Recurrent Focal Segmental Glomerular Sclerosis Research Articles

Anti-nephrin autoantibodies: novel predictors of post-transplant recurrence of focal segmental glomerular sclerosis.

Post-transplant recurrence of focal segmental glomerular sclerosis (FSGS) is a major challenge in the field of kidney transplantation. Currently, the most reliable predictor of FSGS recurrence is disease recurrence in a previous allograft. Recent studies suggest a possible causal role of anti-nephrin autoantibodies in the primary disease (primary FSGS and minimal change disease), as well as post-transplant recurrence of FSGS. In this issue of Kidney International, Batal etal. evaluate pretransplant anti-nephrin autoantibodies as a specific predictor of FSGS recurrence and demonstrate colocalization of nephrin and punctate IgG in anti-nephrin-positive patients with disease recurrence.

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

#5677 UPAR ACTIVATION BY UPARANT INDUCED FUNCTIONAL AND STRUCTURAL RECOVERY OF PODOCYTES AFTER FSGS-SERUM DAMAGE

Abstract Background and Aims Idiopathic focal segmental glomerular sclerosis (FSGS) is characterized by progressive damage to the renal parenchyma leading to end-stage renal disease, frequent recurrence after kidney transplantation and no specific therapeutic intervention. Since the podocytes (PODO) are the principal target of FSGS injury, their protection could be an efficient, targeted therapy. In this context, we investigated a potential therapeutic approach based on a new peptide, UPARANT, capable of modulating the Urokinase-type plasminogen activator receptor (uPAR) on PODO. Method PODO were activated with 4% sera of 5 patients with recurrent FSGS for 48 h and then treated with 100 nM of UPARANT for 48 h. Proteins were then extracted for TMT proteomics. The Gene Ontology system database, valid for large-scale analysis, was used to identify the significantly enriched biological pathways and molecular functions. An in vitro model of a glomerular filtration barrier composed of PODO-endothelial co-culture was used to assess the change in filtration capacity by albumin (BSA) permeability test. The difference from baseline BSA percentage was measured after damage induced with sera from three FSGS patients and after 48 h of treatment with UPARANT. Results First, we found that UPARANT could counteract the BSA permeability induced by FSGS sera in the PODO-endothelial co-culture (P = .04, P = .03, and P = .02, respectively). The proteomic analysis of PODO indicated that UPARANT induced the positive regulation of plasma membrane repair mechanisms (Annexin 2 P = .007 and AHNAK P = .03); this process was strongly linked to the activation of molecular functions related to both S100 and calcium-dependent proteins. Moreover, UPARANT induced the overexpression of Endophilin-B1 (P = .02) and Vimentin (P = .02), both involved in the assembly and organization of the actin filament. Conclusion We demonstrated that UPARANT efficiently counteracts in vitro the effects of FSGS sera on PODO, leading to the recovery of the spatial organization of PODO, acting on the structural integrity of the plasma membrane and restoring cytoskeletal plasticity and dynamism. This might result in vivo in the protection of the integrity of the filtration barrier.

Can Kunxian Capsule, a Novel Tripterygium Preparation be Used as an Adjuvant Treatment of Early Recurrent Focal Segmental Glomerular Sclerosis After Renal Transplantation? A Case Report

Focal segmental glomerular sclerosis (FSGS) tends to recur after kidney transplantation, particularly when genetic testing is negative. Once the recurrence happens, the renal graft function can rapidly become impaired, following a massive urine protein loss. Despite intensive plasmapheresis and high-dose rituximab treatment, the complete remission rate remains below 50%. The Kunxian capsule, representing a new generation of tripterygium preparation, has shown promising results in controlling proteinuria in patients with IgA nephropathy. It is unclear whether Kunxian capsule treatment would also produce a favorable response in cases of FSGS recurrence. Here we report favorable results with this approach in a patient with early recurrent FSGS after kidney transplantation; we treated this patient successfully with a Kunxian capsule, a low dose of rituximab (200 mg), and reduced sessions of plasmapheresis. Complete remission, with a 90% reduction in total urine protein (0.81 g/24 h vs 8.3 g/24 h), was achieved within 2 weeks post-treatment. Of interest, the complete remission state in this patient has been maintained over 20 months with continuous administration of Kunxian capsules after the cessation of plasmapheresis. The potential mechanisms involved here include direct podocyte protection and the anti-inflammatory and immunosuppressive properties of triptolide in the Kunxian capsule. Our case may offer a new reference option for treating recurrent FSGS in the future.

