Treatment of Alport syndrome: beyond animal models

Alport syndrome (AS) is a hereditary glomerulopathy due to abnormal composition of the glomerular basement membrane, leading to end-stage renal disease (ESRD). Studies of animal models of AS have suggested a variety of potentially effective therapies, but none of these has been definitely shown to prevent or delay ESRD in human AS. Studies in Alport mice suggest that angiotensin inhibition not only has antiproteinuric effects but suppresses cytokine and collagen production as well as tubulointerstitial fibrogenesis and inflammation. For these reasons, many Alport patients are treated empirically with angiotensin antagonists. Cyclosporine may reduce proteinuria in AS, but the risk of nephrotoxic side effects complicates long-term therapy in children. Current data on the role of HMG-CoA reductase inhibition are sparse, so therapy should be limited to adults with dyslipoproteinemia. Results of some, but not all, studies suggest that bone marrow–derived cells may ameliorate disease in Alport mice. However, until experimental doubts concerning the superiority of bone-marrow transplantation over other treatments are resolved by additional investigation, human research subjects should not be exposed to cell-based therapies that may carry substantial risks. In summary, all potential therapies are off-label use in children. As a consequence, initial therapeutic trials should focus on the safety and efficiency of medical treatment, as well as the optimal timing of therapy.