Aldose reductase inhibitors and diabetic kidney disease.

Diabetic kidney disease, or diabetic nephropathy, is the leading cause of kidney failure in developed countries and is projected to place an increasingly heavy burden on medical, social and economic systems worldwide. Existing therapies can slow, but do not stop, disease progression. Recent data from preclinical models and patients with diabetes emphasize the need for reducing excess metabolic flux through aldose reductase, an enzyme that plays a critical role in transducing the metabolic abnormalities that cause fibrosis in the diabetic kidney. The background and developmental history of aldose reductase inhibitors are reviewed briefly, as are metabolic, hemodynamic and genetic data linking aldose reductase to diabetic kidney disease. A new paradigm defining the pathogenic role of aldose reductase, the 'metabolic flux hypothesis', is presented, along with updated pharmacological goals for achieving success with this class of inhibitors in diabetic kidney disease.