P8.108: Therapeutic Plasma Exchange, Rituximab and Steroids in Pediatric Kidney Transplant Recipients With Early Recurrence of FSGS: A Single Large Pediatric Hospital Experience

Focal segmental glomerular sclerosis (FSGS) is the most common glomerular disease leading to end-stage renal disease (ESRD) in children. FSGS frequently recurs after kidney transplant and may cause graft failure. Therapeutic plasma exchange (TPE), rituximab and steroids have been used to treat post-transplant FSGS recurrence, but limited data is available to support their combined efficacy. We conducted a retrospective cohort study of all kidney transplant recipients at a single pediatric center between 2007 and 2018 to determine frequency of FSGS and early recurrence of nephrotic syndrome within 4 days of transplant. Primary outcome was graft survival and secondary outcome was remission of nephrotic syndrome. FSGS was the indication for renal transplant in 11% of cases(n=29). Of these, 24% of patients had early FSGS recurrence after transplant(n=7). Treatment was at the discretion of the treating physician, but generally included TPE, rituximab and steroids. Five responded; the other two returned to chronic dialysis. 22 patients without recurrence experienced 100% 1-year graft survival. For all FSGS recipients, including those with recurrence, 3-year graft survival was 94.4%. 5/7(71%) of recipients with recurrence achieved partial or full remission of nephrotic syndrome following treatment. This study, the largest to uniformly employ the combination of TPE, rituximab and high-dose steroids, supports the efficacy of this treatment for pediatric patients with FSGS recurrence.

Good outcomes after pediatric intraperitoneal kidney transplant.

Kidney transplantation in small children is technically challenging. Consideration of whether to use intraperitoneal versus extraperitoneal placement of the graft depends on patient size, clinical history, anatomy, and surgical preference. We report a large single-center experience of intraperitoneal kidney transplantation and their outcomes. We conducted a retrospective review of pediatric patients who underwent kidney transplantation from April 2011 to March 2018 at a single large volume center. We identified those with intraperitoneal placement and assessed their outcomes, including graft and patient survival, rejection episodes, and surgical or non-surgical complications. Forty-six of 168 pediatric kidney transplants (27%) were placed intraperitoneally in children mean age 5.5±2.3years (range 1.6-10years) with median body weight 18.2±5kg (range 11.4-28.6kg) during the study period. Two patients (4%) had vascular complications; 10 (22%) had urologic complications requiring intervention; all retained graft function. Thirteen patients (28%) had prolonged post-operative ileus. Eight (17%) patients had rejection episodes ≤6months post-transplant. Only one case resulted in graft loss and was associated with recurrent focal segmental glomerular sclerosis (FSGS). Two patients (4%) had chronic rejection and subsequent graft loss by 5-year follow-up. At 7-year follow-up, graft survival was 93% and patient survival was 98%. The intraperitoneal approach offers access to the great vessels, which allows greater inflow and outflow and more abdominal capacity for an adult donor kidney, which is beneficial in very small patients. Risk of graft failure and surgical complications were not increased when compared to other published data on pediatric kidney transplants.

