Thin glomerular basement membrane nephropathy: incidence in 3471 consecutive renal biopsies examined by electron microscopy.
ABSTRACT 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).
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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 · 9.47 Impact Factor
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ABSTRACT: The recent description of multiple gene defects in hereditary podocytopathies and in hereditary glomerular basement membrane diseases has dramatically improved the current state of our knowledge on the renal glomerular filtration barrier. Recently described mutations in collagen IV and laminin in patients with hematuria and severe nephrotic syndrome add to other experimental data supporting the hypothesis that the glomerular basement membrane (GBM) may also have a significant role in protein filtration, a function previously attributed exclusively to the podocytes. Collagen IV heterozygous mutations were thought to cause only a mild form of renal disease (thin basement membrane nephropathy--TBMN). However, data from our laboratory show that many patients who carry such mutations may later on in life develop focal and segmental glomerulosclerosis, on top of the TBMN and the microscopic hematuria, a situation that frequently progresses to chronic renal failure or even end-stage renal disease. The role of unknown modifier genes may explain the heterogeneity of symptoms in TBMN and other glomerular diseases and in particular the selected development of chronic renal failure. The molecular communication between GBM and podocytes may also be a key factor in the search for these major genetic modifiers while their understanding may improve novel drug design for glomerular diseases.Connective tissue research 01/2008; 49(3):283-8. DOI:10.1080/03008200802148280 · 1.98 Impact Factor