normoglycemia [68]. The renoprotective pared to 42% in the placebo arm [55]. Later studies have effect of HMG CoA reductase inhibitors in patients with supported this finding [46]. Long-term studies (4 years) type 1 or type 2 diabetes with micro- or macroalbuminin hypertensive patients with type 2 diabetes and micro- uria appears to be highly variable [69]. Recently, we albuminuria have revealed a similar beneficial effect of demonstrated that intensified multifactorial intervention ACE inhibition and long-acting dihydropyridine calcium (pharmacologic therapy targeting hyperglycemia, hyperantagonists [48] and -blockers [49] on progression to tension, dyslipidemia, and microalbuminuria) in patients overt nephropathy. In contrast, a shorter term study (one with type 2 diabetes and microalbuminuria substantially year) dealing with fewer patients reported a greater ben- slows progression to nephropathy, retinopathy, and aueficial effect of ACE inhibition versus a long-acting dihy- tonomic neuropathy [60]. dropyridine calcium antagonist in hypertensive patients Mogensen and colleagues published a consensus rewith type 2 diabetes and microalbuminuria [62]. The role port on the detection, prevention, and treatment of diaof short-term “dual blockade” of the renin-angiotensin betic nephropathy with special reference to microalbusystem in hypertensive, microalbuminuric patients with minuria [70]. They recommended that physicians try to type 2 diabetes also has been evaluated [63]. A combina- improve blood glucose control and treat with ACE inhibtion of candesartan and lisinopril was even more effective itors. This recommendation is very cost-effective, mainly than monotherapy for reducing blood pressure in such because treatment for end-stage renal disease is so expatients, and the same trend was apparent for the reduc- pensive. From a pragmatic therapeutic standpoint, pretion in urinary albumin excretion rate. A long-term (two venting the progression of renal disease is most likely years) randomized double-blind, placebo-controlled trial to be achieved by a non-glycemic intervention such as evaluating the renoprotective effects of angiotensin II treatment with ACE inhibitors [56, 65]. type 1 receptor blockade in hypertensive, microalbumi- Tertiary prevention. As I mentioned earlier, arterial nuric patients with type 2 diabetes was terminated in hypertension, albuminuria, and poor glycemic control November 2000. are the most important risk factors for a progressive Table 2 shows the five randomized studies comparing decline in GFR in diabetic nephropathy, while dietary the renal effect of intensified blood glucose control com- protein intake generally has been found to play a minor pared to conventional treatment in patients with type 1 or no role. However, a meta-analysis based on five 2046 Nephrology Forum: Diabetic nephropathy Table 2. Randomized studies comparing the renal effects of intensive (I) blood glucose control versus conventional (C) treatment in patients with type 1 diabetes and microalbuminuria Baseline Change in number End of urinary albumin Follow-up with micro- Normo- study micro- excretion rate Study [Ref] years albuminuria albuminuria albuminuria Nephropathy %/year P DCCT [51] 6.5 0.09 I 38 23 0.15 for progression to nephropathy studies in patients with type 1 diabetes and microalbu- that the reduction in albuminuria and blood pressure minuria or proteinuria showed that a low-protein diet induced by ACE inhibition is primarily caused by inter- (0.8 g/kg/day) significantly slowed the increase in uri- ference with the renin-angiotensin system. Furthermore, nary albumin excretion rate or the decline in GFR or the study suggests that losartan represents a valuable creatinine clearance (relative risk 0.56; 95% CI, 0.40 to new drug in the treatment of hypertension and protein0.77) [71]. Flaws in design (short-term, non-randomized uria in patients with type 1 diabetes and nephropathy. cross-over study and self-control studies), methods (cre- Furthermore, we demonstrated that losartan can reduce atinine clearance), and insufficient adjustment for other the abnormally elevated size-selective property of the progression promoters, including antihypertensive treat- glomerular membrane in diabetic nephropathy, and that ment with ACE inhibitors, have weakened the strength this mechanism plays an important role in the antiproof that conclusion [72]. Much more robust data are at teinuric effect of this compound [75]. Finally, in a dose hand in nondiabetic renal disease [71]. Randomized trial escalation study of losartan (50, 100, and 150 mg daily) data dealing with the impact of improved glycemic con- we demonstrated that the optimal dose of losartan is 100 trol on progression of diabetic nephropathy is restricted mg daily for renoprotection and blood pressure reducto one study dealing with a limited number of patients tion in patients with type 1 diabetes and nephropathy [49]. [abstract; Andersen et al, Diabetologia 43 (Suppl 1): Recently, De Jong et al stressed the importance of A261, 2000]. utilization of careful measurement of urinary protein ex- I should stress that the antiproteinuric effect of ACE cretion when evaluating the renoprotective properties of inhibition in patients with diabetic nephropathy varies treatment; the analysis suggests that