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Dr. Nicolas Werner
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The use of inhibitors of the renin angiotensin system (RAS) can significantly reduce mortality and morbidity in patients with cardiovascular disease 1-7. In addition, in patients with and without diabetes, angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB) slow progression of nephropathy 8-10. However, in clinical practice the use of inhibitors of the RAS in appropriate doses is limited due to dose-related changes in serum creatinine and potassium levels in patients with advanced renal insufficiency.
Why do ACE-I increase serum creatinine levels? ACE-I reduce the intraglomerular pressure. In combination with a decreased effective arterial blood volume which results in a reduced pressure in the afferent arteriole, the single nephron is no longer able to maintain glomerular filtration pressure and filtration rate (GFR). The combination of ACE-I therapy and hypoperfusion of the kidneys (e.g. after aggressive diuretic therapy in patients with low output heart failure) with the loss of the kidneys' ability for pressure autoregulation, are the most common causes for an acute rise in serum creatinine following RAS inhibition 11.
In large-scale prospective clinical ACE-I trials, patients with advanced renal insufficiency were excluded for the above mentioned reasons and consequently data on renal outcome and change of cardiovascular risk has not been determined in this group of patients.
Hou and collegues recently investigated the effect of benazepril in 422 Chinese patients with non-diabetic renal insufficiency 12. The patients were divided according to their creatinine levels: Group 1 included patients with creatinine levels of 1.5 to 3.0 mg/dl (n=104) while group 2 included patients with levels of 3.1 to 5.0 mg/dl (n=224). After a 8 week run-in, patients in group 1 received 10mg benazepril bid whereas patients in group 2 received 10mg benazepril or placebo (n=112 each). Patients were followed for a mean of 3.4 years. In order to achieve a blood pressure of less than 130/80 mmHg the use of antihypertensive drugs other than ACE-I or ARB was allowed. The primary outcome was a combined end point consisting of a doubling of serum creatinine levels, end-stage renal disease or death. Secondary end points were the rate of urinary protein excretion, and the progression of renal disease (creatinine level, clearance, GFR).
102 patients (22%) in group 1, 44 patients (41%) in group 2 (benazepril), and 65 patients (60%) in group 2 (placebo) reached the primary endpoint. Treatment with benazepril significantly reduced the occurrence of the primary endpoint compared to placebo. However, patients with creatinine levels of 1.5-3.0 mg/dl (group 1) had a significant better outcome with benazepril treatment compared to patients with creatinine levels between 3.1 and 5.0 mg/dl (group 2) under the same dose of benazepril (p=0.003). Compared with placebo treatment, benazepril resulted in a significant risk reduction (43%, p=0.005) in group 2 patients independently of blood pressure reduction (p=0.009). Interestingly, benazepril was able to reduce the risk for end-stage renal disease by 40% (p=0.02) and significantly improved secondary endpoints.
The results of the study demonstrate that benazepril mediates renal protection even in advanced stages of renal disease in non-diabetic patients. This effect was blood pressure independent. Health care providers may reconsider the restricted use of inhibitors of the RAS in patients with chronic renal disease. By any means, treatment with ACE-I in renal insufficiency requires close monitoring of renal function and serum potassium levels. Absolute contraindications for ACE-I are bilateral renal stenosis, the occurrence of a Quincke edema during therapy with ACE-I, and serum potassium levels of >5.5 mmol/L. Further studies are necessary to demonstrate whether renoprotection is a class effect of ACE-I in advanced renal disease and whether data can be transferred to the Caucasian population.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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N. Werner1,2 and M. Böhm2 1 Medizinische Klinik und Poliklinik Klinik für Innere Medizin II Universitätsklinikum Bonn 53105 Bonn
2 Klinik für Innere Medizin III Universitätsklinikum des Saarlandes 66421 Homburg-Saar
Correspondence: Nikos Werner, MD Medizinische Klinik und Poliklinik Innere Medizin II Universitätsklinikum Bonn Sigmund-Freud-Str. 25 53105 Bonn phone +49-228-287-5217/5218 fax +49-228-287-6423 Email: email@example.com
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