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by System Administrator - Friday, 6 May 2011, 12:12 PM
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Nephron Digest
(Nephron 118-1-11)
April 2011


Renal Genetics: From Elitist Science to Clinically Practical and Relevant

A special issue has been Published by Nephron on Advances in Renal genetics in April 2011. Considerable advances have been made in recent years in identification of genes linked to the predisposition as well as progression of kidney diseases. This has translated to considerable clinical advances in understanding of CKD, prognosis and even management.

Genetics of CKD Conall O’Seaghdha and Caroline Fox update readers on data emerging from genomic wide associations studies (GWAS) linking a number of genes to the predisposition and progression of CKD. TCF7L2 gene polymorphism has been linked to increased type2DM in the general population. It is also associated with increased risk of CKD. Mutations of GREM1, coding for Gremlin, has been associated with a 70% increased risk of diabetic nephropathy. MYH9 (Non-muscle Myosin Heavy Chain) gene mutations have been associated with increased risk of FSGS, CKD and ESRD in African-Americans. The evidence for MYH9 as a nephropathy gene is compelling. The apolipropotein gene (APOL1), on chromosome 22, has also been associated with FSGS in African-Americans.

Albert Ong and Olivier Devuyst explore the integration of genetic knowledge into clinical practice in ADPKD. They use PKD as an example of translation of genetic knowledge to clinical practice and new treatments is most informative. Initially linkages were made between ADPKD and chromosomes 16 (PKD1) and 4 (PKD2). Soon it became apparent that these genes are linked to the coding of two key proteins; polycystins 1 and 2. Subsequently, the physiology and pathophysiology of these molecules became better understood.; polycystin1 being a large complex membrane receptor-like protein while polycystin2 resembling a non-selective calcium channel protein. Genetic abnormalities of these proteins predispose through a second-hit +/- modifiers to cysts formation in susceptible individuals through stimulation of intra-cellular transduction pathways involving a rise in cAMP as well as the activation of mTOR. This has led to a number of clinical trials aimed at reducing intracellular cAMP through a vasopressin type2 receptor antagonist (Tolvaptan: The TEMPO trial) or through mTOR inhibition by Sirolimus or Everolimus as well as a long acting Somatostatin analogue (octreotide). So far the latter studies have shown some effects on cysts size and kidney volume progression but little impact on the progression of renal insufficiency.

McCarthy and Saleem review advances in the genetics of nephrotic syndrome (NS). They provide a comprehensive list of genetic abnormalities linked to NS; these are invariably linked to podocytes associated proteins. These mutations impact on the integrity of the podocytes, slit diaphragm and filtration barrier causing NS and progressive FSGS. Mutations predisposing to childhood NS include that of NPHS1 associated with Nephrin abnormalities and Finnish type NS, NPHS2 associated with podocin abnormalities and familial FSGS and WT1 mutations associated with Wilm’s tumors. In adult NS, mutations of ACTN4 linked to actinin, CD2AP and TRPC6 cause autosomal dominant FSGS. A growing literature advocates the screening of children with SRNS for mutations in the genes encoding nephrin, podocin and WT1 in order to direct clinical management. Also screening for genetic polymorphism of, for instance, NPHS1 has been put forward to guide transplantation in FSGS and chances of recurrence.

Bleyer, Zivna and Kmoch comment on Uromodulin-associated kidney disease. Mutations of the gene encoding uromodulin [UMOD] (Tamm-Horsfall protein) are responsible for an autosomal dominant inheritance of hyperuricemia and chronic, progressive, tubulointerstitial disease leading to CKD from 3rd to7th decade of life. Those affected develop severe hyperuricemia in childhood and gout in their teens. UMAK (uromodulin-associate kidney disease) will undoubtedly become increasingly recognised.

Genetics of renal transplantation by Bernd Kruger and Bernd Schroppel. The authors review evidence derived from genomic wide associations studies (GWAS) on genetic variations/mutations and their impact on the different stages of renal transplantation. For Delayed Graft Function (DGF), they point to the key role of the Toll-Like Receptor network, in particular mutations of TLR4 and increased risk of DGF. Genes associated with acute rejection include those coding for TLR4, CCR5, THN-alpha and IL-6. VEGF mutations have been associated with improved long term graft survival whilst MDR1 polymorphism has been linked to chronic allograft injury. Pharmacogenetics and its understanding of the metabolism of CNIs and MMF are increasingly relevant to the management and dosing of these immunosuppressive agents. 

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