Effects of statins on renal sodium and water handling

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1 Nephrol Dial Transplant (2008) 23: doi: /ndt/gfm807 Advanced Access publication 8 December 2007 Original Article Effects of statins on renal sodium and water handling Acute and short-term effects of atorvastatin on renal haemodynamics, tubular function, vasoactive hormones, blood pressure and pulse rate in healthy, normocholesterolemic humans Lone Paulsen 1, Charlotte Holm 1, Jesper Nørgaard Bech 2, Jørn Starklint 1 and Erling Bjerregaard Pedersen 1,2 1 Department of Medical Research, Holstebro Hospital and Aarhus University, Denmark and 2 Department of Medicine, Holstebro Hospital, Holstebro, Denmark Abstract Background. Statins have a beneficial effect on cardiovascular morbidity and mortality due to a reduction in plasma cholesterol. However, statins seem to have effects beyond the lowering of plasma cholesterol. We hypothesize that these effects are caused by an effect on renal function. Methods. We measured the effects of atorvastatin (AS) on renal function in two randomized, placebo-controlled, double-blinded and crossover studies in healthy man. In an acute trial (Study 1), 19 subjects received either 80 mg AS as a single dose or placebo. In a short-term trial (Study 2), 20 subjects received either 80 mg AS or placebo daily for 4 weeks. In both studies glomerular filtration rate (GFR), renal plasma flow (RPF), plasma concentrations of angiotensin II (Ang II), renin (PRC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), aldosterone (Aldo), vasopressin (AVP) and blood pressure (BP) were determined. Results. In Study 1 AS decreased fractional excretion of sodium (FE Na ) significantly (P = 0.035), but very modestly, and reduced diastolic BP (P = 0.024). Apart from this, we found no significant differences in GFR, RPF, tubular function and vasoactive hormones in either Study 1 or 2. Conclusions. An acute dose of AS decreased FE Na and DBP in healthy humans. The reduction in fractional urinary sodium excretion was very modest and transitory, and most likely secondary to the fall in diastolic blood pressure (DBP). However, renal haemodynamics, tubular function, vasoactive hormones and blood pressure were unchanged during short-term statin treatment in healthy man. Keywords: atorvastatin; glomerular filtration rate; healthy humans; renal plasma flow; sodium excretion Correspondence and offprint requests to: Lone Paulsen, Department of Medical Research, Holstebro Hospital, Lægårdvej 12, DK-7500 Holstebro, Denmark. Tel: ; Fax: ; 55@stofanet.dk Introduction Statin therapy is associated with reductions in cardiovascular morbidity and mortality [1,2]. The beneficial effects of statins are cholesterol lowering, but other non-lipiddependent (pleiotropic) effects may largely account for the clinical benefits of these agents. Pleiotropic effects have important clinical implications for the cardiovascular system and may include a beneficial effect on kidney function beyond their lipid-ameliorating action as well. In rats and pigs, statins prevented the development of renal injury and enhanced renal perfusion [3,4]. In patients with cardiovascular disease and moderate to severe kidney disease, statins reduce proteinuria and kidney function loss [5,6]. In patients with autosomal dominant polycystic kidney disease treatment with simvastatin increases glomerular filtration rate (GFR), renal plasma flow (RPF) and endothelial function, probably explained by the direct effect of statins on NO production [7]. No information is available about the acute and short-term effects of atorvastatin (AS) on renal function and blood pressure in healthy humans. For the first time, we investigated the effect of AS on renal salt and water handling in healthy subjects. We performed two randomized, placebo-controlled, crossover studies of the acuteand short-term effect of AS in healthy man. The purpose was to measure the effect of AS on renal haemodynamics, tubular function, vasoactive hormones and blood pressure. We wanted to test the hypothesis that treatment with a single dose of AS in an acute (Study 1) and short-term trial, i.e. 4 weeks of treatment with AS (Study 2) changes renal function. Improvements of renal function may explain some of the pleiotropic effects of statins. Subjects and methods Subjects The inclusion criteria in both studies were (1) age years, (2) body mass index <30. The following were C The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Effects of statins on renal sodium and water handling 1557 considered as exclusion criteria in both studies: (1) a history or clinical signs of disease of the heart, lungs, kidneys or endocrine organs; (2) abnormal laboratory screening tests (i.e. abnormal b-haemoglobin, p-sodium, p- potassium, p-albumin, p-creatinine, p-glucose, p-bilirubin, p-alaninaminotransferasis and p-alkaline phosphatase, albuminuria or glucosuria); (3) malignant neoplasm; (4) hypertension; (5) alcohol abuse: (6) medical