COMPLETE INHIBITION OF RENAL RESERVE IN CHRONIC RENAL FAILURE BY A COMBINATION OF ACEI AND ARB

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1 COMPLETE INHIBITION OF RENAL RESERVE IN CHRONIC RENAL FAILURE BY A COMBINATION OF ACEI AND ARB CG Musso ¹, J Reynaldi¹, N Imperiali ¹, L Algranati ¹, DG Oreopoulos ² Nephrology Department Hospital Italiano de Buenos Aires - Argentina¹ Nephrology Department Toronto Western Hospital - Canada² Abstract Renal reserve (RR) is the kidney s capability to increase its basal glomerular filtration rate (GFR) by at least 20% after an adequate stimulus such as a high protein intake. Angiotensin converting enzyme inhibitors have been proposed as agents to inhibit glomerular hyperfiltration. However, some studies have found that these drugs are not able to modify the RR in chronic kidney disease (CKD) patients. We carried out a prospective study in order to evaluate the behaviour of the RR on the CKD patients receiving, in a random sequence, either no medication (period 1), or enalapril 10 mg (period 2), or losartan 50 mg (period 3), or both of them (period 4). Material and Methods: We studied five CKD patients (stages 3, 4) on a low protein diet. Exclusion criteria were cardiac failure, arrhythmia, hypothyroidism, cirrhosis, and use of non-steroidal anti-inflammatory agents. Each patient underwent a RR test (creatinine clearance with cimetidine before and after an oral protein overload) during the above mentioned sequence of medications, with a two week wash-out period (free of drug) between protocols. Results A mean difference was calculated between the pre and post protein load value for all patients at each treatment period (1: no medication, 2: angiotensin converting enzyme inhibitor (ACEI): enalapril, 3: angiotensin receptor blocker (ARB): losartan and 4: enalapril + losartan). We compared these means applying an ANOVA test. Even though, the p value was not significant (p: 0.2), probably due to the small number of patients studied, we detected a clear trend to a smaller difference between pre and post protein load GFR in the group 4 (enalapril + losartan). pre - post differences for each treatment Means medias 1

2 1: no medication, 2 enalapril, 3: losartan, 4: enalapril + losartan Conclusion: The combined therapeutic scheme (enalapril 10 mg + losartan 50 mg) showed a trend to prevent the increase in GFR after a protein overload. 2

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4 Introduction Assessment of renal function in patients with CKD is necessary to allow for the adjustment of medication, to evaluate disease progression, and to determine the time for initiation of replacement therapy. Creatinine clearance is not a reliable test for this purpose because a considerable part of creatinine excretion in the urine is due to tubular secretion (1). The most practical, low cost, and reliable method for evaluating glomerular filtration rate (GFR) seems to be the cimetidine-aided creatinine clearance (CACC), especially that which uses oral doses of the drug. Because cimetidine inhibits creatinine secretion in the proximal tubules, the ratio of the cimetidine-aided creatinine clearance and GFR is about 1.1 ± 0.02 (2,3,4). Renal reserve (RR) is the kidney s capacity to increase its basal glomerular filtration rate (GFR) by at least 20% after an adequate stimulus such as a protein overload (5). This glomerular hyperfiltration may have a deleterious effect on GFR if it is sustained over long periods. Angiotensin converting enzyme inhibitors (ACEI) have been proposed as agents that inhibit glomerular hyperfiltration (6). However, some studies found that these drugs do not modify the RR in patients with CKD (7). We carried out a prospective study in order to evaluate the change in RR in patients with CKD receiving a randomized sequence of : no medication, enalapril 10 mg, losartan 50 mg, or both of them. 4

5 Material and Methods In this preliminary study, we evaluated five patients with chronic kidney disease (stage 3 and 4), in whom the diagnosis of CKD was based on clinical data, and on the GFR determined by CACC, ultrasound and/or renal biopsy. Exclusion inclusion criteria were: Inclusion criteria: Resting GFR between ml/minute/1.73m2 determined by CACC. Patients on a low protein diet: 0.8 g/kg/day (provided by nutritionist) Exclusion criteria: Presence of cardiac failure, hypothyroidism, cardiac arrhythmia, angina, and /or cirrhosis. Patients on chronic treatment with non-steroidal antiinflammatory agents. All patients signed an informed consent approved by our institution s Ethics Committee. In each patient, we performed first a resting GFR using a CACC test and, after that, a RR test as described by Hellerstein et al (7). Two weeks before performing these studies, we stopped all ACEI and angiotensin II receptor blocker (ARB) medications. During this period, the patient was seen weekly and if s/he became hypertensive was treated with a calcium channel blocker or methyldopa. After both test (resting CACC and RR) were performed, the patient continued on a low protein diet, adding consecutively, in a random fashion, enalapril 10 mg/day, losartan 50 mg/day, or both drugs in the same dose each. RR was measured after two weeks on each regimen. Each patient was tested with all the three schemes and RR was measured at the end of each period. The three different treatment periods of 14 days each were separated by two weeks without medication. 5

