Abstract
Familial focal segmental glomerulosclerosis (FSGS) is a heterogeneous renal disease characterized by heavy proteinuria and progressive renal insufficiency. Previous reports have demonstrated several mutations in genes affecting the podocyte in Mendelian-inherited families, and yet the correspondence between severity, clinical course and genotype remains unclear. There is generally no response to immunosuppressive agents, but some patients or families with familial FSGS show a level of responsiveness equal to that of sporadic FSGS patients. Recently, cyclosporine (CsA) has been successfully used to treat adults with FSGS and is regarded as the main second-line drug. We herein report a nephrotic boy with familial FSGS, who successfully achieved remission following administration of CsA despite the lack of response to steroid.
The patient was first brought to our hospital at one year of age. Moderate proteinuria had been noted since birth, but renal excretory function was normal. He underwent the first renal biopsy showing FSGS at two years of age, and prednisolone (PDN) was soon initiated according to the protocol of the International Study of Kidney Disease in Children. He obtained partial remission through PDN induction therapy, with relapse prevented for the subsequent six years. His sister also presented with proteinuria in infancy, and so we performed rebiopsy on the siblings when the proband was five and his sister was four. Histological studies demonstrated that both siblings had FSGS, partial global sclerosis with interstitial fibrosis and positive expressions of podocin, nephrin, and α-actinin in the glomeruli. Furthermore, we demonstrated a genome-wide linkage analysis of genes affecting the podocyte and causing familial FSGS (NPHS-1, NPHS-2, ACTN4, etc.), but there was no locus identified in this family. At the age of nine, the patient developed gastroenteritis and relapsed into nephrotic syndrome. Although we restarted steroid therapy with blockade of the renin-angiotensin system, he developed resistance to PDN and heavy proteinuria persisted. We subsequently administered CsA as a single daily dose while maintaining a two-hour post-dose (C2) level of 600 to 800 ng/ml. This CsA therapy markedly decreased the urinary protein-to-urinary creatinine ratio (UP/UC) from 7.49 to 0.70 in four months. Except for transient headache, there have not been any significant adverse effects of CsA. He has maintained remission to date.
Several mechanisms that explain the ability of CsA to induce reduction of proteinuria in nephrotic syndrome have been proposed, for example reduction in glomerular plasma flow or filtration pressure. CsA therapy may reduce proteinuria without severe side effects in some patients with familial FSGS. Affirmative administration of CsA therapy should be considered, not least in genetically-unknown familial FSGS.
