Effect of pravastatin on kidney function and urinary protein excretion in autosomal dominant polycystic kidney disease

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1 Scandinavian Journal of Urology and Nephrology, 2010; 44: ORIGINAL ARTICLE Effect of pravastatin on kidney function and urinary protein excretion in autosomal dominant polycystic kidney disease ROBERT G. FASSETT 1,2,3, JEFF S. COOMBES 3, DAVID PACKHAM 4, KENNETH F. FAIRLEY 5 & PRISCILLA KINCAID-SMITH 5 1 Royal Brisbane and Women s Hospital, Brisbane, Queensland, Australia, 2 School of Human Movement Studies and 3 School of Medicine, The University of Queensland, Brisbane, Australia, 4 Department of Nephrology, Northern and Royal Melbourne Hospitals, Victoria, Australia, and 5 Department of Nephrology, Epworth Hospital, Melbourne, Victoria, Australia Abstract Objective. Autosomal dominant polycystic kidney disease (ADPKD) is progressive, resulting in end-stage kidney failure in most patients. Experimental and clinical studies have suggested that statins may slow the progression of chronic kidney disease in general and ADPKD specifically. Material and methods. This randomized open-label clinical trial was conducted to assess the effect of pravastatin 20 mg on kidney function and urinary protein excretion in patients with ADPKD. Sixty patients were initially recruited but 49 of these received either pravastatin 20 mg or no treatment for 2 years. Trial visits were conducted every 3 months, assessing kidney function by estimated glomerular filtration rate and 24 h urine creatinine clearance and urinary protein excretion. Results. There were no significant (p > 0.05) changes in markers of kidney function or urinary protein excretion between groups over the 2 years despite a significant fall in total serum cholesterol in pravastatin-treated patients (p = 0.029). Conclusion. This trial found that taking 20 mg pravastatin for 2 years had no significant effect on kidney function or urinary protein excretion in patients with ADPKD. The lack of statistical power limits the external validity of these findings. A larger, longer duration study using a higher dose of a more potent statin is required. Key Words: Autosomal dominant polycystic kidney disease, chronic kidney disease, creatinine clearance, estimated glomerular filtration rate, pravastatin, proteinuria Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a progressive disease responsible for 5 6% of patients reaching end-stage kidney failure and requiring dialysis each year in Australia [20]. As there are no specific therapies for ADPKD, recent clinical interventions have focused on non-specific approaches to slow kidney disease progression. These approaches include using agents such as angiotensinconverting enzyme inhibitors (ACEIs) [2] and the combination of ACEIs and angiotensin II receptor blockers (ARBs) [3]. Reduced dietary protein intake [4] and strict blood pressure control [5] are also often prescribed, as in any progressive kidney disease. Statins may also have a role in the treatment of chronic kidney disease (CKD) by improving vascular outcomes and perhaps slowing disease progression [6 8]. The effect of statins on kidney function may relate not only to their cholesterol-lowering properties, but also their pleiotropic effects including their ability to reduce inflammation and fibrosis [9 12]. Lovastatin decreased the severity of experimental polycystic kidney disease in the Han:SPRD rat [13]. Other experimental studies and small clinical trials have suggested that statins can reduce urinary Correspondence: R. G. Fassett, Director of Renal Research, Renal Medicine, Level 9, Ned Hanlon Building, Royal Brisbane and Women s Hospital, Brisbane, Queensland, Australia Tel: Fax: rfassett@mac.com (Received 24 February 2009; accepted 21 September 2009) ISSN print/issn online Ó 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: /

