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Thin glomerular basement membrane disease

2001; Elsevier BV; Volume: 60; Issue: 2 Linguagem: Inglês

10.1046/j.1523-1755.2001.060002799.x

1523-1755

L.A.H. Monnens,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Isolated microscopic hematuria that begins in childhood and is of glomerular origin has a rather limited differential diagnosis, with Alport syndrome, IgA nephropathy, and benign familial hematuria as the most prevalent conditions. In a series of 322 children with persistent hematuria for longer than 6 months, biopsies were classified as IgA nephropathy in 78 patients, Alport syndrome in 86 patients, and thin basement membrane nephropathy in 50 patients. The biopsies in 48 patients showed normal glomeruli and one patient had a more rare disorder1.Piqueras A.I. White R.H.R. Raafat F. et al.Renal biopsy diagnosis in children with hematuria.Pediatr Nephrol. 1998; 12: 386-391https://doi.org/10.1007/s004670050471Crossref PubMed Scopus (53) Google Scholar. Patients with benign familial hematuria usually have persistent hematuria, although intermittent hematuria does occur in some patients. Episodic gross hematuria is rare. Proteinuria, progression to renal failure, or extrarenal symptoms such as hearing loss are not present. Thinning of the glomerular basement membrane (GBM), the hallmark of this disease, is usually uniform, but focal alteration involving at least 50% of the GBM may occur. To define thin GBM disease, it is important to realize that the thickness of the GBM depends on the age and gender of the patient. The most extensive study of GBM thickness in children was performed by Morita et al, who calculated thickness from 100 to 340 nm at 1 year of age to 190 to 440 nm at 9 years of age and older2.Morita M. White R.H.R. Raafat F. et al.Glomerular basement thickness in children.Pediatr Nephrol. 1988; 2: 190-195Crossref PubMed Scopus (27) Google Scholar. Dische found that the GBM is thinner in female patients than in male patients3.Dische F.E. Measurement of glomerular basement membrane thickness and its application to the diagnosis of thin-membrane nephropathy.Arch Pathol Lab Med. 1992; 116: 43-49PubMed Google Scholar. Considering the differing results obtained by investigators, the conclusion by Dische that a local “normal range” should be established in each unit is appropriate. Thin glomerular basement can sometimes be associated with other glomerulopathies4.Cosio F.G. Falkenhain M.E. Sedmak D.D. Association of thin glomerular basement membrane with other glomerulopathies.Kidney Int. 1994; 46: 471-474Abstract Full Text PDF PubMed Scopus (80) Google Scholar,5.Auwardt R. Savige J. Wilson D. A comparison of the clinical and laboratory features of thin basement membrane disease and IgA glomerulonephritis.Clin Nephrol. 1999; 52: 1-4PubMed Google Scholar. Coleman and Stirling noted GBM thinning in minimal-change disease6.Coleman M. Stirling J.W. Glomerular basement membrane thinning is acquired in minimal change disease.Am J Nephrol. 1991; 11: 437-438Crossref PubMed Scopus (15) Google Scholar. In an unpublished study of 37 children with minimal-change nephrotic syndrome, investigators in our unit demonstrated that 65% of the patients had thin segments of more than 5% and 37% of the patients with more than 15%, respectively, of the GBM [M te Loo, unpublished observation, 2000]. Thin GBM disease begs for a molecular explanation. The attenuation of the GBM, as such, is not the cause of the hematuria. By morphometric analysis of newly transplanted kidneys, Dische et al were able to demonstrate that thin basement membranes were present in between 5.2 and 9.2% of the general population7.Dische F.E. Anderson V.E.R. Keane S.J. et al.Incidence of thin membrane nephropathy: morphometric investigation of a population sample.J Clin Pathol. 1990; 43: 437-460Crossref Scopus (73) Google Scholar. An important step in this investigation was the demonstrated segregation of biopsy-proved thin GBM disease with the locus for autosomal-recessive Alport syndrome in 8 of 22 families8.Buzza M. Wilson D. Savige J. Segregation of hematuria in thin basement membrane disease with haptotypes at the loci for Alport syndrome.Kidney Int. 2001; 59: 1670-1676https://doi.org/10.1046/j.1523-1755.2001.0590051670.xAbstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar. In this issue of Kidney International, the same investigators showed a heterozygote mutation in Col4A4 gene in thin GBM disease9.Buzza M. Wang Y.Y. Dagher H. et al.Col4A4 mutation in thin basement membrane disease previously described in Alport syndrome.Kidney Int. 2001; 60: 480-483Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar. Additional molecular abnormalities can be expected and should allow a clearer delineation of thin GBM disease. What should be the strategy when a diffuse thin GBM is found in a patient with isolated hematuria? In most kindred with benign familial hematuria, autosomal-dominant inheritance is observed. However, in a few families, the inheritance appears to be autosomal-recessive or it occurs sporadically. An X-linked Alport syndrome can mostly be excluded based on the inheritance pattern. A diffuse thinning of the GBM was the only abnormality seen in a 15-year-old boy with X-linked Alport syndrome10.Rizzoni G. Massella L. Muda A.O. α5 COL IV chain distribution in glomerular basement membrane in a male with X-linked Alport syndrome and thin basement membrane.Pediatr Nephrol. 2000; 15: 325PubMed Google Scholar. However, the autosomal-recessive form of Alport syndrome caused by mutation in COL4A3 or COL4A4 genes (found in approximately 14% of the cases) and the recently described autosomal-dominant form caused by COL4A3 mutation11.Van der Loop F.T.L. Heidet L. Timmer E. et al.Autosomal dominant Alport sydrome caused by a COL4A3 splice site mutation.Kidney Int. 2000; 58: 1870-1875https://doi.org/10.1046/j.1523-1755.2000.00358.xAbstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar remain a possibility. Hopefully, aberrant laminin α2 deposition in GBM, as is present in X-linked and autosomal-recessive forms of Alport syndrome12.Kashtan C.E. Kim Y. Lees G.E. et al.Abnormal glomerular basement membrane laminins in murine, canine, and human Alport syndrome: Aberrant laminin α2 deposition is species independent.J Am Soc Nephrol. 2001; 12: 252-260PubMed Google Scholar, will not be found in thin GBM disease.