Diabetes is the leading cause of kidney failure in the United States. The rising incidence of renal failure due to diabetes, especially type 2 diabetes, is a growing worldwide concern. The proportion due to diabetes of all cases of end-stage renal disease (ESRD) reached 50% at the most recent assessment. Approximately 30% of people with type 1 diabetes and 20% of those with type 2 diabetes develop progressive diabetic kidney disease.
Renal failure results from a progressive decline in the ability of the kidney to filter wastes from the blood. Evidence of kidney dysfunction, which is often present at the time of diagnosis in type 2 diabetes, is characterized by an increase in urine protein excretion (“microalbuminuria”) that usually precedes a decline in kidney filtration function. Treatment seeks to optimize glucose control, but this is difficult to achieve with available anti-diabetic therapy. Reducing systemic factors such as blood pressure and treatment with inhibitors of the renin-angiotensin system may slow the rate of progression of diabetic nephropathy, but do not stop the process of glomerulosclerosis that encroaches upon the glomerular filtration surface area. Over time, microalbuminaria proteinuria escalates to proteinuria and the filtration function of the kidney continues to decrease, marked by a rise in the serum creatinine level and an inexorable progression to ESRD requiring dialysis or transplantation.
Diabetic nephropathy requires therapy that specifically targets factors underlying its development and that are effective regardless of glycemic status. Albumin modified by Amadori-glucose adducts is a plasma-borne factor that activates cell signaling pathways and modulates the expression of molecular mediators that causally contribute to the development of diabetic nephropathy. In preclinical studies, GLY-230 has been shown to inhibit the formation of this Amadori-modified protein, decrease microalbuminuria, ameliorate abnormalities in molecular mediators, and attenuate glomerulosclerosis and the development of renal insufficiency despite prevailing hyperglycemia. In clinical studies in patients with diabetes, GLY-230 significantly reduced abnormal urine levels of markers indicating damage to the kidney filtration barrier.
A717, Glycadia’s humanized monoclonal antibody, addresses advanced diabetic nephropathy. In preclinical studies, chronic administration of the murine form of A717 to diabetic mice significantly decreased urine protein excretion, mesangial matrix accumulation, renal collagen IV and fibronectin overproduction, and lessened the rise in serum creatinine.
Diabetic Nephropathy References
Kidney International 61:2025-2032, 2002:
Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-ß1.
Kidney International 68:1554-1561, 2005:
Evidence linking glycated albumin to altered nephrin and VEGF expression, proteinuria, and diabetic nephropathy.
American Journal of Physiology Renal Physiology 292:F789-795, 2007:
Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV sub chain production and development of renal insufficiency.
American Journal Nephrology 31:110-116, 2010:
Anti-glycation and anti-albuminuric effects of GLY-230 in human diabetes
Biochim Biophys Acta 1830:5480-5485, 2013:
Clinical, pathophysiological and structure/function consequences of modification of albumin by Amadori-glucose adducts
Physiological Reports 1(4), 2013, e00083
Inhibiting Amadori-modified albumin formation improves biomarkers of podocyte damage in diabetic rats