Effective Treatment of a Post-renal Transplantation Patient with Early Recurrent Focal Segmental Glomerulosclerosis and Concomitant Hemolytic Uremic Syndrome, a Case Report

While recurrence of primary Focal Segmental Glomerular Sclerosis (FSGS) is common post renal transplantation (30%-80%), a concomitant presentation of hemolytic uremic syndrome (HUS) and recurrent FSGS has never been reported. In addition, treatment of recurrent FSGS and HUS post-renal transplantation is challenging; and usually individualized based on center's experience. Here, we reported a case of a pediatric patient with early recurrence of FSGS and concomitant HUS post-renal transplantation. This patient had a complete hematological and renal response following the administration of Eculizumab and Rituximab, respectively. Withdrawal of Tacrolimus as well as plasmapheresis did not improve kidney function. Therefore, we concluded that both Eculizumab and Rituximab could achieve remission in comparable cases when administered at fixed intervals.

ACTH Gel in Resistant Focal Segmental Glomerulosclerosis After Kidney Transplantation.

Treatment of focal segmental glomerular sclerosis (FSGS) after kidney transplantation is challenging with unpredictable outcomes. The objective was to investigate the use of adrenocorticotropic hormone (ACTH) analogue gel in kidney transplant recipients with de novo or recurrent FSGS resistant to therapeutic plasma exchange (TPE) and/or rituximab. We performed a retrospective review of cases of de novo or recurrent resistant FSGS at 2 large US transplant centers between April 2012 and December 2016. Proteinuria was measured by urine protein to creatinine ratio. We identified 20 cases of posttransplant recurrent and de novo FSGS resistant to conventional therapy with TPE and rituximab. Mean ± SD age was 49 ± 15.5 years, 14 (70%) were male, 13 (65%) were whites, and 8 (38%) had previous kidney transplants. Median (interquartile range) of recurrent and de novo FSGS was 3 (0.75-7.5) months posttransplant. The majority of patients, 15 (75%), received TPE as a treatment at the time of diagnosis and 10 (50%) received rituximab, which was started before the use of ACTH gel. There was a significant improvement of urine protein to creatinine ratio from a mean ± SD of 8.6 ± 7.6 g/g before ACTH gel to 3.3 ± 2.3 g/g after the use of ACTH gel (P = 0.004). Ten (50%) patients achieved complete or partial remission. Although, the response varied among the recipients, ACTH gel might be an effective therapy for posttransplant resistant FSGS cases that fail to respond to TPE and rituximab.

A case report of adrenocorticotropic hormone to treat recurrent focal segmental glomerular sclerosis post-transplantation and biomarker monitoring.

Background: Recurrent focal segmental glomerular sclerosis (rFSGS) in renal transplant recipients (RTR) is difficult to predict and treat. Early rFSGS is likely from circulating factors and preformed antibodies.Methods: We present the case of a 23-year-old white man who presented with rFSGS and acute renal failure, requiring dialysis 9-months after a 1-haplotype matched living-related transplant. We retrospectively analyzed serum samples from various clinical stages for rFSGS biomarkers: serum glomerular albumin permeability (Palb), soluble urokinase-type plasminogen activator receptor (suPAR) serum level with suPAR-β3 integrin signaling on human podocytes, and angiotensin II type I receptor-antibody (AT1R-Ab) titer.Results: All biomarkers were abnormal at 1-year pre-transplant prior to initiation of dialysis and at the time of transplant. After initiation of hemodialysis, β3 integrin activity on human podocytes, in response to patient serum, as well as AT1R-Ab were further elevated. At the time of biopsy-proven recurrence, all biomarkers were abnormally high. One week after therapy with aborted plasmapheresis (secondary to intolerance), and high dose steroids, the Palb and suPAR-β3 integrin activity remained significantly positive. After 12-weeks of treatment with high-dose steroids, rituximab, and galactose, the patient remained hemodialysis-dependent. Three-months after his initial presentation, we commenced adrenocorticotropic hormone (ACTH, Acthar® Gel), 80 units subcutaneously twice weekly. Four-weeks later, he was able to discontinue dialysis. After 8-months of maintenance ACTH therapy, his serum creatinine stabilized at 1.79 mg/dL with <1 g of proteinuria.Conclusion: ACTH therapy was associated with improvement in renal function within 4 weeks. The use of rFSGS biomarkers may aid in predicting development of rFSGS.

