Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation

Abstract

Renal transplantation (RTx) is the only curative treatment for most cases of congenital and infantile nephrotic syndrome (NS) caused by genetic defects in glomerular podocyte proteins. The outcome of RTx in these children is usually excellent, with no recurrence of nephrotic syndrome. A subgroup of patients with the Finnish type of congenital nephrosis (CNF), shows, however, a clear risk for post-RTx proteinuria. Most of these patients have a homozygous truncating mutation (Fin-major mutation) in the nephrin gene (NPHS1), leading to total absence of the major podocyte protein, nephrin. After RTx, these patients develop anti-nephrin antibodies resulting in nephrotic range proteinuria. Plasma exchange combined with cyclophosphamide and anti-CD20 antibodies has proved to be successful therapy for these episodes. NS recurrence has also occurred in a few patients with mutations in the podocin gene (NPHS2). No anti-podocin antibodies have been detectable, and the pathophysiology of the recurrence remains open. While most of these episodes have resolved, the optimal therapy remains to be determined.

Fig. 1

The model of the slit diaphragm (SD) showing some of the major components (top). Nephrin is a transmembrane protein with extracellular Ig-domains (circles) and one fibronectin type domain (hexagon) (middle). Fin-major (nt121(del2)) mutation leads to a truncated protein of only 90 residues (out of 1,241 amino acids). E189X mutation also results in severely truncated protein (189 residues). Podocin is an intracellular protein belonging to the stomatin family (bottom). Both R138Q and R138X are common mutations leading to a severely truncated podocin protein. Similarly, L347X, which is caused by a single nucleotide deletion (948delT) in the last podocin exon, results in a truncated protein