with type 1 and type 2 diabetes have shown a term treatment trials with blood-pressure-lowering agents correlation between serum cholesterol concentration documented the validity of this concept in humans [2, 19]. and progression of diabetic nephropathy, at least in uniEvidence suggests that a special vascular vulnerability variate analyses [3, 4, 14, 15], although some studies have Nephrology Forum: Diabetic nephropathy 2043 failed to demonstrate cholesterol as an independent risk factor in multiple regression analysis. Our recent study of 301 patients followed during seven years indicates that elevated serum cholesterol acts as an independent promoter of progression [16]. Dietary protein restriction retards the progression of renal disease in virtually every experimental animal model tested [32]. Surprisingly, the major observational studies of patients with type 1 and type 2 diabetes and nephropathy have failed to show an impact of dietary protein intake on the rate of decline in GFR [3, 4, 7, 14, 27-29]. Christiansen suggested two decades ago that smoking Fig. 1. Average change in the rate of decline in glomerular filtration was an independent risk factor for the initiation of dia- rate (GFR) during long-term angiotensin-converting-enzyme inhibition betic glomerulopathy in patients with type 1 diabetes [33]. frequently combined with diuretics in patients with type 1 diabetes and This finding has been confirmed in numerous studies nephropathy, according to the I/D polymorphism of the angiotensinconverting- 0.01, [reviewed in 34]. In addition, some but not all studies DD vs. II ID. (From [40].) suggest that smoking can act as a progression promoter in patients with type 1 and type 2 diabetes and proteinuria [34]. More information is needed to draw a firm conclusion. (Fig. 1). Four other studies have demonstrated that the The increased synthesis of angiotensin II plays an im- D allele is a risk factor for an accelerated course of portant role in the initiation and progression of diabetic diabetic nephropathy in patients with type 1 diabetes [28, nephropathy by affecting hemodynamic and non-hemo- 29, 41, 42], although in one of the studies the tendency dynamic mechanisms [1]. Studies have shown that an towards a more rapid decline in renal function in the insertion (I)/deletion (D) polymorphism of the angioten- DD genotype was not significant [28]. The potential consin-converting enzyme (ACE) gene (ACE/ID) is associ- tribution from other relevant candidate genes remains ated with the level of circulating ACE and with an in- to be evaluated. creased risk of coronary heart disease in non-diabetic Prevention patients [35]. The plasma ACE level in patients with the DD genotype is about twice that of patients with the Treatment strategies include: primary prevention, that II genotype, and patients with the ID genotype have is, treatment modalities applied to any normalbuminuric intermediate values. Yoshida et al followed 168 protein- diabetic patient at risk; secondary prevention, that is, treaturic patients with type 2 diabetes for 10 years and found ment modalities applied to a diabetic patient with a high in an analysis of the clinical course of the three ACE risk (for example, microalbuminuria) for the development genotypes that the majority of the patients with the DD of diabetic nephropathy; and finally, tertiary prevention, genotype (95%) progressed to ESRD within 10 years that is, treatment of overt diabetic nephropathy aimed at [36]. Moreover, the DD genotype appears to increase preventing or delaying the development of ESRD. the mortality once dialysis is initiated. Two recent studies Primary prevention. Risk factors and markers for prohave confirmed that the D allele has a deleterious effect gression from normo- to micro- and macroalbuminuria on renal function in patients with type 2 diabetes [37, 38]. have been identified in patients with both type 1 and type Furthermore, more severe diabetic glomerulopathy le- 2 diabetes [43]. The two main treatment strategies that sions have been documented both during the develop- have been evaluated are blood-pressure–lowering drugs ment and the progression of renal disease in type 2 dia- and improved glycemic control. Three randomized plabetic patients with the D allele [abstract; Solini et al, cebo-controlled trials in normotensive type 1 and type 2 Diabetologia 43 (Suppl 1):A14, 2000]. Furthermore, mi- diabetic patients with normalbuminuria have suggested a croalbuminuric type 1 patients carrying the D allele have beneficial effect on the development of microalbuminuria an increased progression of diabetic glomerulopathy, a [44–46]. In contrast to these three studies, which were finding based on renal biopsies taken at baseline and carried out as placebo-controlled trials, the literature conafter 26 to 48 months of follow-up [39]. tains three new studies comparing the effect of ACE We showed an accelerated initial loss and a sustained inhibitors versus a long-acting dihydropyridine calcium loss of GFR during ACE inhibitor treatment of albumin- antagonist [47, 48], or blockade [49] in hypertensive uric type 1 patients homozygous for the DD polymor- type 2 diabetic patients with normoalbuminuria. All three phism of the ACE gene [40]. The DD genotype indepen- studies reported a similar beneficial renoprotective effect dently influenced the sustained rate of decline in GFR of blood