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Diabetes and CKD: Pitfalls - Monitoring response to therapy

Posted Sep 15 2013 12:00am
The glomerular basement membrane is a thin layer of extracellular membrane proteins that is an important part of the filtration barrier, particularly glomerular permselectivity, by preventing proteins from crossing into the filtrate. The major proteins in the GBM are laminin, type IV collagen, nidogen and the heparan sulphate proteoglycan agrin. Interestingly, in the past, I was taught that the highly negative charge on agrin played the major role in mediating charge selectivity. However, recent studies have shown that mutations in the gene encoding agrin, leading to a reduction in charge along the GBM, have no effect of glomerular function in mice. Similarly, deletion of agrin has little effect on permselectivity further suggesting that the role of the proteoglycans in selective filtration is minor at best.

There are two conditions associated with genetic defects in glomerular basement membrane proteins

Syndrome Gene(s) affected Protein Phenotype Alports Syndrome COL4A3 COL4A4 COL4A5 Type IV Collagen, α3, α4, α5 subunits Initial normal formation of GBM but eventually hematuria, proteinuria and eventual ESRD with characteristic splitting of the GBM. COL4A5 mutations are commonest and are X-linked. Other forms are autosomal. Pierson Syndrome LAMB2 Laminin β2 Autosomal recessive disorder with variable phenotype depending on the particular mutation. However, ocular abnormalities (microcoria) are present at birth and the majority of affected individuals progress to ESRD within the first few weeks/months of life. Extrarenal manifestations including hypotonia and neurodevelopmental defects have been reported.


Please see this excellent review in Nature Reviews Nephrology for further information.


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