therapy apart from oral contraceptives; (7) pregnancy or breast feeding; (8) blood donation <1 month before the studies. Withdrawal criteria in both studies included the following: (1) development of one or more of the exclusion criteria, (2) side effects of AS or other used drugs during the study, (3) poor compliance and (4) unwillingness to participate. Ethics The local medical ethics committee approved both studies and were carried out according to their rules. Written informed consent was obtained from all participants. Design Both studies were randomized, double-blinded, placebocontrolled and crossover. In Study 1, healthy subjects received 80 mg AS or placebo per os in the morning of the experimental day. In Study 2, healthy subjects received 80 mg AS or placebo per os daily for 4 weeks. There was a time interval of at least 4 weeks between the two experimental days in both studies. Number of subjects In both studies, the number of subjects needed was calculated at a significance level of 5% and with a power of 90%. For RPF, the minimum relevant difference was estimated to be 30 ml/min and the corresponding SD was estimated to be 40 ml/min. Thus, subjects were needed. Recruitmen of subjects In both studies, healthy subjects were recruited by announcements and notices in public institutions and private companies in the city of Holstebro, Denmark. Experimental procedure In Study 1, the subjects were instructed to fast overnight before each of the experimental days, but were allowed to drink water freely until the beginning of the study. A 24-h urine collection was performed the day before the study day and the subjects received 300 mg lithiumcarbonate at 22:00 h for measurement of lithium clearance. The subjects drank a glass of tap water before they met in the Research Laboratory at 07:45 h. Smoking was prohibited during the study. The subjects were in the supine position during the experimental period until 14:30 h, apart from when voiding. The subjects received 80 mg AS or placebo per os at 08:00 h. Indwelling catheters were placed in both forearms, one for infusion of 51 Cr EDTA and 125 I hippuran and one for withdrawal of blood samples. The subjects drank a glass of water (175 ml) every half hour. At 08:30 h, we infused a priming dose of 51 Cr-labelled EDTA and 125 I-labelled hippuran for the measurement of GFR and RPF, followed by constant infusions of both. Nine clearance periods were performed each of 30 min duration between 10:00 and 14:30 h. Urine was collected for measurement of sodium, lithium, volume, 51 Cr EDTA, 125 I hippuran and osmolarity in each period. Blood samples were drawn at the end of each clearance period for measurement of plasma concentrations of sodium, lithium, 51 Cr EDTA, 125 I hippuran and osmolarity. Blood samples were drawn at 11:30, 12:30, 13:30 and 14:30 h to determine plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), aldosterone (Aldo), vasopressin (AVP), angiotensin II (Ang II) and renin (PRC). BP and PR were measured every 30 min throughout the study. The subjects were weighed before and after the study. The experimental procedure in Study 2 was the same as in Study 1, except that five clearance periods were performed instead of nine between 10:00 and 12:30 h, blood samples for analysis of hormones were drawn once at 11:30 h instead of four times and endothelin-1 (ET- 1) in plasma and aquaporin 2 in urine (u-apq2) were measured. Measurements We measured GFR and RPF using the renal clearance of 51 Cr EDTA and 125 I hippuran by a constant infusion technique. ANP, BNP, AVP and Ang II in plasma were determined by radioimmunoassay as previously described [8,9]. Aldo was determined using a kit from Diagnostic Systems Laboratories Inc. (TX, USA). PRC was measured with a commercial immunoradiometric assay (Nichols Institute Diagnostics, Paris, France). U-AQP2 was measured by radioimmunoassay, as previously described [10]. ET-1 was measured by immunoassay (R&D Systems, Inc., Minneapolis, MN, USA). Minimal detection level was <1.0 pg/ml. Plasma and urinary lithium (P-Li, U-Li) were measured by atomic absorption spectrometry. Plasma osmolality (P-osm) and U-osm were measured by freezing-point depression (Advanced Instruments, Inc. The Advanced Model 3900, multisampling osmometer). Plasma and urinary concentrations of sodium (P-Na, U-Na) were measured by routine methods at the Department of Clinical Biochemistry, Holstebro Hospital (Holstebro, Denmark). BP and PR were determined using a digital blood pressure meter. All clearances were standardized to a body surface area of 1.73 m 2. Statistics SPSS, version 13.0 was used for the statistical analyses. Friedman s test was used for paired comparison between several groups. Wilcoxon s signed rank test was used for paired comparison between two groups, i.e. of the mean values of the results from each of the clearance periods during AS and placebo treatment, respectively. Data are given as medians with quartiles. The significance level was at P = 0.05.

