Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria

Familial hematuria (FH) is associated with at least two pathological entities: thin basement membrane nephropathy (TBMN), caused by heterozygous COL4A3/COL4A4 mutations, and C3 nephropathy caused by CFHR5 mutations. It is now known that TBMN patients develop proteinuria and changes of focal segmental glomerulosclerosis when biopsied. End-stage kidney disease (ESKD) is observed in 20% of carriers, at ages 50-70. A similar progression is observed in CFHR5 nephropathy. Recent evidence suggests that NPHS2-R229Q, a podocin polymorphism, may contribute to proteinuria in TBMN and to micro-albuminuria in the general population. NPHS2-R229Q was screened in a Cypriot FH cohort. 102 TBMN patients with three known COL4 mutations and 45 CFHR5 male patients with a single mutation were categorized as Mild or Severe, based on the presence of microhematuria only, or proteinuria and chronic kidney disease. Nine R229Q carriers were found in the Severe category and none in the Mild (p=0.010 for genotypic association; p=0.043 for allelic association, adjusted for patients' relatedness), thus supporting the possible contribution of 229Q allele in disease progress. Our results offer more evidence that in patients with FH, NPHS2-R229Q predisposes to proteinuria and ESKD. R229Q may be a good prognostic marker for young hematuric patients.