6 During the study all patients were evaluated monthly by blood pressure, plasma potassium and creatinine measurement. If required, blood pressure was controlled by increasing the dose of calcium channel blockers or methyldopa. ANOVA test was applied for the statistical analysis Results Each study period was 14 days long (enalapril 10 mg/day, losartan 50 mg/day and on both of them respectively). Period I was the control period. We calculated a mean difference between the pre- and post -renal reserve test CACC measurement (pre and post protein overload) for all patients at each stage (1,2,3,4). We compared these means by applying an ANOVA test. Even though the p value was not significant (p: 0.2), probably due to the small number of tested patients (n = 5), a clear trend was detected to a smaller difference between pre- and post-protein load GFR in period 4 (enalapril + losartan). Conversely, this difference was the highest in the period 1 (controls). pre - post differences for each treatment Means medias Figure 1: pre-post difference for each treatment Discussion Renal reserve (RR) is the kidney s capacity to increase its basal glomerular filtration rate (GFR) by at least 20% after an adequate stimulus such as a protein overload (8). 6

7 It is generally accepted that the amino acid components of the protein per se induce the renal response through local vasodilatation and hyperfiltration (9). The renal response to protein or amino acids load, is attributed to tubular-glomerular feedback (TGF). It is postulated that specialized cells in the walls of the distal tubule, called macula densa, sense some indicator of the tubular flow rate (sodium or chloride concentration or transport rate), and signal to the afferent arteriole to vasoconstrict or vasodilate in response to changes in this indicator. An increase in plasma amino-acid levels would result in an increase in the filtered load of amino acids at any given GFR and would provoke an increase in tubular amino-acid reabsorption. Because amino acids and sodium are cotransported in the proximal tubule, proximal sodium chloride reabsorption would also increase, resulting in a decrease in sodium delivery to the distal tubule and macula densa. The TGF mechanism results in afferent arteriolar vasodilatation and a consequent increase in renal blood flow and GFR. It has been proposed that this vasodilatation phenomenon is the result of a local release of prostaglandins, nitric oxide and kinins (10-14). Proximal tubule dysfunction (e.g. Fanconi syndrome) or blockage of the macula densa function (e.g. loop diuretics), do not lead to an increase in the GFR after a protein overload. This indicates that the normal RR response requires a normal proximal tubule and macula densa function. Moreover, several lines of evidence suggest that extrarenal factors are not required to enable hyperfiltration to take place. Angiotensin II contributes to glomerular hyperfiltration by stimulating efferent arteriolar vasoconstriction, in this way leading to an increase in the glomerular filtration fraction. Moreover, this hormone also induces sodium reabsorption in the proximal tubules by 7

8 stimulating the sodium-proton antiporter. As a result the amount of luminal sodium detected in the macula densa diminishes, leading to vasodilatation of the afferent arteriole and consequently to hyperfiltration (1,10). It is known that ACEI and ARB inhibit glomerular hyperfiltration, and one can speculate that the RR response would be blocked in patients on any of these drugs. However, only in the period 4 of our study (enalapril + losartan) did we observe an almost total blockage of RR response (pre-post glomerular filtration rate diference around zero). In the other periods (enalapril or losartan alone), the RR response was lower compared to the basal one, but not completely abolished. Since ACEIs work by inhibiting angiotensin II synthesis and in addition by stimulating kinin production, and ARBs act by blocking angiotensin II receptors, it makes sense that a combination of these agents would obtain a complete RR inhibition. The partial RR inhibition observed in period 2 could be explained by the binding of those angiotensin II molecules, produced by the not inhibited converting enzymes, to their receptors, as well as the concomitant induced kinin vasodilatation. On the other hand, in those patients on ARB treatment, angiotensin II molecules, which were produced by the not inhibited converting enzymes, will not be bound to their receptors and consequently will not have any effect (15,16). It seems that there is a direct relationship between the degree of angiotensin II inactivation and the renal reserve response. Conclusion: In this preliminary report, we observed that the combined effect of enalapril 10 mg + losartan 50 mg led to almost complete inhibition of the renal reserve namely the increase in GFR after a protein overload in patients with stage 3 or 4 chronic kidney disease. 8

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