Glomerular disease recurrence in second and subsequent kidney transplants

Primary glomerular diseases such as primary focal segmental glomerular sclerosis (FSGS), IgA Nephropathy and membrano-proliferative glomerulonephritis (MPGN) may recur in renal transplants, and can potentially lead to graft failure. The rate of recurrence in second and subsequent renal transplants, following failure of the first graft due to recurrence, is unclear. A retrospective review of the Irish transplant database from 1982 to 2009 was performed. Patients were included for analysis if their first graft failed due to biopsy-confirmed recurrent glomerular disease (primary FSGS, IgA nephropathy or MPGN) and they underwent subsequent re-transplantation. 3,330 deceased and living renal transplants were performed during the time period in question. 33 patients had a deceased donor renal transplant following recurrence of primary FSGS, IgA nephropathy or MPGN causing first graft failure. Clinically significant disease recurrence was seen in 44% of re-transplants at 10 years. Median second graft survival in this group was 9.1 years. The median graft survival was 10.5 years for all other re-transplants performed in Ireland during the same time period. Clinically significant disease recurrence does not necessarily affect re-transplants following loss of the first graft to disease recurrence. Selected patients who experience first graft failure due to recurrent glomerular disease should not be precluded from receiving a second transplant.

Treatment of Recurrent Focal Segmental Glomerular Sclerosis Posttransplant With a Multimodal Approach Including High-Galactose Diet and Oral Galactose Supplementation

Treatment of Recurrent Focal Segmental Glomerular Sclerosis Posttransplant With a Multimodal Approach Including High-Galactose Diet and Oral Galactose Supplementation

Focal segmental glomerular sclerosis in renal transplant recipients: predicting early disease recurrence may prolong allograft function

Recurrence of focal segmental glomerular sclerosis (FSGS) in the allograft following renal transplantation can be graft threatening. To assess risk factors associated with FSGS recurrence, we analyzed 22 patients with FSGS who underwent transplantation between 1996 and 2004. Five patients (Group I, 23%) developed FSGS post-transplantation. Of these patients, 60% had undergone bilateral nephrectomy (BN) for progressive disease compared with none of the patients that were free of recurrence (Group II) (p = 0.0006). Other factors linked with recurrent FSGS were time to first dialysis (Group I: 3.1 +/- 1.1 yr vs. Group II: 11.9 +/- 1.9 yr; p = 0.03), pre-transplant proteinuria (Group I: 7.0 +/- 1.8 g/d vs. Group II: 2.5 +/- 0.7 g/d; p = 0.02), young age at transplantation (p = 0.09) and female sex (Group I: 80% vs. Group II: 24%; p = 0.021). Eighty percent of Group I patients received a living related transplant vs. 24% in Group II (p = 0.021). All grafts continue to function at last follow-up with comparable serum creatinines. Overall, post-transplant FSGS recurrence may be associated with BN, severity of pre-transplant FSGS, female gender, and living donation. These patients should be monitored closely for early recurrence and may benefit from early plasmapheresis to restore and facilitate long-term graft function.

Treatment of focal segmental glomerular sclerosis with rituximab: 2 case reports

Primary focal segmental glomerular sclerosis (FSGS) recurs in 20 - 40% of patients after kidney transplantation. Rituximab has been used to treat several glomerular diseases. We treated two renal-transplant patients with recurrence of FSGS with rituximab. Despite a prophylactic perioperative therapy of plasmapheresis (PE) and i.v. cyclosporine A, Patient 1 developed significant proteinuria, at 1 day after his first kidney transplantation. After two infusions of rituximab (375 mg/m2) he had complete remission. A second relapse, which occurred on Day 40, was also successfully treated by PE and one additional infusion of rituximab. 10 months after transplantation, he still has complete remission from recurrent nephrotic syndrome. Patient 2 also developed significant proteinuria, but 1 day after a second kidney transplantation. Nephrotic syndrome persisted despite 27 sessions of PE and cyclophosphamide therapy. At 13 months after transplantation, he received four infusions of rituximab (375 mg/m(2)), but this was ineffective. There is a need to demonstrate whether or not rituximab therapy is of interest to prevent and to treat nephritic syndrome in renal-transplant patients who suffer from FSGS.

