.8] versus 4.4 [2.3-8.1] g/d, respectively; P <0.001), lower median albuminemia (2.4 [1.9-3.0] versus 2.9 [1.8-3.7] g/dl, respectively; P =0.12), and lower median eGFR (48 [26-73] versus 60 [42-92] ml/min per 1.73 m 2 , respectively; P =0.01) than patients with not otherwise specified FSGS. The proportion of patients with remission of proteinuria was similar in patients with collapsing FSGS and patients with not otherwise specified FSGS (65.7% [23 of 35] versus 63.2% [72 of 114], respectively; P =0.84). The overall renal outcome (ESRD defined as eGFR<15 ml/min per 1.73 m 2 , dialysis, or transplantation) of patients with collapsing FSGS was not poorer than that of patients with not otherwise specified FSGS in multivariate analyses after adjusting for baseline characteristics and immunotherapy (hazard ratio, 1.78; 95% confidence interval, 0.92 to 3.45)., Conclusions: Compared with not otherwise specified FSGS, idiopathic collapsing FSGS presented with more severe nephrotic syndrome and lower eGFR but had a similar renal survival after controlling for exposure to immunosuppressive treatment. These results highlight the importance of early diagnosis and institution of immunosuppressive therapy in patients with collapsing FSGS., (Copyright © 2016 by the American Society of Nephrology.)

Background and Objectives: Glomerular IgM deposition is commonly shown in primary FSGS and sometimes accompanied by C3 deposition. Clinical presentation and treatment outcomes of these patients are not investigated in detail., Design, Setting, Participants, &measurements: One hundred six consecutive patients with biopsy-proven primary FSGS from 2004 to 2014 were enrolled retrospectively. Clinical features and treatment outcomes were compared between patients with and without IgM/C3 deposition., Results: Fifty-eight (54.7%) patients presented with IgM glomerular deposition on sclerotic segments. C3 and C1q depositions were shown exclusively in patients with IgM deposition (34.5% versus 0.0%; P<0.001 and 8.6% versus 0.0%; P=0.04, respectively). Patients with IgM deposition were younger (median; range: 24.5; 18.8-39.0 versus 46.5; 26.0-64.0 years old; P=0.001), had higher level of serum IgM (142.5; 96.3-206.0 versus 107.0; 71.0-140.0 mg/dl; P=0.01), and had higher level of eGFR (median; range 97.7; 48.0-135.8 versus 62.1; 33.7-93.9 ml/min per 1.73 m(2); P=0.01) at the time of kidney biopsy. The percentage of sclerosis lesions was significantly higher in patients with C3 deposition (median; range: 21.7%; 15.3%-31.1% versus 9.2%; 6.6%-20.0%; P=0.002). Although patients received comparable immunosuppressive treatments during 58.9 (29.5-81.1) months of follow-up, a significantly higher prevalence of refractory cases (no response or steroid dependent) occurred in patients with combined IgM and C3 deposition compared with patients with IgM deposition alone or without IgM deposition (58.8% versus 22.2% versus 15.6%, respectively; P=0.004). Multivariate analysis identified combined IgM and C3 deposition (odds ratio, 11.32; 95% confidence interval, 2.26 to 56.65; P=0.003) as an independent risk factor for refractory patients; 19 of 98 patients developed renal dysfunction when their serum creatinine levels increased >30% from baseline and reached >1.5 mg/dl. Combined IgM and C3 deposition (hazard ratio, 5.67; 95% confidence interval, 1.34 to 23.84; P=0.02) was identified as an independent risk factor for renal dysfunction., Conclusions: Patients with primary FSGS and IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes, which indicate that IgM and C3 deposition might involve disease progression via complement activation., (Copyright © 2016 by the American Society of Nephrology.)

Background and Objectives: The relationship of kidney function and CKD risk factors to structural changes in the renal parenchyma of normal adults is unclear. This study assessed whether nephron hypertrophy and nephrosclerosis had similar or different associations with kidney function and risk factors., Design, Setting, Participants, & Measurements: From 1999 to 2009, 1395 living kidney donors had a core needle biopsy of their donated kidney during transplant surgery. The mean nonsclerotic glomerular volume and glomerular density (globally sclerotic and nonsclerotic) were estimated using the Weibel and Gomez stereologic methods. All tubules were counted in 1 cm(2) of cortex to determine a mean profile tubular area. Nephron hypertrophy was identified by larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density. Nephrosclerosis was identified by higher globally sclerotic glomerular density., Results: The mean (± SD) age was 44 ± 12 years, 24-hour urine albumin excretion was 5 ± 7 mg, measured GFR was 103 ± 17 ml/min per 1.73 m(2), uric acid was 5.2 ± 1.4 mg/dl, and body mass index was 28 ± 5 kg/m(2). Of the study participants, 43% were men, 11% had hypertension, and 52% had a family history of ESRD. Larger glomerular volume, larger profile tubular area, and lower nonsclerotic glomerular density were correlated. Male sex, higher 24-hour urine albumin excretion, family history of ESRD, and higher body mass index were independently associated with each of these measures of nephron hypertrophy. Higher uric acid, higher GFR, and older age were also independently associated with some of these measures of nephron hypertrophy. Hypertension was not independently associated with measures of nephron hypertrophy. However, hypertension and older age were independently associated with higher globally sclerotic glomerular density., Conclusions: Nephron hypertrophy and nephrosclerosis are structural characteristics in normal adults that relate differently to clinical characteristics and may reflect kidney function and risk factors via separate but inter-related pathways., (Copyright © 2014 by the American Society of Nephrology.)

