Focal segmental glomerulosclerosis (FSGS) is a rare but devastating glomerular disease, seen in approximately 20% of cases of the nephrotic syndrome in children and 40% of such cases in adults, with an estimated incidence of 7 per 1 million. In adults, FSGS is the most common cause of nephrotic syndrome(NS) in the USA and a frequent cause of advancing kidney failure. FSGS is currently stratified into the following subtypes: genetic, secondary (adaptive, drug-induced or virus-induced) and, as an exclusion diagnosis, a primary or idiopathic form.
In both children and adults, the primary form of FSGS is a common cause of steroid–resistant NS(SRNS), and as shown in Figure 1, it is the most common primary glomerular cause of end stage kidney disease in theUSA(5, 6).Almost 50 years since Rene Habib first described and coined the term FSGS, we still know very little about the pathogenesis of primary FSGS. Various theories include a systemic immunological dysregulation leading to the generation of unidentified circulating factor(s) that triggers podocyte injury, versus intrinsic changes in the podocyte actin cytoskeleton or the glomerular filtration slit barrier.The unifying feature is diffuse podocyte injury with consequent leakage of protein in the urine and progressive glomerular scarring. With relatively scant knowledge even now of its pathogenesis, primary FSGS causes tremendous morbidity for patients, and is highly challenging to treat.
Perhaps the most definitive distinguishing feature of primary FSGS is the relatively early, massive and often devastating recurrence of proteinuria after kidney transplantation, first described by Hoyer et al in 3 children in 1972. Reported rates of recurrent FSGS (rFSGS) are wide, ranging from 17% to 55% in smaller studies and from 9% to 32% in registry-based studies. Because FSGS is rare, most published studies are limited by small sample size and thus insufficient power to precisely determine treatment efficacy. and outcomes of rFSGS. Administrative or voluntary registries with large sample sizes, such as the ANZDATA, North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) or the US Renal Data System(USRDS), are limited by missing data, misclassification of glomerular disease diagnoses, and failure to capture cases of rFSGS that do not lead to graft loss, rendering data unreliable for drawing robust conclusions.
The management of rFSGS following kidney transplantation remains extremely challenging, for a variety of reasons. The rarity of the event has made it difficult to conduct randomized trials. Due to lack of randomized trials, treatment recommendations are based on small study cohorts, case series, and case reports. Interpretation of the published literature is hindered by the heterogeneity regarding the diagnosis of primaryFSGS (truly idiopathic, exclusion of genetic causes, availability of renal biopsies and electron microscopy), disease recurrence (clinical parameters, availability of H&E histology, and electron microscopy), and definition of remission.
As in primary FSGS affecting native kidneys, response to therapy for post-transplant rFSGS is often poor, with only 40%–60% of patients achieving any response, and these responses are often incomplete and not sustained. Most commonly, FSGS recurrence portends a negative impact on graft survival. Baum et al reported a loss of the living donor survival advantage of kidney transplants in FSGS recipients. From ANZDATA, Francis et al showed a 5-year allograft survival of only 52%in recipients with rFSGS, versus 83% in those without. There is no established standard for the treatment of recurrent FSGS post-transplant. Instead, various therapeutic regimens are applied with a wide variability in time of initiation of treatment, number of apheresis sessions, timing/dosing of depleting antibodies and concomitant immunosuppressive regimens.
To summarize so many conflicting results, the management of recurring disease after transplant represents a great challenge in achieving optimal outcomes in patients with FSGS. One of the critical barriers to studying rFSGS is the lack of a national interconnected, multi-institutional longitudinal infrastructure able to reach adequate numbers of affected children and provide the depth of information necessary to characterize response to treatments. That is the focus of this pilot project application.
1. We will test the hypothesis that a greater cumulative number of TPE sessions, performed over at least 3 months, is associated with higher rates of complete remission of rFSGS.
2. We will test the hypothesis that in patients who do not achieve a complete remission with TPE alone, the use ofTPE +anti-CD20 Absis associated with a greater rate of partial remission than the use ofTPE + costimulatory blockade (CTLA4Igs).