New potential agents in treating diabetic kidney disease: the fourth act.
Despite the worldwide epidemic of chronic kidney disease complicating diabetes mellitus, current therapies directed against nephroprogression are limited to angiotensin conversion or receptor blockade. Nonetheless, additional therapeutic possibilities are slowly emerging. The diversity of therapies currently in development reflects the pathogenic complexity of diabetic nephropathy. The three most important candidate drugs currently in development include a glycosaminoglycan, a protein kinase C (PKC) inhibitor and an inhibitor of advanced glycation. In targeting primary mechanisms by which hyperglycaemia contributes to diabetic complications, these drugs could provide risk reduction complementary to the partial reduction proven for ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers). Glycosaminoglycans act to restore glycoproteins present in reduced amounts in the glomerular basement membrane and mesangium of diabetic animal models. Components of the drug sulodexide prevent pathological changes and proteinuria in diabetic rats. Reductions in albuminuria, a hallmark of early diabetic kidney disease, have been reported in initial human trials. In the US, a multicentre phase II study has been completed, with an interim analysis indicating reduction in urinary albumin losses. Pivotal phase II trials have begun in patients with type 2 diabetes. A second metabolic pathway of diabetic complications is overexpression of PKC. Several activators of this family of intracellular kinases have been identified and PKC activation may result in tissue damage through a variety of mechanisms. In animal models, the inhibitor ruboxistaurin reduces albuminuria, diabetic histological changes and kidney injury. Like sulodexide, drug development of ruboxistaurin has reached completion of a phase II evaluation with mixed results. The third metabolic target is the nonenzymatic formulation of advanced glycation end-products (AGEs) through well described biochemical pathways. Multiple pathways lead to AGE accumulation in tissues in diabetes and diverse AGE products are formed. AGE deposition has been implicated in animal models of diabetic nephropathy. The leading AGE inhibitor currently in development is pyridoxamine, which has multiple actions that inhibit glycation. Pyridoxamine is an efficient AGE inhibitor in experimental diabetes. A phase II study in diabetic patients with nephropathy reported mixed efficacy results and a favourable safety profile. Phase III evaluation of pyridoxamine has not begun. These three classes of potential therapies, if successfully developed, will confirm that diabetic kidney disease has entered the era of biochemical treatments.
Williams
Mark E
ME
Renal Unit, The Joslin Diabetes Center, Boston, Massachusetts 02215, USA. mark.williams@joslin.harvard.edu
D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D006025:Glycosaminoglycans / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008301:Maleimides / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011733:Pyridoxamine / Q000627:therapeutic use; D012076:Renal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D015507:Drugs, Investigational; D017127:Glycation End Products, Advanced; D006025:Glycosaminoglycans; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D012076:Renal Agents; D011733:Pyridoxamine; C099154:ruboxistaurin; C007858:glucuronyl glucosamine glycan sulfate; D011493:Protein Kinase C