**5. Diabetic nephropathy**

Diabetes represents the most common single cause of end-stage renal disease (ESRD) in the United States and Europe. There can be several factors responsible for this, including an increased prevalence of T2DM, longer life spans among patients with diabetes, and better recognition of kidney disease [40]. Comparing with subjects with type 1 diabetes mellitus, only a smaller fraction of those with T2DM develop ESRD, but due to the increased prevalence of T2DM, these individuals represent more than a half of those with diabetes on dialysis. There are numerous variables in progressing to nephropathy, including racial/ethnic variability because Native Americans, Hispanics and African Americans are at much greater risk of developing ESRD than non-Hispanic white subjects with T2DM [40].

The first clinical signs of nephropathy are represented by low, but abnormal, levels (≥30 mg/day or 20µg/min) of albumin in the urine (previously referred to as microalbuminuria). The detection of albumin in the urine increases the risk of progression to persistent albumi‐ nuria, progressive decline in glomerular filtration rate (GFR), increased blood pressure and cardiovascular morbid-mortality. But because T2DM may be present for many years before diagnosis, a higher proportion of individuals with T2DM have microalbuminuria and overt nephropathy shortly after diagnosis. It is known that without treatment, 20-40% of patients with T2DM and microalbuminuria progress to overt nephropathy. Nevertheless, after 20 years from the onset of nephropathy, only 20% will have progressed to ESRD [40]. The explanation comes from the greater risk among subjects with diabetes and chronic kidney disease of dying from cardiovascular disease than progressing to ESRD.

Several clinical trials indicate that the onset and development of diabetic nephropathy may be significantly influenced by numerous interventions including tight glucose control and also use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. This is the reason why annual screening for microalbuminuria is critical since it can lead to early diagnosis of nephropathy. Numerous studies, including the well-known Diabetes Control and Compli‐ cations Trial and United Kingdom Prospective Diabetes Study indicated that intensive glycemic control represent a very important step in reducing the risk of developing microal‐ buminuria and overt nephropathy [40].

New data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial offers hope regarding the benefic effects of tight glucose control on decreasing the risk of nephropathy [41]. In the ADVANCE trial, after almost 5 years, subjects that were on intensive glycemic control had a 10% relative reduction in the combined outcome of major macrovascular and microvascular events. This was happening mainly because of a 21% relative reduction in the risk of developing nephropathy. The intensive glucose control is also important because it is associated with a 9% reduction in new onset microalbuminuria [41]. Results of this study are of great importance since renal impair‐ ment is strongly associated with future risk of major vascular events, and death in patients with diabetes. Nevertheless, the role of modified renal glucose reabsorption in the progression of diabetic nephropathy is not elucidated [4].
