Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years

Abstract

BackgroundNephrotic syndrome (NS) presenting early in life is caused by heterogeneous glomerular diseases. We retrospectively evaluated whether histological diagnosis in children presenting with NS in the first year of life predicts remission or progression to end-stage kidney disease (ESKD).MethodsThis is a single centre retrospective review of all children diagnosed with NS before one year of age between 1990 and 2009. All subjects had a renal biopsy, which was independently blindly reviewed by a single renal pathologist for the purpose of this study.ResultsForty-nine children (25 female) who presented at 0.1–11.6 (median 1.6) months were included with 31 presenting within the first three months of life. Histopathological review diagnostic categories were; 13 Mesangial proliferative glomerulopathy (MesGN), 12 Focal and segmental glomerulosclerosis (FSGS), 11 Finnish type changes, eight Diffuse Mesangial Sclerosis (DMS), three Minimal change disease (MCD) and one each of Dense Deposit Disease (DDD) and Membranous nephropathy. Two children died from haemorrhagic complications of the biopsy. Eight children achieved remission (four MesGN, one Finnish type changes, one FSGS, one MCD and one membranous) with patient and renal survival of 73 % and 43 %, respectively, at follow-up duration of 5–222 (median 73) months (with five lost to follow-up). All children with Finnish-type histopathological changes presented within five months of age. Due to the historical nature of the cohort, genetic testing was only available for 14 children, nine of whom had an identifiable genetic basis (seven NPHS1, one PLCE1 and one ITGA3) with none of these nine children achieving remission. All of them had presented within four months of age and required renal replacement therapy, and two died.ConclusionsHistopathological findings are varied in children presenting with NS early in life. Whilst groups of histological patterns of disease are associated with differing outcomes, accurate prediction of disease course in a specific case is difficult and more widespread genetic testing may improve the understanding of this group of diseases and their optimal management

Genetics of hereditary nephrotic syndrome: a clinical review

“…Hereditary, autosomal-dominant NS is rare, occurring mostly in juvenile and adult familial cases. Dominant mutations in ACTN4 , TRPC6 , and INF2 are associated with late-onset proteinuria and progress to ESRD during the third and fourth decades of life13141737). Inheritance patterns for recently reported genetic mutants responsible for hereditary NS are listed in Table 1.…”

“…In non-Finnish populations, CNS is actually a clinically and genetically heterogeneous group of disorders caused by mutations in WT1 , PLCE1 , LAMB2 , or NPHS2 . Therefore, early-onset NS (CNS and INS) is usually caused by mutations in NPHS1, or less commonly by mutations in WT1 , PLCE1 , LAMB2 , NPHS2I , or LMX1B 1432333437383940). Patients with CNS mostly presented steroid-resistant proteinuria in the first few days of life, and rapidly progressed to ESRD by the age of 2–8 years; NPHS1 mutations were detected in more than half of all cases.…”

“…For specific genes and specific mutations within the same gene of podocytes, there can be a correlation between genotypes and renal histologic patterns1737).…”

“…Individuals with CNS and the renal histology of DMS usually have mutations in the following genes: PLCE1 , LAMB2 , WT1 , NPHS1 , NPHS2 , or GMS1 ; however, MCN and FSGS are rarely seen in CNS1737384647). Data from human genetics and from mouse models of SRNS/FSGS show that the renal histologic patterns of DMS and FSGS lie at different ends of the spectrum of a shared pathogenesis.…”

Relevanz der genetischen Diagnostik erblicher Nephropathien in der Klinik

“…Während steroidsensiblen Formen des nephrotischen Syndroms in erster Linie immunologische Ursachen zugrunde liegen, finden sich bei steroidresistenten Formen (SRNS) auch ohne positive Familienanamnese sehr häufig genetische Ursachen [14]. Die genetische Diagnostik stellt somit einen wesentlichen Bestandteil im Rahmen der Abklärung dar und hat unmittelbare therapeutische Konsequenzen in Bezug auf den Einsatz von Immunsuppressiva.…”