Focal segmental glomerular sclerosis in kidney allograft recipients: an evidence-based approach

Focal segmental glomerular sclerosis (FSGS) causes kidney failure in 2.5% of all end-stage kidney disease patients. FSGS recurs in 20% to 30% of kidney allografts. In a third of kidney recipients with recurrent FSGS, graft loss is attributed to recurrent disease. Complicating the understanding of recurrent FSGS are the facts that (a) many patients with end-stage kidney disease do not undergo a kidney biopsy before transplant and (b) “de novo” FSGS is not uncommon after transplant, occurring in up to 30% of allografts. This review aims to clarify the definitions of recurrent FSGS and to identify risk factors for treatable recurrent FSGS. The pathophysiology of FSGS and therapeutic strategies from clinical trials are discussed.

34 Chronic Immunoadsorption/Plasma Exchange in Patients With Recurrence of Focal Segmental Glomerular Sclerosis After Kidney Transplantation

Background Recurrence of focal segmental glomerular sclerosis (FSGS) in a transplanted kidney can lead to graft failure. Membrane plasma exchange (PE) and immunoadsorption (IA) have been reported to be sometimes successful in preventing of FSGS recurrence in transplanted kidneys. The aim of the study is to evaluate the effect of chronic PE/IA on graft function in two transplanted patients with recurrence of FSGS in transplanted kidney.Methods A man, 45 years old, with biopsy proven FSGS in native kidneys was transplanted in January 2001. Soon after transplantation, recurrence of FSGS in transplanted kidney was observed and therefore several cycles of IA therapy were performed after transplantation. Since August 2001 he began chronic IA therapy every 3 weeks. Fresenius‐Excorim membrane plasma exchange monitor with PF 2000 plasmafilter, (Gambro), has been used. One volume of plasma was exchanged per PE. Vascular access was by AV fistula.A woman, 42 years old, with biopsy proven FSGS in native kidneys was transplanted in December 1998. Because of recurrence of FSGS in transplanted kidney she began (after several cycles of IA) with chronic IA in August 2001. Fresenius‐Excorim immunoadsorption monitor was used. One to 2 plasma volumes have been processed per session, and vascular access was by AV fistula.Results Daily proteinuria in the man decreased from 2.27 g in 2001 to 1.13 g in 2004 (50.2% decrease) and serum creatinine increased from 118 µmol/L to 130 µmol/L (9.2% increase).Daily proteinuria in the woman decreased from 3.89 g in 2001 to 2.0 g in 2004 (48% decrease) and serum creatinine increased from 96 µmol/L to 109 µmol/L (12% increase). PE/IA therapy was otherwise uneventful.Conclusions Chronic PE/IA therapy stabilized renal graft function and substantially diminished daily proteinuria. The man lived with kidney graft for more than 3.5 years and woman more than 5.5 years after recurrence of FSGS occurred.

High-dose oral cyclosporin therapy for recurrent focal segmental glomerulosclerosis in children

Background:Focal segmental glomerular sclerosis (FSGS) has a high propensity for recurrence after renal transplantation, with a 50% risk for graft failure from recurrent disease. Methods:We report on the efficacy of high-dose oral cyclosporin A (CsA) in the treatment of recurrent FSGS in children. Between August 1991 and January 2003, a total of 24 patients with FSGS underwent transplantation at 1 institution. Sixteen patients (67%) had recurrent disease. In these 16 patients, CsA dose was increased gradually until remission was achieved or there was evidence of renal toxicity. Seven patients also underwent plasma exchange. Results:Thirteen patients (81%) achieved remission. Remission was complete in 11 patients and partial in 2 patients. The CsA dose necessary for inducing remission ranged from 6 to 25 mg/kg/d. Four of these patients also underwent plasma exchange. After remission, CsA dose was reduced gradually toward the standard posttransplantation regimen. Eleven of 13 responders have a functioning graft after a follow-up ranging from 10 months to 12 years. One graft was lost because of recurrent FSGS, and another graft because of recurrence and cellular rejection; noncompliance was a factor in both losses. The 3 patients with disease that did not respond to high-dose CsA therapy lost their grafts because of recurrent FSGS. A common factor in these 3 patients was the inability to increase the CsA dose because of early evidence of nephrotoxicity, evidenced by an increase in serum creatinine level. Conclusion:High-dose oral CsA therapy is effective in producing long-lasting remission of recurrent nephrotic syndrome in children with FSGS.

