Pyridoxamine, advanced glycation inhibition, and diabetic nephropathy.

Diabetic nephropathy remains the most common cause of ESRD, accounting for more than 40% of patients treated with dialysis. The standard therapy fordiabetic nephropathy consists of early detection, aggressive glycemic control, and treatment of hypertension and proteinuria using renin-angiotensin system (RAS) blockade. Both angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective in slowing the progression of diabetic nephropathy. Despite the standard of care, many patients continue to progress, and the prevalence of patients with ESRD secondary to diabetic nephropathy continues to rise. More effective agents are sorely needed. The molecular pathogenesis of diabetic nephropathy is not fullyunderstood,butbothhemodynamicandmetabolicmechanisms are likely involved. Tackling the hemodynamic factors with RAS blockade has proven beneficial. Many therapeutic agents that may be able to interfere with metabolic pathways are currently under investigation, and a few may be promising. For example, reduced insulin receptor signaling on the podocytes due to insulin resistancemay accelerate diabetic kidney changes, and insulin sensitizers such as thiazolidinediones reduce albuminuria in clinical studies. Albumin-induced oxidation products activate stress genes and tubular apoptosis in diabetic nephropathy. Chronic inflammation and increased oxidative stress are also frequently associated with endothelial and mesangial cell injury, mesangial space expansion, and diabetic glomerulosclerosis, and the antioxidant and inflammation modulator, bardoxolone methyl, slows the progression of disease in patients with advanced diabetic nephropathy. The antifibrotic agent pirfenidone also decreases the rate of decline in estimated GFR among patients with diabetic kidney disease. Studies using other agents, however, have been disappointing. While endothelin expression is increased in diabetic nephropathy and has potent vasoconstrictive, proinflammatory, and profibrotic effects, its blockade using avosentan does not deter diabetic nephropathy andmay increase risk of heart failure and edema. Also, sulodexide, a glycosaminoglycan that can alter the glomerular capillary barrier and reduce albuminuria in animalmodels, failed to decrease albuminuria in patientswith type 2 diabetes. Persistent hyperglycemia modifies lipids and proteins by nonenzymatic covalent binding of sugar residues through a series of complex biochemical reactions, leading to the formation of advanced glycation end products (AGEs). High levels of AGEs are present in diabetic patients, and experiments in animal models suggest that AGEs induce direct injury to the mesangial cells and podocytes as they upregulate gene expression of collagen and TGFb1 in diabetic glomerular lesions. AGEs mediate their actions by receptor-dependent or -independent mechanisms. The receptors for AGEs are expressed on podocytes, and the inhibition of their activity reduces the expression of TGFb, mesangial expansion, and basement membrane thickening. Therefore, inhibition of AGE formation seems to be an attractive therapeutic option that may alter the pathogenesis and delay the progression of diabetic kidney disease. Agents that have been found to affect tissue and/or circulating AGE levels include aspirin, thiamine, thiazolidinediones, carnosines, ACEIs, ARBs, and pyridoxamine. The fact that many of these agents also have direct hemodynamic effects may be confounding. Pyridoxamine (Pyridorin; NephroGenex, Inc.) inhibits the formation of AGEs from glycated proteins and by trapping pathogenic reactive carbonyl compounds, the intermediates in the formation of AGEs. It delays the development of diabetic nephropathy and reduces albuminuria in animal models of both type 1 and type 2 diabetic nephropathy. Two phase II clinical studies were conducted in patients with mild to moderate type 1 and type 2 diabetic nephropathy, and the merged results were analyzed post hoc by Williams et al. In this study, the data from 65 patients assigned to 50 mg of pyridoxamine twice daily compared with 63 patients receiving placebo for 24 weeks and that of 57 patients taking 250 mg of pyridoxamine twice daily compared with 27 patients taking placebo for 20 weeks were combined for evaluation of safety and efficacy. In separate analyses, pyridoxamine had some or little effect on change in renal function comparedwith baseline. However, after merging the data, pyridoxamine appeared to have a significant effect in reducing the slope of creatinine change from baseline compared with placebo (percent serum creatinine changed5248%, P50.03), and the effect was even more impressive among the subgroup with type 2 diabetes and baseline serum creatinine.1.3mg/dl. Although pyridoxamine did not affect urine albumin excretion, it significantly reduced plasma AGE level compared with the placebo group. Whereas the result here was encouraging, the posteriori and subgroup analyses might be associated with unintended biases. Notably, the authors documented a higher incidence of serious adverse events such as cardiovascular events or infections among the higher pyridoxamine dose group, but the events were thought to be unrelated to the medication. Published online ahead of print. Publication date available at www.jasn.org.