Introduction Focal segmental glomerulosclerosis (FSGS) is a histologic (pathologic) diagnosis that encompasses numerous specific clinical entities with potential varied etiologies. Steroid-resistant nephrotic syndrome (SRNS) is a specific clinical phenomenon that may vary histologically from minimal change nephrotic syndrome (MCNS) to FSGS, but it also may be associated with other specific histological diagnoses. 1 2 2 Lancet 3 The purpose of this teaching review article will be to address the factors that influence the incidence of recurrence of NS/FSGS in renal allografts, establish the known risk factors for recurrence, and delineate the current preventive and therapeutic approaches to the recurrence of NS/FSGS in pediatric renal allograft recipients. What is the incidence of recurrence of post-transplant NS/FSGS? 4 5 5 What is the incidence of subsequent recurrence in a patient who manifested clinical recurrence in a previous graft? 4 6 7 What is the incidence of recurrence in recipients with mutations of genes that encode for podocin? 8 9 10 Do patients with the glomerular tip lesion who receive a renal allograft manifest recurrence of the NS? 11 Does race impact on the recurrence of NS/FSGS? 12 5 13 14 Has the incidence of recurrence changed with the introduction of new immunosuppressive regimens? 2 14 14 4 What are the risk factors for the recurrence of NS/FSGS? 15 16 17 Does the presence of an identified circulating factor predispose to the recurrence of NS/FSGS? 15 Is induction therapy a risk factor for the recurrence of NS/FSGS? 16 17 18 19 2 14 Is native nephrectomy a risk factor for the recurrence of NS/FSGS? 14 p 20 Does the recurrence of NS/FSGS impact on the allograft survival rate? 21 14 22 23 p Does age at the time of transplantation impact on graft survival in recipients with FSGS? 21 24 Should an LD graft be utilized in children with ESRD secondary to FSGS? 4 25 28 5 p 22 29 30 28 31 What are the therapeutic options available to produce a remission following the recurrence of NS in recipients with FSGS? 32 33 34 35 36 37 With the use of angiotensin-converting enzyme/angiotensin receptor blocker (ACE/ARB) therapy to reduce proteinuria in patients with various forms of renal disease, it would seem logical to extend the use of these agents to recipients with the recurrence of NS/FSGS. However, there has been no controlled study of the use of these drugs either alone or as adjunctive to other therapeutic regimens. Can pre-operative PP reduce the risk of recurrence of NS/FSGS? 38 39 40 7 Certainly, the utilization of pre-operative and prophylactic post-operative PP appears promising in high-risk patients. Controlled multicenter trials are warranted to delineate the optimal preventative and therapeutic approaches. Conclusions The incidence of recurrence of nephrotic syndrome/focal segmental glomerulosclerosis (NS/FSGS) has remained at ~30% for the past four decades, despite the introduction of newer and more potent immunosuppressive regimens. Multiple risk factors have been identified to predispose or precipitate clinical recurrence. However, no prospective multicenter studies have validated the relationships. Mutations of the gene encoding for podocin may identify a population of patients with NS/FSGS who are at a lower risk for clinical recurrence. Because of the potential for an increased incidence of recurrence and/or graft loss, living donor (LD) grafts should be used with constraint. Graft survival rates in recipients with NS/FSGS are decreased. However, if a remission can be induced, the outlook for long-term graft survival is substantially improved. Various therapeutic regimens, including pre-operative plasmapheresis (PP), high-dose cyclosporine, IV cyclosporine, and adjunctive cyclophosphamide, have proven to be effective. However, there have been no multicenter controlled studies to delineate the optimal therapeutic approach. Recent use of pre-operative and/or post-operative prophylactic PP to prevent the recurrence of NS/FSGS is exciting. Controlled trials are required to validate efficacy and delineate a precise preventative regimen. Questions Comparable in whites and African-Americans Less in whites than Hispanics Less with re-transplants than with primary grafts Not influenced by pre-transplant plasmapheresis Between 30% and 40% A living donor graft is not available The initial graft was lost as a result of recurrence The parental donor is not an obligatory podocin heterozygote The potential live-donor is a haplotype mismatch The potential live-donor is a B-antigen mismatch A reduction in the magnitude of proteinuria to 3.0 g/kg/day The lack of histologic evidence of FSGS during the initial post-transplant month Inducing a complete remission of the NS The immediate use of post-transplant plasmapheresis The use of a one haplotype-matched live-related donor Includes cyclophosphamide and plasmapheresis Includes one week of pre-transplant plasmapheresis Includes post-operative tacrolimus and plasmapheresis Includes post-operative sirolimus and plasmapheresis Has not been delineated Has not been reported with the “Finnish” type Is >80% in recipients with diffuse mesangial sclerosis Is uniform with Fin-major/Fin-minor genotype Is associated with the development of antinephrin antibodies Is associated with anti-podocin antibodies Race Native kidney nephrectomy Recurrence in a prior graft Podocin mutation None of the above