Thin basement membrane nephropathy: is there genetic predisposition to more severe disease?

Abstract

Sirs, For a patient who presents with isolated microscopic hematuria, three different disease entities that enter the differential diagnosis are: (a) immunoglobulin A (IgA) nephropathy, with no family history, that may also express itself with macroscopic hematuria; (b) Alport syndrome, which may present with episodes of macroscopic hematuria during childhood and should most frequently be explained by a family history of chronic kidney disease (most frequently X-linked, 85% and, less frequently, of autosomal recessive inheritance); (c) thin basement membrane nephropathy (TBMN), which invariably leads to benign familial microscopic hematuria (BFMH), with family history and infrequent episodes of macroscopic hematuria, while it is normally not expected to be accompanied by severe kidney disease, apart from low-grade proteinuria. TBMN as a heritable condition has been attributed to heterozygous mutations in the collagen type IV, alpha 3 and alpha 4 (COL4A3/COL4A4) genes on chromosome 2q36– 37, by nearly 50%. It should not be a surprise if closer look and improved techniques prove that COL4A3/COL4A4 mutations account for an even higher portion of TBMN cases that presently have been overlooked. The term TBMN, with only few exceptions, has largely been used as a synonym for benign familial microscopic hematuria, which nearly always is the only symptom, with excellent prognosis [1–3]. Those few exceptions are worth concentrating on, in view of a recent publication from my laboratory, which provides voluminous exceptional data from a population on the island of Cyprus [4]. In that report we described 13 families with the dual diagnosis of TBMN and focal segmental glomerulosclerosis (FSGS), while, in ten of them, we identified three heterozygous mutations in the COL4A3/COL4A4 genes. Combination of that data with more recent work concludes that, in a total of 59 patients over the age of 51 years, approximately two in three had developed proteinuria and chronic kidney disease, while about one in three had progressed to end-stage kidney disease (ESKD), as evidenced by the need for hemodialysis or kidney transplantation [4, 5 and unpublished results]. Older publications had attested to similar exceptions as regards the prognosis of TBMN, reporting on relatively small numbers of patients, a few of whom had presented also with additional glomerular pathologies that included proteinuria, FSGS and chronic kidney disease, occasionally also ESKD. As early as 1985, Dische et al. [6] reported on 14 TBMN patients aged 11–51 years, several of whom had progressive disease including hypertension and renal impairment, while one had reached ESKD. Nieuwhof et al. [7], in a prospective 12-year follow-up study of 19 patients with TBMN and microscopic (18/19) or macroscopic hematuria (1/19), were the first to clearly associate TBMN with late-onset renal impairment in elderly patients. In 13.5% of their patients focal global glomerulosclerosis was detected, while six first-degree relatives reached ESΚD, prompting the authors to conclude that TBMN predisposes to premature glomerular obsolescence, which, with sufficient time, leads to increased incidence of hypertension and late-onset renal insufficiency. Interestingly, the same authors mentioned that in a separate series of TBMN patients they had noted an increased proteinuria associated with FSGS in the renal biopsy. Based on their admittedly small patient cohort the authors commented that the prognosis of TBMN may not be as benign as generally Pediatr Nephrol (2009) 242:877–879 DOI 10.1007/s00467-008-1042-4