3 1558 L. Paulsen et al. Table 1. The effect of acute treatment with atorvastatin (80 mg) compared to placebo (Study 1), and the effect of short-term treatment for 4 weeks with atorvastatin (80 mg) daily compared to placebo (Study 2) in healthy subjects Study 1 (n = 19) Study 2 (n = 20) Atorvastatin Placebo P Atorvastatin Placebo P V (ml/min) ( ) ( ) NS ( ) ( ) NS (C H2 O) (ml/min) ( ) ( ) NS ( ) ( ) NS C Na (ml/min) ( ) ( ) NS ( ) ( ) NS FE Na ( ) ( ) ( ) ( ) NS C Li (ml/min) ( ) ( ) NS ( ) ( ) NS FE Li ( ) ( ) NS ( ) ( ) NS U Na V(µmol/min) ( ) ( ) NS ( ) ( ) NS The effect variables were urine output (V), free water clearance (C H2 O), sodium clearance (C Na ), fractional excretion of sodium (FE Na ), clearance of lithium (C Li ), fractional excretion of lithium (FE Li ) and absolute sodium excretion (U Na V). Nine clearance periods were performed in Study 1 and five periods in Study 2. The mean values of the effect variables for the nine and five clearance periods are given for the AS and placebo periods in Study 1 and 2, respectively. Friedman s test did not show significant differences in the effect variables between the clearance periods either during atorvastatin or placebo treatment in neither Study 1 nor 2. Wilcoxon s test was used for comparison of medians. Data are given as medians with 25 and 75 percentiles. Results Demographics In Study 1, 19 healthy subjects were included: (1) males/females (14/5); (2) age, 31 years (26 39); (3) BMI, 23.8 ( ); (4) systolic blood pressure (SBP), mmhg, 112 ( ); (5) diastolic blood pressure (DBP), mmhg, 68 (65 73); (6) pulse rate, beats/min, 52 (49 61). All routine laboratory tests were normal. In Study 2, 20 healthy subjects were included: (1) males/females (13/7); (2) Age, 32 years (26 43); 3. BMI, 25.3 ( ); (4) SBP, mmhg, 109 ( ); (5) DBP, mmhg, 68 (60 74); (6) pulse rate, beats/min, 53 (49 57). All routine laboratory tests were normal. Baseline and laboratory characteristics for healthy subjects in Study 1 and 2 are given as medians with 25 and 75 percentiles. Renal haemodynamics A single dose of AS did not change GFR (ml/min) [AS: 92 (89 105); placebo 94 (87 104), P = NS], RPF (ml/min) [AS: 445 ( ); placebo 455 ( ), P = NS], or the filtration fraction (FF) [AS: ( ); placebo ( ), P = NS]. Neither did treatment with AS for 4 weeks change GFR (ml/min) [AS: 102 (92 108); placebo 100 (96 110), P = NS], RPF (ml/min) [AS: 459 ( ); placebo 473 ( ), P = NS], nor did it change the FF [AS: ( ); placebo ( ), P = NS]. Data are given as medians with 25 and 75 percentiles. Tubular function Table 1 shows that the fractional excretion of sodium (FE Na ) was significantly lower in the AS-treated group compared to the placebo group in Study 1 [AS: ( ); placebo: ( ), P = 0.035]. The reduction in FE Na by AS was very modest, and FE Na was unchanged in Study 2. Table 3 shows also that neither AS given acutely nor short-term induced any significant changes in V, C H2 O,C Na, C Li and FE Li. AS given for 4 weeks showed no significant changes in u-aqp2 [AS: 0.82 ( ) ng/ml; placebo: 0.79 ( ) ng/ml]. 24-h sodium excretion The 24-h urinary sodium excretion [AS: 204 ( ) mmol/24 h; placebo: 205 ( ) mmol/24 h] and urinary sodium/urinary creatinine ratio [AS: ( ); placebo: ( )] were not changed significantly after AS. However, in the shortterm study 24-h urinary sodium excretion was 26% lower in the AS-treated group compared to placebo [AS: 167 ( ) mmol/24 h; placebo: 225 ( ) mmol/24 h, P = 0.005]. This difference was also present when urinary sodium excretion was evaluated in relation to urinary creatinine excretion [AS: ( ); placebo: ( ), P = 0.028]. Vasoactive hormones Table 2 shows that no significant changes were measured in ANP, BNP, Aldo, AVP, Ang II and PRC after AS treatment in neither the acute nor the short-term study. AS given for 4 weeks showed no significant changes in ET-1 [AS: 0.65 ( ) pg/ml; placebo: 0.65 ( ) pg/ml] either. Blood pressure Table 3 shows that the DBP was significantly decreased by AS [AS: 62 (59 71) mmhg; placebo: 65 (62 71) mmhg, P = 0.024] in Study 1, whereas we found no significant

