Is diabetic nephropathy disappearing from clinical practice?

Diabetic nephropathy remains a major cause of mortality and morbidity in the diabetic population (1). This occurs not only as a result of the development of end-stage renal disease but albuminuria and impaired renal function also are major risk factors for premature cardiovascular disease in both forms of diabetes (2). Thus, strategies that can attenuate or prevent the development of diabetic renal disease remain as the major aims in the optimal management of the diabetic patient. In this issue of the journal, a report from a Norwegian group provides promising data suggesting a reduced risk of nephropathy in a group of patients with type 1 diabetes diagnosed more than 20 yr ago who were recently reassessed with respect to the presence of microvascular complications (3). In that study, it was suggested that the risk of nephropathy has decreased further over the past decade, although the exact explanation for this improving prognosis remains to be fully determined. Historical studies from the Steno center performed in patients more than 20 yr ago suggested that almost one half of patients with type 1 diabetes would develop renal disease, as assessed primarily by urinary albumin excretion (4). Subsequent studies in Denmark confirmed a gradual reduction in the prevalence of nephropathy, as assessed by both micro and macroalbuminuria, over the ensuing decades (5). The gradual decline in diabetic nephropathy was reported more than 10 yr ago in a Swedish study when it was shown that there had been a progressive reduction in the development of persistent albuminuria in subjects with type 1 diabetes diagnosed between 1966 and 1980. The current Norwegian study (3) reports on subjects diagnosed at a similar time between 1973 and 1982 and confirms those findings, emphasizing the changing nature and outlook of diabetic complications, including nephropathy, over the past three decades. Indeed, it appears that this improvement has ultimately translated to a stabilization or reduction in diabetic subjects entering renal replacement programs. Specifically, data from the Danish National Registry Report on Dialysis and Transplantation (6) described a 15% decrease in the number of diabetic patients referred for dialysis or transplantation since 2002, halting and possibly reversing an inexorable increase in diabetic patients on renal replacement therapy that has been seen over the past few decades. It remains unknown as to why there appears to be a decrease in diabetic renal disease. It is likely that it has occurred as a result of improved treatment, with several investigators suggesting that it is the multifactorial and more intensive approach now widely used in the management of diabetic patients that has been the main explanation for this phenomenon (6, 7). The Steno 2 study clearly demonstrated in subjects with type 2 diabetes that an approach involving improved glycemic control, widespread use of inhibitors of the renin–angiotensin system and lipid-lowering agents was associated not only with reduced progression of albuminuria but also with a decrease in other complications (7). This strategy is also likely to have been useful in patients with type 1 diabetes, although the multifactorial approach has not been specifically examined in this population. Furthermore, as recently described in an inception cohort study of subjects with type 1 diabetes diagnosed between 1979 and 1984 who were followed at the Steno hospital, glycemic control and blood pressure are major predictors for the development of renal disease (8).Nevertheless, the positive findings of intensified glycemic control as clearly demonstrated in the Diabetes Control and Complications Trial (9), the convincing evidence of angiotensinconverting enzyme (ACE) inhibition in subjects with early or overt renal disease (10, 11) and the benefits of statins on cardiovascular disease in subjects with type 1 diabetes in the Heart Protection Study (12) provide the rationale for a multifactorial approach in the type 1 diabetic patient. A major issue remains as to the underlying molecular and cellular mechanisms that are responsible for the development and progression of diabetic complications such as nephropathy. Increasingly it is appreciated that metabolic and hemodynamic factors not only promote the development of nephropathy but also may interact to amplify renal injury (13). For example, metabolic factors such as advanced glycated