Thin GBM nephropathy: Premature glomerular obsolescence is associated with hypertension and late onset renal failure

Abstract

Thin glomerular basement membrane (GBM) nephropathy, also called familial benign hematuria, is characterized by chronic hematuria and uniform thinning of the lamina densa of the glomerular basement membrane. It generally holds an excellent renal prognosis. Alport syndrome in early stages can also show attenuation of the GBM; conversely, renal insufficiency has been reported in familial benign hematuria. To discern early Alport syndrome from thin GBM nephropathy, we carried out a prospective epidemiological study in which 19 normotensive and non-azotemic adult patients with chronic microscopic (18 of 19) and macroscopic (1 of 19) hematuria and biopsy-proven thin GBM nephropathy were followed for a median of 12 years (range 9 to 15 years). Renal biopsies of thin GBM patients at entry showed an increased incidence of focal global glomerulosclerosis when compared to disease controls as IgA nephropathy (P = 0.047) and normal renal tissue (P = 0.0075). All renal biopsies showed the presence of the Goodpasture antigen when tested immunohistochemically. Presence of Alport syndrome was excluded clinically as none of the patients had complaints of hearing loss or abnormalities by audiography and ophthalmology. At the end of follow-up, the incidence of hypertension in thin GBM nephropathy (35%) exceeded that of healthy clinical controls (P = 0.048), and one hypertensive patient developed mild renal failure. In the normotensive patients, the glomerular filtration rate at follow-up as measured by inulin clearance was reduced in three out of seven; these were over 50 years of age. Although no family members were known to have renal disease at inclusion, within four families six elderly first degree relatives had developed unexplained renal insufficiency at the end of follow-up. Thus, thin GBM nephropathy predisposes to premature glomerular obsolescence, leading in time to increased incidences of hypertension and late onset renal insufficiency.

Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice

“…It should be noted that it was suggested that the molecular type of COL4A3/A4 mutations and additional modifier genes are likely to influence the severity of the renal phenotype eventually (35,36,37). Second, hypertension in adults with TBMN was reported previously and is likely to worsen the general prognosis of affected patients (13,25). Third, clinical reports suggest that individuals with TBMN must be viewed to be in a pool of patients who generally display above-average rates of mortality.…”

“…Although TBMN is considered to have a good prognosis owing to a nonprogressive nephropathy, numerous hints in the literature suggest a reduced lifespan in affected individuals. First, the possibility that TBMN may not be benign in terms of ultimate prognosis has been considered before (13,14,18,30,25), and ESRD similar to that seen in AS was reported in adults with heterozygote COL4A3/A4 mutations (occasionally also referred to as "autosomal dominant Alport syndrome") (15,34 -37). It should be noted that it was suggested that the molecular type of COL4A3/A4 mutations and additional modifier genes are likely to influence the severity of the renal phenotype eventually (35,36,37).…”

“…Renal biopsies from patients with TBMN reveal uniform or diffuse attenuation of the GBM without the typical lamellation and thickening that is seen in AS (21). Secondarily, focal segmental glomerulosclerosis and tubulointerstitial fibrosis are histopathologic features of TBMN in some cases (13,16). There is increasing evidence that TBMN predisposes to development of concomitant IgA nephropathy, mesangial proliferative glomerulonephritis, and other nephropathies (11,(22)(23)(24).…”

“…A spate of new data have become available concerning individuals with thin basement membrane nephropathy (TBMN) showing heterozygous mutations in the COL4A3 and COL4A4 genes (4 -10). TBMN, or familial benign hematuria (11) first was described in 1926 (12) and is a very common hereditary disorder that clinically is characterized by persistent or recurrent hematuria that can be aggravated by increased BP in approximately 30% of patients (5,(13)(14)(15), proteinuria (15)(16)(17)(18)(19), hearing loss, and/or progression toward chronic renal failure (11,(13)(14)(15)17,20). The trait is inherited in an autosomal dominant pattern (8).…”

Canadian guidelines for the management of asymptomatic microscopic hematuria in adults

“…16,19,20 A small proportion may also develop renal insufficiency due to glomerular disease. [21][22][23] As a result, some form of patient follow-up is recommended after negative initial evaluation for AMH.…”