Advanced glycation end-products in diabetic nephropathy

Throughout the industrialized (well-fed) Adverse effects of hyperglycaemia, once thought an epiphenomenon in the pathogenesis of diabetic microworld, diabetes mellitus is the most prevalent cause of end-stage renal disease (ESRD). Diabetic nephropathy and macrovascular complications, presently are a central focus of active clinical and basic investigation is as likely to develop in long-duration non-insulindependent diabetes (type 2) as in insulin-dependent [3]. For example, the US Diabetes Control and Complications Trial (DCCT) found that intensive diabetes mellitus (type 1). Nephropathy in diabetes follows a well outlined course, starting with microalbumetabolic control, meaning better regulation of ambient plasma glucose concentration, retarded developminuria through proteinuria, azotaemia and culminating in ESRD. Renal functional decline in diabetic ment or progression of diabetic microalbuminuria, retinopathy and neuropathy [4]. Sustained euglycaenephropathy is slowed by establishment of euglycaemia and normalization of hypertensive blood pressure. mia reduces the enlarged kidney size typical of early hyperfiltration [5]. Furthermore, there is inferential Diabetic ESRD patients, compared with other causes of ESRD, sustain greater mortality and morbidity due reason to continue to strive for euglycaemia even after the patient lapses into uraemia. Careful metabolic to concomitant systemic disorders, especially coronary artery and cerebrovascular disease. A central role for glucose regulation during the progressive decline in renal function typical of diabetic nephropathy is glucose toxicity, especially the adverse impact of accumulated advanced glycosylated end-products (AGEs), rewarded by better survival once maintenance haemodialysis becomes necessary [6 ]. appears likely from experimental data generated both in induced diabetic rodents and diabetic individuals. Treatment with aminoguanidine raises the possibility of blocking end-organ damage in diabetes without the necessity for correcting hyperglycaemia. Toxicity of glucose Whereas initial formulations of how glucose might be Background toxic to tissues and organs were simplistic (Figure 2), subsequently, an enormous literature documents the Registries of end-stage renal disease (ESRD) in 1997, injurious consequences of complex protein–kinin–enin the US, Japan and industrialized Europe, show that zyme interactions stimulated by a high ambient plasma diabetes mellitus is the most prevalent cause of treated glucose concentration (Figure 3). Based on observarenal failure world-wide. More than a decade previtional studies tying glycaemic control to proteinuria ously, Mauer and Chavers grasped the trend in ESRD and decline in glomerular filtration rate (GFR) plus demographics in stating that ‘Diabetes is the most more than half a dozen interventive studies predicting important cause of ESRD in the Western world’ [1]. and confirming the DCCT, it is established that hyperBoth the incidence and prevalence of diabetic ESRD glycaemia is the main metabolic perturbation causing patients have increased yearly over the past decade. irreversible kidney damage in diabetes. There are three Statistics for 1995, listed in the 1997 report of the candidate mechanisms to explain how hyperglycaemia United States Renal Data System ( USRDS), underdamages tissues [7]: (i) Acceleration of the aldose score this point. Of 257 266 US patients receiving either reductase pathway leading to toxic accumulation of dialytic therapy or a kidney transplant in 1995, 80 667 sorbitol in nerves. (ii) Activation of isoform(s) of had diabetes [2], a prevalence rate of 31.4%. During protein kinase C (PKC) in vascular tissue initiating a 1995, of 71 875 new (incident) cases of ESRD, 28 740 cascade of events culminating in diabetic complications (40%) had diabetes (Figure 1). [8]. PKC activity is increased in renal glomeruli, retina, aorta and heart of diabetic animals, probably because Correspondence and offprint requests to: E. A. Friedman, MD, Chief, of increased synthesis de novo of diacylglycerol (DAG), Renal Disease Division, Department of Medicine, State University a major endogenous activator of PKC [9]. of New York, Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, New York 11203, USA. (iii) Accelerated non-enzymatic glycosylation with © 1999 European Renal Association–European Dialysis and Transplant Association