Extracorporeal Plasma Treatment in Primary and Recurrent Focal Segmental Glomerular Sclerosis: A Review

Extracorporeal Plasma Treatment in Primary and Recurrent Focal Segmental Glomerular Sclerosis: A Review

Extracorporeal Plasma Treatment in Primary and Recurrent Focal Segmental Glomerular Sclerosis: A Review

This review summarizes the state of the art of apheresis in focal segmental sclerosing glomerulonephritis (FSGS) based on the current literature. FSGS is a major cause of nephrotic syndrome and renal insufficiency and has a high tendency to recur after renal transplantation. In many instances, treatment with steroids and/or immunosuppressive agents is without effect. Therapeutic plasma exchange (as well as immunoadsorption in some instances) was performed in primary (pFSGS) and recurrent (rFSGS) FSGS. Proteinuria could be improved and renal function was stabilized in 58% of rFSGS adults, in 74% of rFSGS children, and in 44% of pFSGS in adults. Treatment was successful if implemented early, i.e., in the stage of minimal change glomerulopathy before significant sclerosis had developed. This approach will probably be realistic only in the regular follow-up after transplantation. Furthermore, some patients with full-blown pFSGS were treated successfully in a prophylactic indication immediately prior to transplantation which decreased the incidence of recurrence to 26% in treated patients versus 54% in controls. Due to the uncontrolled study design and small patient cohorts in most trials, the major disadvantage of the reports currently available on the use of apheresis in FSGS is their low level of evidence from which the previous conclusions had to be drawn. Large prospective, controlled and randomized clinical trials are urgently needed for recommendations based on high-level evidence.

Long-term evaluation of children with nephrotic syndrome and focal segmental glomerular sclerosis.

We studied the long-term outcome of a group of children with the nephrotic syndrome who showed the histological lesion of focal segmental glomerular sclerosis (FSGS) during the course of their illness. Of 25 such children studied, a complete follow-up ranging from 3 to 19 years was available in 24. Two distinct groups could be identified. Patients in the first group were characterized by steroid resistance (SR) from the onset, whereas those in the second group were initially steroid sensitive (SS), and had the histological lesion of minimal change which, over time, evolved into FSGS. SR patients had a mean age of 7.7 +/- 3.7 years compared to SS patients who were 3.5 +/- 2.5 years old (p less than 0.01). There were more females (11 of 14) in the SR group than in the SS group (3 of 10; p less than 0.02). The incidence of hematuria was higher in the SR patients (9 of 14) than SS patients (2 of 10; p less than 0.05). SR patients also exhibited a greater degree of growth retardation at the end of the follow-up period (9 of 13 compared to 1 of 8 SS patients; p less than 0.02). SR patients reached end-stage renal failure earlier (2.3 +/- 1.3 years) than SS patients (10 +/- 5.8 years; p less than 0.01) after the initial biopsy. Of the 13 kidney transplanted into 9 SR patients, recurrence of FSGS was noted in two allografts. Of the 4 kidneys transplanted into 2 SS patients, recurrence was seen in 1. The overall recurrence rate of FSGS in allografts was 17.6%. Our study suggests that the two varieties of FSGS occurring in nephrotic patients may be distinct nosologic entities rather than a single disease with varied manifestations.