Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

Aims/hypothesis. It has been suggested that aldosterone plays a role in the initiation and progression of renal disease independently of arterial blood pressure and plasma angiotensin II levels. We evaluated the influence of plasma aldosterone levels on progression of diabetic nephropathy during long-term blockade of the renin-angiotensin-aldosterone system. Methods. A total of 63 hypertensive patients with type 1 diabetes and diabetic nephropathy were treated with losartan, 100 mg once daily, for a mean follow-up period of 35 months. Plasma aldosterone, GFR, albuminuria and 24-h blood pressure were determined at baseline and at regular intervals during the study. Results. Patients were divided according to their increasing or decreasing levels of plasma aldosterone during long-term losartan treatment in an escape group (n=26) and a non-escape group (n=37). In the escape group, aldosterone levels increased from (geometric mean [95% CI]) 57 pg/ml (43-76 pg/ml) at 2 months, to 102 pg/ml (78-134 pg/ml) at the end of the study (p<0.01). The corresponding levels in the non-escape group were 83 pg/ml (69-102 pg/ml) and 49 pg/ml (40-60 pg/ml; p<0.01). The median rate of decline in GFR was 5.0 ml·min −1 ·year −1 (range 0.4-15.9 ml·min − 1 ·year −1 ) in the escape group, compared with 2.4 ml·min −1 ·year −1 (−1.6 to 11.0 ml·min −1 ·year −1 ) in the non-escape group (p<0.005). The increase in plasma aldosterone correlated with the rate of decline in GFR (r 2 =0.19, p<0.001), corresponding to a decline in GFR of 1.5 ml·min −1 ·year −1 for every two-fold increase in plasma aldosterone. Pre-treatment and treatment values of plasma aldosterone were not related to albuminuria or to changes in albuminuria during the study. Conclusions/interpretation. Our data suggest that aldosterone escape during long-term blockade of the renin-angiotensin-aldosterone system is associated with an enhanced decline in GFR in patients with type 1 diabetes and diabetic nephropathy.

Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN. Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection.

Abstract. Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients. This study tested whether dual blockade of the renin-angiotensin system (RAS) with both an angiotensin-converting enzyme (ACE) inhibitor (ACE-I) and an Angiotensin-II receptor blocker (ARB) is superior to either drug alone in type I diabetic patients with diabetic nephropathy (DN). A randomized double-blind crossover trial was performed with 8-wk treatment with placebo, 20 mg of benazepril once daily, 80 mg of valsartan once daily, and the combination of 20 mg of benazepril and 80 mg of valsartan. Twenty type I diabetic patients with DN were included. At the end of each treatment period, albuminuria, 24-h BP, and GFR were measured. Eighteen patients completed the study. Placebo values were: albuminuria [mean (95% CI)], 701 (490 to 1002) mg/24 h; BP [mean (SEM)], 144 (4)/79 (2) mmHg, and GFR [mean (SEM)], 82 (7) ml/min per 1.73 m 2 . Treatment with benazepril, valsartan, or dual blockade significantly reduced albuminuria and BP compared with placebo. Benazepril and valsartan were equally effective. Dual blockade induced an additional reduction in albuminuria of 43 % (29 to 54 %) compared with any type of monotherapy, and a reduction in systolic BP of 6 (0 to 13) mmHg and 7 (1 to 14) mmHg (versus benazepril and valsartan, respectively) and a reduction of 7 (4 to 10) mmHg diastolic compared with both monotherapies. GFR was reversibly reduced on dual blockade compared with monotherapy and placebo. All treatments were safe and well tolerated. In conclusion, dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN.Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetes (1,2). Antihypertensive treatment, especially ACE-I, has been shown to reduce albuminuria, to diminish loss of kidney function, and to improve survival in type I patients with DN (1-3). Studies of diabetic and nondiabetic kidney disease suggest the initial degree of reduction in albuminuria after blockade of the reninangiotensin system (RAS) predicts an attenuated rate of decline in GFR, as reviewed by Rossing (1). As a consequence, albuminuria may serve as a surrogate end point for monitoring treatment efficacy and prognosis in DN (4).A superior effect on BP and a tendency toward a more pronounced drop in urinary albumin excretion of dual blockade of the RAS compared with single blockade has been reported in type II patients with microalbuminuria (5). We have recently shown additional drop in albuminuria and diastolic BP when adding an angiotensin receptor blocker (ARB) to angiotensinconverting enzyme inhibitor (ACE-I) treatment in type l patients with albuminuria Ͼ1 g/24 h and BP Ͼ135/85 mmHg, despite conventional antihypertensive therapy including three different agents (6). However, this subgroup is highly selected; therefore, it may differ from the patients in general with DN, especially with regard to RAS activity and ...

The angiotensin II subtype 1 receptor antagonist, losartan, reduces albuminuria and MABP similar to the effect of ACE inhibition. These results indicate that the reduction in albuminuria and blood pressure during ACE inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy.

