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Background Focal segmental glomerulosclerosis (FSGS) in pediatric patients is typically difficult to treat and will progress to end-stage renal disease (ESRD) in about 10% of cases. Following kidney transplantation, FSGS can recur in up to 56% of renal allografts-with a near 100% recurrence in subsequent transplants. Methods Four different pediatric centers across the USA and the UK employed a protocol using LDL-apheresis (LDL-A) and pulse solumedrol to treat recurrent FSGS after transplantation in seven patients. All the patients included in this series demonstrated immediate, or early, recurrence of FSGS, which clinically presented as nephrotic-range proteinuria within hours to days after implantation of the kidney. Results All patients experienced reductions in urinary protein to creatinine ratios resulting in partial or complete remission. All patients demonstrated improvements in their estimated GFRs at their most recent follow-up since LDL-A discontinuation. Conclusions This case series describes the successful treatment, across four different pediatric centers, of seven pediatric patients with recurrent post-transplant FSGS using the Liposorber® LA-15 in combination with pulse solumedrol., Author(s): Lokesh Shah [sup.1] , David K. Hooper [sup.2] , Daryl Okamura [sup.3] , Dean Wallace [sup.4] , Divya Moodalbail [sup.5] , Caroline Gluck [sup.5] , Ania Koziell [sup.6] , [...]

Background: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. Methods: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. Results: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. Conclusions: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. [ABSTRACT FROM AUTHOR]

Background Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. Methods We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. Results We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein-protein interactions to intracellular myosin 1E. Conclusions COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non-COL4 'podocyte gene' mutations in XLAS when clinical nephropathy is more severe than expected for an individual's age and sex., Author(s): Rachel Lennon[sup.1] [sup.2] [sup.3] , Helen M. Stuart[sup.4] , Agnieszka Bierzynska[sup.5] , Michael J. Randles[sup.1] [sup.2] , Bronwyn Kerr[sup.4] , Katherine A. Hillman[sup.6] , Gauri Batra[sup.7] , Joanna Campbell[sup.8] [...]

Byline: Chulananda D. A. Goonasekera (1), Ania B. Koziell (1), Sally A. Hulton (2), Michael J. Dillon (1) Keywords: Key words: Focal segmental glomerulosclerosis; Vincristine therapy Abstract: Over the last 10 years, eight children have received vincristine for the treatment of steroid- and cyclophosphamide-resistant nephrotic syndrome at Great Ormond Street Hospital for Children, London. We present our experience of these eight cases and put forward a case for reassessing the effectiveness of vincristine in this disorder. In our series, two children treated with vincristine achieved complete remission with preserved renal function, including relapses in one. Both had primary steroid- and cyclophosphamide-resistant focal segmental glomerulo sclerosis (FSGS). Of the other cases, four also had primary FSGS, one familial FSGS and one mesangioproliferative glomerulonephritis. We discuss in general the pros and cons of vincristine therapy in nephrotic syndrome versus the cytotoxic agents that are currently used and the differences in clinical features among the responders and non-responders in this small group. In addition, we explore why this may have occurred and summarise the literature over the last 25 years, where vincristine appeared to have been beneficial, especially in secondary forms of nephrotic syndrome associated with malignancy. We conclude that vincristine therapy warrants re-examination as it could be a valuable alternative therapeutic agent in some cases of FSGS with relatively minor side effects. Author Affiliation: (1) Institute of Child Health and Great Ormond Street Children's Hospital NHS Trust, 30 Guilford Street, London WC1 N1EH, UK, GB (2) Department of Nephrology, The Birmingham Children's Hospital NHS Trust, Ladywood, Middleway, Birmingham B16 8ET, UK, GB Article note: Received September 1, 1997 received in revised form December 12, 1997 accepted December 15, 1997