Background and Objectives: FSGS is the primary cause of childhood nephrotic syndrome leading to ESRD. Permeability factors, including circulating serum soluble urokinase-type plasminogen activator receptor (suPAR), have been postulated as putative causes in adults with primary FSGS. Similar results have yet to be proven in children., Design, Setting, Participants, & Measurements: This cross-sectional single-center study assessed the association of serum suPAR in children with FSGS or other glomerular and nonglomerular kidney diseases., Results: This study examined 110 samples retrieved from 99 individuals (between January 2011 and April 2012), aged 1-21 years; of these individuals, 20 had primary FSGS, 24 had non-FSGS glomerular disease, 26 had nonglomerular kidney disease, and 29 were healthy controls. suPAR levels were not significantly different in children with FSGS, non-FSGS glomerular disease, and healthy controls (P>0.05). However, suPAR levels (median [25%-75%]) were higher in children with nonglomerular kidney disease (3385 pg/ml [2695-4392]) versus FSGS (2487 pg/ml [2191-3351]; P<0.05). Female patients with nephrotic-range proteinuria (U-Pr/Cr >2) had lower suPAR levels than those without proteinuria (2380 pg/ml [2116-2571] versus 3125 pg/ml [2516-4198], respectively; P<0.001). This trend was not seen among male participants; suPAR levels in all female participants were lower than in male participants (P=0.03). Thirty-four patients studied were kidney transplant recipients; transplant status was not associated with suPAR levels in patients with FSGS or non-FSGS diagnoses, independent of proteinuria, race, or sex (P>0.05)., Conclusions: On the basis of these results, circulating suPAR is unlikely the leading cause for childhood idiopathic FSGS.

Background and Objectives: In the FSGS Clinical Trial, 22 cyclosporine-treated and 20 mycophenolate/dexamethasone-treated patients experienced a complete or partial remission after 26 weeks, completed 52 weeks of treatment, and were studied through 78 weeks. Herein, changes in the urine protein/creatinine ratio (UP/C) and estimated GFR (eGFR) throughout the entire study period are defined., Design, Setting, Participants, and Measurements: The FSGS Clinical Trial, which was conducted from November 2004 to January 2010, enrolled patients aged 2-40 years, with eGFR ≥40 ml/min per 1.73 m(2) and UP/C >1 mg/mg after ≥4 weeks of corticosteroid therapy. Both groups received lisinopril or losartan throughout the study. UP/C and eGFR were measured at 0, 26, 52, and 78 weeks., Results: The median UP/C in the cyclosporine- and mycophenolate/dexamethasone-responsive patients fell by 89.8% and 82.7% at 52 weeks; the fall was largely sustained at 78 weeks (74.7% and 80.3%, respectively). The mean eGFR fell by 19.4% in the cyclosporine group and rose by 7.0% in the mycophenolate mofetil/dexamethasone group at 52 weeks, but subsequently rose by 16.4% and fell by 2.6%, respectively, in the two groups from 52 to 78 weeks., Conclusions: In this subset of responding FSGS patients, the improvement in UP/C after cyclosporine or mycophenolate/dexamethasone treatment was largely sustained for 6 months after therapy. Reduction in eGFR in the cyclosporine group was improved 6 months after cyclosporine was stopped although the levels were lower than baseline in seven patients who entered the study with decreased eGFR.

Background and Objectives: Treatment with IFN is rarely associated with nephrotic syndrome and renal biopsy findings of minimal-change disease or FSGS., Design, Setting, Participants, & Measurements: We report 11 cases of collapsing FSGS that developed during treatment with IFN and improved after discontinuation of therapy., Results: The cohort consists of seven women and four men with a mean age of 48.2 yr. Ten of the 11 patients were black. Six patients were receiving IFN-alpha for hepatitis C virus infection (n = 5) or malignant melanoma (n = 1), three were receiving IFN-beta for multiple sclerosis, and two were treated with IFN-gamma for idiopathic pulmonary fibrosis. After a median and mean [corrected] duration of therapy of 4.0 and 12.6 months, respectively, patients presented with acute renal failure (mean creatinine 3.5 mg/dl) and nephrotic-range proteinuria (mean 24-hour urine protein 9.7 g). Renal biopsy revealed collapsing FSGS with extensive foot process effacement and many endothelial tubuloreticular inclusions. Follow-up was available for 10 patients, all of whom discontinued IFN. At a mean of 23.6 months, nine of 10 patients had improvement in renal function, including one with complete remission and two with partial remission. Among the seven patients with available data, mean proteinuria declined from 9.9 to 3.0 g/d. Four of the seven patients were treated with immunosuppression, and there was no detectable benefit., Conclusions: Collapsing FSGS may occur after treatment with IFN-alpha, -beta, or -gamma and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions. Optimal therapy includes discontinuation of IFN.

