Increased glomerular filtration rate after withdrawal of long-term antihypertensive treatment in diabetic nephropathy

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 ...

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“…The finding is in accordance with previous results (16) and is likely to be caused by the changes in systemic BP.…”

Section: Discussionsupporting

confidence: 83%

Additive Effect of ACE Inhibition and Angiotensin II Receptor Blockade in Type I Diabetic Patients with Diabetic Nephropathy

Jacobsen¹,

Andersen²,

Jensen³

et al. 2003

Journal of the American Society of Nephrology

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194

146

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“…23 On the basis of extensive animal data, including micropuncture data from Brenner's group, an elevated FF is assumed to reflect elevated glomerular pressure, which contributes to long-term renal risk by glomerular capillary hypertension. 45 The validity of the glomerular hypertension hypothesis in humans is supported by intervention data in CKD, demonstrating predictive power of FF reduction for long-term renal prognosis 46,47 and by observational data in renal transplant recipients. 21 The combination of lower ERPF and higher FF indicates a higher postglomerular efferent arteriolar tone that can affect renal sodium handling by altering peritubular Starling forces, hampering sodium excretion, and hence contributing to sodium-sensitive hypertension.…”

Section: Discussionmentioning

confidence: 91%

Central Body Fat Distribution Associates with Unfavorable Renal Hemodynamics Independent of Body Mass Index

Kwakernaak

Zelle

Bakker

et al. 2013

Journal of the American Society of Nephrology

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Central distribution of body fat is associated with a higher risk of renal disease, but whether it is the distribution pattern or the overall excess weight that underlies this association is not well understood. Here, we studied the association between waist-to-hip ratio (WHR), which reflects central adiposity, and renal hemodynamics in 315 healthy persons with a mean body mass index (BMI) of 24.9 kg/m 2 and a mean 125 I-iothalamate GFR of 109 ml/min per 1.73 m 2 . In multivariate analyses, WHR was associated with lower GFR, lower effective renal plasma flow, and higher filtration fraction, even after adjustment for sex, age, mean arterial pressure, and BMI. Multivariate models produced similar results regardless of whether the hemodynamic measures were indexed to body surface area. Thus, these results suggest that central body fat distribution, independent of BMI, is associated with an unfavorable pattern of renal hemodynamic measures that could underlie the increased renal risk reported in observational studies.

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“…Several observations suggest that sulodexide activity in the kidney is complex, possibly modulating the renal expression of genes involved in renal remodeling: first, the persistence of the hypoalbuminuric effect up to 4 mo after cessation of therapy with the higher doses of sulodexide; second, the number of responders increases over the 4 mo of treatment, suggesting the hypoalbuminuric effect of sulodexide increases over time; and third, the similar extent of the hypoalbuminuric effect in patients with/without concomitant ACEI-therapy and the sharp difference between the persistent, posttreatment urinary albumin lowering effect of sulodexide and the rapid rise in AER seen shortly after discontinuation of ACEI therapy (36).…”

Section: Discussionmentioning

confidence: 91%

Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

Gambaro

Kinalska²,

Oksa³

et al. 2002

Journal of the American Society of Nephrology

172

126

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Abstract. Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensinconverting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine Յ150 mol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 Ϯ 0.18 at T0 to 3.98 Ϯ 0.11 at T4 (P Ͻ 0.05), which was maintained till T8 (4.11 Ϯ 0.13; P Ͻ 0.05 versus T0). Moreover, the sulodexideinduced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P ϭ 0.03; 49% [30 to 63%], P ϭ 0.0001; and 74% [64 to 81%], P ϭ 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P ϭ 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro-or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect.Diabetes is the most common cause of end-stage renal disease (ESRD) in Western countries. In the United States, diabetes currently accounts for 44% of all new cases of ESRD (1). Despite advances in clinical care, the incidence of diabetes mellitus type 2 (DM2)-related cases of ESRD is rapidly increasing (2), and survival of DM-related ESRD patients on dialysis is markedly low (3,4).The anatomic hallmarks of diabetic nephropathy (DN) include thickening of the glomerular basement membrane (GBM) and mesangial expansion with hyalinosis both in the mesangium and capillary lumen. These lesions lead to glomerular fibrosis, which progressiv...

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Increased glomerular filtration rate after withdrawal of long-term antihypertensive treatment in diabetic nephropathy

Cited by 86 publications

References 24 publications

Additive Effect of ACE Inhibition and Angiotensin II Receptor Blockade in Type I Diabetic Patients with Diabetic Nephropathy

Additive Effect of ACE Inhibition and Angiotensin II Receptor Blockade in Type I Diabetic Patients with Diabetic Nephropathy

Central Body Fat Distribution Associates with Unfavorable Renal Hemodynamics Independent of Body Mass Index

Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

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