Disease of the Month Thin Basement Membrane Nephropathy

T hin basement membrane nephropathy (TBMN) is the most common cause of persistent hematuria in children and adults, the other main causes being IgA nephropathy and Alport syndrome (1–3). In addition to hematuria, patients with TBMN usually have minimal proteinuria, normal renal function, and uniformly thinned glomerular basement membranes (GBM), as determined by electron microscopy. TBMN, which affects at least 1% of the population, is a lifelong nonprogressive disorder associated with family history. TBMN was first described approximately 80 yr ago as a curable form of hemorrhagic nephritis (4). Later, many cases of this microscopic, painless hematuria with good prognosis were shown to be inherited, and this fact is emphasized in the numerous names used for the disease in the literature, such as “congenital hereditary hematuria” (5), “hereditary hematuria” (6), “familial hematuric nephritis” (7), “familial benign hematuria” (8), “benign familial hematuria” (9,10), “familial benign essential hematuria” (11,12), “benign hereditary nephritis” (13), and “benign essential hematuria” (14). TBMN has also been referred to as familial hematuria (15), but that is a misnomer, as it does not distinguish it from the progressive Alport syndrome (3). Commonly used names are “thin membrane nephropathy” (16–18), “thin basement membrane disease” (19–25), “thin GBM nephropathy” (26), and “thin GBM syndrome” (27). The term “thin basement membrane nephropathy” is currently most widely used (1,2,28–36), and this name is to be preferred, as it refers to a renal disorder that is associated with observable structural changes in the basement membrane (3) without necessarily being a “true disease.” It has been and still is a major clinical challenge to differentiate between TBMN characterized by nonprogressive hematuria and Alport syndrome with progressive hematuria as the main symptom. The connection between recurrent benign hematuria and thin GBM was first noted in electron microscopic analysis of kidney specimens in 1973 (11). This typical histopathologic feature of TBMN, i.e., uniform thinning of the GBM, could be found also at the early stages of Alport syndrome, which suggested that the pathomechanisms of the two diseases might overlap. This connection was verified at the gene level during the early 1990s, when the type IV collagen genes COL4A3, COL4A4, and COL4A5 were discovered and shown to be mutated in X-linked and autosomal Alport syndromes (37–41), with subsequent demonstration of mutations in COL4A3 and COL4A4 in TBMN (10). At present, 40% of TBMN cases have been associated with the COL4A3 and COL4A4 genes (23,42), but it remains to be verified whether female carriers who are carriers for a mutation in the COL4A5 gene can develop true TBMN. In principle, DNA-based diagnosis of TBMN is possible, but such tests are not commercially available. At present, the clinical diagnosis still is made mainly on the basis of persistent hematuria with minimal proteinuria and normal renal function, combined with electron microscopy examination of biopsy showing thinned GBM; the use of immunologic examination of the type IV collagen 3 to 5 chains still is not being used extensively. However, as discussed below, these methods are insufficient; therefore, the majority of TBMN cases are still considered to be undiagnosed.