4 Effects of statins on renal sodium and water handling 1559 Table 2. The effects of a single dose of atorvastatin (80 mg) compared to placebo (Study 1) and 4-weeks treatment with atorvastatin (80 mg) daily compared to placebo (Study 2) in healthy subjects on plasma concentration of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), aldosterone (Aldo), vasopressin (AVP), angiotensin II (Ang II) and renin (PRC) Study 1 (n = 19) Study 2 (n = 20) Atorvastatin Placebo P Atorvastatin Placebo P ANP (pmol/l) ( ) ( ) NS ( ) ( ) NS BNP (pmol/l) ( ) ( ) NS ( ) ( ) NS Aldo (pmol/l) ( ) ( ) NS ( ) ( ) NS AVP (pmol/l) ( ) ( ) NS ( ) ( ) NS Ang II (pmol/l) (9 22) (10 19) NS (5 13) (6 13) NS PRC (µmol/l) (14 30) (12 32) NS (13 24) (10 23) NS In Study 1 hormones were measured four times during nine clearance periods. In Study 2 hormones were measured once during five clearance periods. The mean values of the effect variables are given for the AS and placebo periods in Study 1 and 2, respectively. Friedman s test did not show significant differences in the effect variables between the clearance periods either during atorvastatin or placebo treatment in neither Study 1 or 2. Wilcoxon s test was used for comparison of medians. Data are given as medians with 25 and 75 percentiles. Table 3. The effects of a single dose of atorvastatin (80 mg) compared to placebo (Study 1) and 4-weeks treatment with atorvastatin (80 mg) daily compared to placebo (Study 2) in healthy subjects on systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse rate (PR) Study 1 (n = 19) Study 2 (n = 20) Atorvastatin Placebo P Atorvastatin Placebo P SBP (mmhg) ( ) ( ) NS ( ) ( ) NS DBP (mmhg) (59 71) (62 71) (60 71) (61 72) NS MAP (mmhg) (74 86) (77 86) NS (75 85) (76 87) NS PR (beats/min) (48 59) (49 60) NS (52 60) (53 62) NS Effect variables were measured corresponding to nine clearance periods in Study 1 and five periods in Study 2. The mean values of the effect variables for the nine and five clearance periods are given for the AS and placebo periods in Study 1 and 2, respectively. Friedman s test did not show significant differences in the effect variables between the clearance periods either during atorvastatin or placebo treatment in neither Study 1 nor 2. Wilcoxon s test was used for comparison of medians. Data are given as medians with 25 and 75 percentiles. differences in the SBP. AS did not change SBP or DBP in Study 2. Discussion The present report comprises two randomized, placebocontrolled, crossover studies of the acute and short-term effect of AS in healthy man on renal haemodynamics, tubular function, vasoactive hormones and blood pressure. AS induced a very modest, although significant reduction in fractional renal excretion of sodium and a fall in DBP in our acute study, whereas SBP was unchanged. AS reduced 24-h urinary excretion of sodium in the short-term study and blood pressure was unchanged. Renal haemodynamics and vasoactive hormones were the same after statin treatment and placebo in both studies. Statins seem to influence blood pressure regulation under certain conditions. Thus, development of hypertension is prevented or postponed in spontaneous hypertensive rats [11], and an antihypertensive effect of statins has been shown in hypertensive patients [12]. DBP decreased slightly in the present study of the acute effect of AS treatment. However, statin treatment did not change blood pressure in the short-term study of 1 month s duration. It seems reasonable to conclude that systemic blood pressure is unaffected by treatment with statins in normotensive subjects. In rats, GFR and renal blood flow increased after treatment with a statin [11]. Statin treatment improved renal function in patients with ischaemic heart disease and in patients with autosomal dominant polycystic kidney disease [7,13]. However, in another study statin treatment did not induce significant changes in GFR or RPF [14].

