Genetic and genomic approaches to glomerulosclerosis

Chronic kidney disease (CKD) is common, progressive and expensive to manage. Although modifiable risk factors can be treated and outcomes improved, CKD remains a chronic disease with excessive morbidity and mortality. The completion of the human genome sequence and the advent of methodologies to define gene function provide new opportunities to manage and treat patients with CKD and other chronic diseases. Despite the lack of clear correspondence between genotype and phenotype and an obvious Mendelian inheritance pattern, CKD susceptibility has a genetic basis. In this review, we focus on recent studies of familial focal segmental glomerulosclerosis and the discoveries that have resulted from both genetic and genomic approaches used to understand its pathogenesis. Key slit diaphragm proteins were discovered using linkage analyses of these rare causes of glomerulosclerosis and subsequent work has characterized slit diaphragm function in health and disease. Podocyte dysfunction is now recognized as a key contributor to the functional and histologic derangements that characterize glomerular dysfunction in many common causes of CKD. In aggregate, these studies provide a paradigm for approaches to better define mechanisms of CKD and to identify novel therapeutic targets.