Approaches to understanding susceptibility to nephropathy: from genetics to genomics.

The incidence of end-stage renal disease (ESRD) is increasing worldwide despite efforts to slow the progression of chronic renal failure (CRF) by controlling blood pressure and hyperglycemia. Two available therapies for ESRD, dialysis and transplantation, are expensive and are at best palliative. Recently, data from several laboratories have demonstrated that ESRD is under substantial genetic control, and efforts to identify these genetic determinants are underway. Identifying genes for ESRD pathogenesis has several goals. First, understanding the genetic basis of ESRD offers a means to clarify the mechanisms that result in kidney pathobiology. Second, better and new treatments for prevention of progression of CRF to ESRD may be developed. Third, individuals at risk could be identified early in their course and targeted for intensive therapy. Finally, the products of genes causing disease become target molecules for gene therapy. In this article, we discuss data from our laboratories, which employ two different molecular genetic strategies for identifying ESRD pathogenesis genes. In contrast to traditional experimental design, both approaches are hypothesis generating, identifying candidate molecules for further study, rather than hypothesis driven and may provide novel insights into mechanisms of renal disease progression.