5 1560 L. Paulsen et al. We found no changes in either GFR or RPF in healthy man in the present study. Thus, in healthy man, statin treatment does not induce significant alterations in renal haemodynamics. In animal experiments, lovastatin increased urine flow, renal sodium excretion and FE Na in spontaneously hypertensive rats [11]. We are the first to study the effect of statins on renal salt and water handling in healthy subjects. We found a very modest reduction in FE Na in the acute study, in contrast to studies in rats [11]. However, AS reduced DBP simultaneously in our study. Most likely, this increased tubular reabsorption of sodium is a transitory phenomenon and secondary to the reduction in blood pressure, and this effect disappeared in the short-term study. Surprisingly, we found a decrease in 24-h urinary sodium excretion in the short-term study, i.e. after 4 weeks of treatment with AS compared to placebo. This difference was also present when we calculated urinary sodium excretion in relation to urinary excretion of creatinine to eliminate a potential loss of urine during the 24-h urine collection. The body weight was the same after AS treatment and placebo for 1 month; thus, sodium and/or water depletion is unlikely. The subjects studied received an unrestricted diet with regard to sodium, water and food intake, and the difference in urinary sodium excretion might reflect variation in sodium intake, which varied considerably according to the variation in urinary sodium excretion at the examinations after placebo as well as after AS treatment. Since C H2 O,C Na,FE Na,C Li,FE Li and u-aqp2 all give some evaluation of tubular function directly or indirectly and since AS did not change any of these effect variables during 1 month of therapy, we have shown that AS does not affect renal tubular function at least in a short-term evaluation. Previous studies have shown that statins reduced plasma concentration levels of ANP [15], BNP [16], Aldo [17], AVP [18], Ang II [19] and ET-1 [15], whereas simvastatin did not change PRC [17]. We showed that AS did not change any of the vasoactive hormones measured in the acute or the short-term study. However, we studied healthy man, and the effect of statins on these hormones might differ between diseases, in which the regulation of the hormones can be abnormal primarily or secondarily to the disease or its complications. Statins differ with regard to lipophilicity and metabolism that may explain differences between studies of statins effect in different populations and in different vascular areas [20]. In conclusion, we demonstrated that the acute effect of AS treatment was a very modest and transitory reduction in fractional urinary sodium excretion, most likely secondary to a decrease in DBP in healthy subjects. However, renal haemodynamics, tubular function, vasoactive hormones and blood pressure were unchanged during short-term statin treatment in healthy man. Acknowledgements. We thank laboratory technicians Lisbeth Mikkelsen, Henriette Hedelund Vorup Simonsen, Anne Mette Ravn Torstensen, Eva Mølgaard Jensen and Susan Milton Rasmussen for skillful technical assistance and commitment. The study received support by grants from Ringkjoebing County and the Foundation for Medical Research in the County of Ringkjoebing. Conflict of interest statement. None declared. References 1. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999; 20: Sever PS, Dahlof B, Poulter NR et al. 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