Background and Objectives: Isolated case reports have shown a beneficial effect of rituximab on pediatric patients with primary FSGS, but there is no information about rituximab treatment of FSGS in adults., Design, Setting, Participants, & Measurements: All patients who had biopsy-proven FSGS and were treated with rituximab in Spain were identified, independent of their positive or negative response, among the nephrology departments that belong to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Their characteristics and outcome after rituximab treatment were studied., Results: Eight patients were identified. Rituximab failed to improve nephrotic syndrome in five of eight patients, who continued to show massive proteinuria and exhibited a rapidly deteriorating renal function in two cases. Among the remaining three patients, two of them showed an improvement of renal function and a remarkable proteinuria reduction and one experienced a beneficial but transitory effect after rituximab. There were no differences in clinical or laboratory characteristics or in the CD20 B lymphocyte count after rituximab between these three patients and the five who had a negative response. The only difference was in the regimen of rituximab administration: Whereas the five patients with a negative response received only four weekly consecutive infusions of 375 mg/m(2), the three remaining patients received additional doses of rituximab., Conclusions: Only a minority (three of eight) of patients in our series of adult patients with FSGS showed a positive influence of rituximab. More studies are necessary to characterize further the optimal dosages and the mechanisms of action of rituximab in FSGS.

Background and Objectives: Patients with primary focal segmental glomerulosclerosis (FSGS) who are resistant to standard therapy are at high risk for progressive chronic kidney disease. Prevention of renal fibrosis represents a promising strategy to slow or halt kidney function decline. This paper presents the results of a Phase I clinical trial of rosiglitazone, a thiazolidinedione, that exerts antifibrotic effects in animal models of FSGS. The primary goal was assessment of safety, tolerability, and pharmacokinetics (PK) of rosiglitazone., Design, Setting, Participants, & Measurements: Eleven patients, including eight boys/men and three girls/women, with mean age 15 +/- 6 yr and estimated GFR 131 +/- 62 ml/min/1.73 m(2), received rosiglitazone, 3 mg/m(2)/d for 16 wk. PK was assessed twice, after the initial dose and after attaining steady state, in a General Clinical Research Center., Results: There were no serious adverse events or cardiovascular complications. Rosiglitazone was well tolerated by all patients, as judged by the Treatment Satisfaction Questionnaire for Medication. The PK studies indicated that the area under the curve was decreased by 40 to 50% and oral clearance of rosiglitazone was increased by 250 to 300% in patients with resistant FSGS compared with healthy controls and patients with nonproteinuric stage 2 chronic kidney disease., Conclusions: Rosiglitazone therapy was safe and well tolerated. PK assessment of potential novel therapies for resistant FSGS is necessary to define appropriate dosing regimens. There is rationale to evaluate the efficacy of rosiglitazone as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials.

Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis., Design, Setting, Participants, & Measurements: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m2, was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment., Results: The monthly change in GFR improved from a median of -0.61 ml/min per 1.73 m2 (interquartile range -1.31 to -0.41) during the baseline period to -0.45 ml/min per 1.73 m2 (interquartile range -0.78 to -0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis., Conclusions: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.

Recessive NPHS2 (podocin) mutations account for up to approximately 30% of steroid-resistant idiopathic FSGS in children and are associated with a reduced risk for disease recurrence after renal transplantation. R229Q, a missense variant that is present in 3.6% of the white population, has been implicated as a common disease-causing mutation. Given these clinical implications, we examined the role of NPHS2 mutations in a cohort of patients with adult-onset FSGS. We used denaturing HPLC to screen for heterozygous and homozygous gene variants in PCR-amplified DNA fragments that contained all exons and splice junctions of NPHS2. Bidirectional sequencing was performed to define all of the gene variants detected. With the use of the denaturing HPLC in a single-blind pilot study, 40 of 43 known NPHS2 mutations were detected from 22 pediatric patients with FSGS to establish a test sensitivity of 93%. This screen then was applied to 87 adult patients with idiopathic FSGS (15 steroid-sensitive, 63 steroid-resistant, and nine familial cases). In this latter cohort, compound heterozygous mutations were detected only in one patient with steroid-sensitive FSGS (R229Q and Q285fsX302) and no homozygous mutations. Overall, R229Q accounted for eight (80%) of ten of the putative mutant alleles that were detected in the study cohort. Contrary to the pediatric experience, recessive NPHS2 mutations are rare in this study population, suggesting that the pathogenesis of FSGS in adults may differ from that in children. These data do not support R229Q as a disease-causing mutation for steroid-resistant FSGS.