Hyperglycemia is a risk marker of morbidity and mortality in acute critical illness, and insulin therapy seems to be beneficial in this patient group. Whether this is true for a population of sepsis patients, as such, has not been investigated in clinical trials, but evidence from in vitro studies and experimental sepsis suggests that this may be the case. The endocrinology of septic patients is characterized by a shift in the balance between insulin and its counter-regulatory hormones favoring the latter. This leads to prominent metabolic derangements composed of high release and low use of glucose, amino acids, and free fatty acids (FFA), resulting in increased blood levels of these substrates. Circulating, proinflammatory mediators further enhance this state of global catabolism. Increased levels of glucose and FFA have distinct effects on inflammatory signaling leading to additional release of proinflammatory mediators and endothelial and neutrophil dysfunction. Insulin has the inherent capability to counteract the metabolic changes observed in septic patients. Concomitantly, insulin therapy may act as a modulator of inflammatory pathways inhibiting the unspecific, inflammatory activation caused by metabolic substrates. Given these properties, insulin could conceivably be serving a dual purpose for the benefit of septic patients.

Recent studies have shown that both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of diabetic nephropathy. To examine whether markers of tubular damage are useful in monitoring the progression of disease, we measured urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), liver-fatty acid-binding protein (LFABP), and kidney injury molecule-1 (KIM-1) in a 3-year intervention study of 63 type 1 diabetic patients with kidney disease. The baseline mean glomerular filtration rate (GFR) was 87 ml/min per 1.73 m(2) and urinary albumin excretion 1141 mg/24 h. Patients with the highest compared with the lowest quartile of urinary NGAL at baseline had higher urinary KIM-1 levels and a significant decrease in their GFR each year. Using linear regression analysis, we found that elevated urinary NGAL and KIM-1 concentrations were associated with a faster decline in GFR, but not after adjustment for known promoters of progression. Urinary LFABP was not related to decline in GFR. Losartan treatment (100 mg/day) reduced urinary KIM-1 by 43% over a 12-month period. Thus, urine biomarker measurements in patients with type 1 diabetic nephropathy did not provide additional prognostic information to that of known progression promoters.

Renoprotective effects of angiotensin II receptor blockade inDiabetic nephropathy is a serious long-term complicatype 1 diabetic patients with diabetic nephropathy.tion in type 1 diabetes mellitus. Diabetic nephropathy, Background. Angiotensin I-converting enzyme (ACE) incharacterized by persistent albuminuria, a relentless dehibitors reduce angiotensin II formation and induce bradykinin cline in glomerular filtration rate (GFR), and raised arteaccumulation. Animal studies suggest that bradykinin may play rial blood pressure, develops in 30 to 40% of all type 1 a role for the effects of ACE inhibition on blood pressure diabetic patients [1]. Previous studies have documented and kidney function. Therefore, we compared the renal and hemodynamic effects of specific intervention in the reninthat inhibition of the renin-angiotensin system by angioangiotensin system by blockade of the angiotensin II subtype-1 tensin I-converting enzyme (ACE) inhibitors consisreceptor to the effect of ACE inhibition. tently reduces albuminuria and retards renal injury [2, 3].Methods. A randomized, double-blind, cross-over trial was However, the principal mechanism of action of these performed in 16 type 1 diabetic patients (10 men), age 42 Ϯ renal effects is not completely understood. ACE is not 2 years (mean Ϯ sem). The study consisted of five periods, each lasting two months. The patients received losartan 50 mg, a very specific enzyme and has other substrates such as losartan 100 mg, enalapril 10 mg, enalapril 20 mg, and placebo bradykinin. Therefore, ACE inhibitors not only decrease in random order. At the end of each period, albuminuria, 24the production of angiotensin II, but also cause accumuhour blood pressure, and glomerular filtration rate (GFR) were lation of bradykinin. Bradykinin is a potent vasodilator determined.acting through the release of prostacyclin, nitric oxide, Results. Both doses of losartan and enalapril reduced albuand endothelial-derived factors [4]. Recent animal and minuria (P Ͻ 0.05) and mean arterial blood pressure (MABP; P Ͻ 0.05), whereas GFR remained stable. Albuminuria was human studies have suggested that bradykinin may play reduced by 33% (95% CI, 12 to 51) on losartan 50 mg, 44% a role in the effects of ACE inhibition on blood pressure (95% CI, 26 to 57) on losartan 100 mg, 45% (95% CI, 23 to 61) and kidney function [5, 6]. Furthermore, angiotensin II on enalapril 10 mg, and 59% (95% CI, 39 to 72) on enalapril is not only generated by the ACE pathway, but also 20 mg, and MABP fell by 9 Ϯ 2, 8 Ϯ 2, 6 Ϯ 3, and 11 Ϯ 3 through alternative pathways such as the chymase pathmm Hg (mean Ϯ sem), respectively. No significant differences way [7]. These alternative pathways are not affected by were found between the effects of losartan 100 mg and enalapril 20 mg. HbA 1C and sodium intake remained unchanged through-ACE inhibition. Therefore, ACE inhibitors will not comout the study, whereas a significant rise in serum potassium pletely block the formation of angiotensin II. Specific occurred during ACE inhibitio...