Thin glomerular basement membrane (GBM) nephropathy is often equated with benign familial hematuria, although it may occur sporadically and may not always be benign. Thin GBM nephropathy is reported to occur in at least 1% of the population, although its reported incidence varies considerably in different studies because there are presently no uniform criteria for its diagnosis by electron microscopy (EM).
To determine the incidence of thin GBM nephropathy in a large sample of renal biopsies using a basic methodology that can easily be applied in any diagnostic EM laboratory.
Direct measurements of GBM thickness were made from electron micrographs at 3 specified points along each of 10 randomly selected glomerular capillaries to determine an average GBM thickness for each of 50 males and 50 females, ages 9 to 80 years, with minimal-change nephropathy or acute interstitial nephritis, without hematuria. The means of the average GBM thickness values were 330 +/- 50 (SD) nm in the males and 305 +/- 45 nm in the females; normal ranges for each sex were defined as being within 2 SD of these means. The average GBM thickness was then similarly determined for renal biopsies with suspected thin GBMs examined from January 2000 to December 2004; a total of 3471 renal biopsies were examined by EM during this period.
Academic medical center renal pathology/EM laboratory.
Excluding biopsies with immunoglobulin A nephropathy, which is known to be frequently associated with thin GBMs, and biopsies with Alport syndrome, 67 biopsies (1.9% of total) had an average GBM thickness below the sex-specific normal range. Of these, 37 biopsies were performed specifically because of hematuria and had an average GBM thickness of 121 to 215 nm (mean, 185 +/- 20 nm). The remaining 30 (0.9%) biopsies, with average GBM thicknesses of 143 to 227 nm (mean, 190 +/- 20 nm), represent cases of incidentally discovered thin GBM nephropathy.
Based on the frequency of incidentally discovered cases and taking into account excluded cases and biopsies (eg, with diabetic nephropathy) in which diagnosis of incidental thin GBM nephropathy by EM is not possible, the incidence of thin GBM nephropathy in our population is estimated to be between 1% and 2%. Diseases most often associated with incidental thin GBM nephropathy were focal segmental glomerulosclerosis (10 cases) and minimal-change nephropathy (5 cases).
"However, some previous investigations that had not attracted the proper attention had alerted to the fact that not all patients with heterozygous COL4A3/COL4A4 mutations would follow a benign course. Instead, they reported on patients who started off with TBMN on biopsy and MH and slowly progressed to proteinuria, hypertension, and chronic or ESKD [13, 50–54]. In some of those works, the authors invoked the association with another glomerulonephritis, such as IgAN, FSGS, minimal change disease, mesangioproliferative glomerulonephritis and others ( and references therein). "
[Show abstract][Hide abstract] ABSTRACT: Familial microscopic hematuria (MH) of glomerular origin represents a heterogeneous group of monogenic conditions involving several genes, some of which remain unknown. Recent advances have increased our understanding and our ability to use molecular genetics for diagnosing such patients, enabling us to study their clinical characteristics over time. Three collagen IV genes, COL4A3, COL4A4, and COL4A5 explain the autosomal and X-linked forms of Alport syndrome (AS), and a subset of thin basement membrane nephropathy (TBMN). A number of X-linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD). A mutation in CFHR5, a member of the complement factor H family of genes that regulate complement activation, was recently shown to cause isolated C3 glomerulopathy, presenting with MH in childhood and demonstrating a significant risk for CKD/ESKD after 40 years old. Through these results molecular genetics emerges as a powerful tool for a definite diagnosis when all the above conditions enter the differential diagnosis, while in many at-risk related family members, a molecular diagnosis may obviate the need for another renal biopsy.
[Show abstract][Hide abstract] ABSTRACT: Mutations in the COL4A3/COL4A4 genes of type IV collagen have been found in approximately 40% of cases of thin basement membrane nephropathy, which is characterized by microscopic hematuria and is classically thought to cause proteinuria and chronic renal failure rarely. Here we report our observations of 116 subjects from 13 Cypriot families clinically affected with thin basement membrane nephropathy. These families first came to our attention because they segregated microscopic hematuria, mild proteinuria, and variable degrees of renal impairment, but a dual diagnosis of focal segmental glomerulosclerosis (FSGS) and thin basement membrane nephropathy was made in 20 biopsied cases. Molecular studies identified founder mutations in both COL4A3 and COL4A4 genes in 10 families. None of 82 heterozygous patients had any extrarenal manifestations, supporting the diagnosis of thin basement membrane nephropathy. During follow-up of up to three decades, 31 of these 82 patients (37.8%) developed chronic renal failure and 16 (19.5%) reached end-stage renal disease. Mutations G1334E and G871C were detected in seven and three families, respectively, and were probably introduced by founders. We conclude that these particular COL4A3/COL4A4 mutations either predispose some patients to FSGS and chronic renal failure, or that thin basement membrane nephropathy sometimes coexists with another genetic modifier that is responsible for FSGS and progressive renal failure. The findings presented here do not justify the labelling of thin basement membrane nephropathy as a benign condition with excellent prognosis.
Journal of the American Society of Nephrology 12/2007; 18(11):3004-16. DOI:10.1681/ASN.2007040444 · 9.34 Impact Factor
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