The next generation of diabetic nephropathy therapies: an update.
Although treatments for diabetic kidney disease are available, many patients still have progressive disease. More effective therapies are urgently needed. Novel agents currently under evaluation in clinical trials are described in this review. Sulodexide, a mixture of three glycosaminoglycans, appears to prevent diabetic nephropathy in experimental models by ameliorating abnormalities in the glomerular basement membrane and mesangial matrix. Pyridoxamine is an inhibitor of advanced glycation end-product (AGE) formation derived from vitamin B(6). Alagebrium is an AGE cross-link breaker. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking, among others. By inhibiting AGE formation or breaking AGE cross-links, experimental models have demonstrated kidney protection. Ruboxistaurin is an inhibitor of protein kinase C beta (PKC-beta), a mediator of signal transduction that leads to cell growth, fibrosis, and tissue injury. In diabetes, PKC-beta is up-regulated and activated in the kidney. Ruboxistaurin prevents diabetic kidney disease in animal models. These agents have appeared promising (by reduction of albuminuria and preservation of kidney function) in phase II studies. To determine whether clinical outcomes (mortality, renal, and cardiovascular events) are improved beyond the current standard of care, phase III trials are planned.
Williams
Mark E
ME
Joslin Diabetes Center, Boston, MA 02215, USA.
Tuttle
Katherine R
KR
D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D018450:Disease Progression; D004791:Enzyme Inhibitors / 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; D023421:Models, Animal; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011733:Pyridoxamine / Q000627:therapeutic use; D012076:Renal Agents / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006025:Glycosaminoglycans; D007211:Indoles; D008301:Maleimides; D012076:Renal Agents; D013844:Thiazoles; D011733:Pyridoxamine; C099154:ruboxistaurin; C007858:glucuronyl glucosamine glycan sulfate; C406794:alagebrium; D011493:Protein Kinase C