2 protein excretion and slow the progressive decline of kidney function in CKD from a broad range of aetiologies [14 17]. This is also supported by three meta-analyses [7,18,19]. However, the most recent meta-analysis did not support a benefit for kidney function despite there being a reduction in proteinuria with statin therapy [8]. In a 4 week study conducted on 10 patients with ADPKD the administration of simvastatin 40 mg was associated with an improvement in kidney function as measured using inulin clearance [20]. Patients with CKD have usually been excluded from large cardiovascular clinical trials assessing the efficacy of statins in reducing morbidity and mortality. However, in some of these studies where patients with CKD were unintentionally included, post hoc analyses have also suggested that statins are effective in slowing the decline of kidney function [21 25]. It was with this background that this prospective randomized open-label clinical trial was conducted in ADPKD patients. The trial assessed whether pravastatin 20 mg could slow the progression of kidney dysfunction in patients with ADPKD. Material and methods The trial was approved by the ethics committees of each institution and conforms to the provisions of the Declaration of Helsinki (as revised in Edinburgh 2000). The trial is registered with the Australian New Zealand Clinical Trial Registry, actr.org (ACTRN ). Study population Sixty patients with ADPKD were recruited from the clinical practices of nephrologists in Melbourne, Victoria, Australia and Launceston, Tasmania, Australia. Patients were included with a confirmed diagnosis of ADPKD based on a kidney ultrasound examination, a positive family history and at all levels of kidney function and serum cholesterol levels. Women of childbearing age and those participating in another investigational within 30 days were excluded. Eligible patients were required to provide written informed consent after receiving the patient information sheet and consent form from a nephrologist at a clinic visit. Over a 2-year period all potentially eligible patients at the clinics with ADPKD who met the inclusion criteria were approached and invited to enter the trial. Patients were randomly assigned to receive either pravastatin 20 mg orally daily or no therapy using repeating blocks of 10 from a computer-generated random number list. The patients were followed with 3 monthly trial visits for 2 years. Outcome measures The primary outcome was kidney function measured by Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (egfr) and secondary outcomes included creatinine clearance, and urinary protein excretion measured with a 24 h urine collection. Measures performed at trial visits At each 3 monthly clinical trial visit fasting blood samples were collected together with a 24 h urine collection and blood pressure measurement. Biochemical analyses Clinical chemistry measures were carried out in the National Accredited Testing Authority (NATA) pathology laboratories at the Launceston General Hospital Launceston, and the Epworth Hospital, Melbourne. Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, serum and urinary creatinine and urinary protein were measured with an automated analyser (Olympus Au600 Clinical Chemistry Analyzer; Mishima Olympus Co., Japan). Glomerular filtration rate was estimated (egfr) using the MDRD formula [26]. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedewald equation [27]. Creatinine clearance was calculated using the standard formula. Data analysis Pravastatin in polycystic kidney disease 57 Mean ± SD and difference of means for lipid values and blood pressures were estimated by repeatedmeasures mixed methods linear regression, with p values corrected for multiple comparisons by the Holm method. For egfr, creatinine clearance and urinary protein excretion the repeated-measures mixed methods linear regression was adjusted for age and gender. Urinary protein excretion showed a markedly skewed distribution and mean ± SD are shown for illustrative purposes only: comparison is performed on a box-cox transformation, with the difference and 95% confidence intervals shown. A p value of < 0.05 was considered statistically significant.

3 58 R. G. Fassett et al. Results Forty-nine patients out of the 60 initially recruited completed the trial. Nine of the 11 who were lost to follow-up had been randomized to the control group. This left 29 patients in the active treatment group and 20 in the control group. Baseline characteristics of the 49 patients are shown in Table I. There were no significant differences (p > 0.05) between groups in relation any of these parameters. Table II shows there was a significant reduction in total cholesterol (p = 0.029) in pravastatin-treated Table I. Baseline characteristics of patients who completed the study. Pravastatin Control group group (n = 29) (n = 20) Female (%) ns Age (years) 53 ± ± 12 ns egfr (ml/min/1.73 m 2 ) 58.5 ± ± 23.2 ns Creatinine clearance (ml/s) 1.31 ± ± 0.41 ns Urinary protein excretion (g/day) 0.37 ± ± 0.23 ns Total cholesterol (mmol/l) 5.22 ± ± 0.75 ns LDL-C (mmol/l) 3.52 ± ± 0.67 ns HDL-C (mmol/l) 1.08 ± ± 0.43 ns Triglyerides (mmol/l) 1.65 ± ± 0.41 ns Systolic BP (mmhg) ± ± 15.0 ns Diastolic BP (mmhg) 87.8 ± ± 9.0 ns Medication: ACEI or ARB 79% 75% ns egfr = estimated glomerular filtration rate; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; BP = blood pressure; ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ns = not significant. Table II. Lipid levels before treatment and mean levels on treatment. p patients but not in controls. LDL-cholesterol decreased in pravastatin-treated patients but this was not statistically significant. There were no differences in pre- to post-trial values for blood pressures in either group and there were no significant (p > 0.05) differences between groups in percentage change for any of the variables (Table III). Table IV shows pretrial and rate of change data for egfr, creatinine clearance and 24 h urinary protein excretion. There was a 23% reduction in the rate of egfr change in pravastatin-treated patients compared with control patients. However, this was not statistically significant (p = 0.78). Conversely, creatinine clearance decreased in pravastatin-treated patients compared with controls but this was also not statistically significant. Urinary protein excretion decreased by 2.8% in pravastatin-treated and increased 21.2% in untreated patients. Discussion ADPKD is a progressive disease with no specific primary treatment to prevent the eventual progression to end-stage kidney disease, hence alternative nonspecific therapies have been explored. This small, open-label, randomized clinical trial compared treatment with pravastatin 20 mg with no therapy. The results of this study showed that taking pravastatin 20 mg for 2 years had no significant effect on kidney function or urinary protein excretion in patients with ADPKD. These findings are in agreement with data reported from the PREVEND IT study [28], where 40 mg pravastatin was administered to people recruited from the general population with microalbuminuria for 4 years. Although these studies involved strictly Comparison a Pretreatment On treatment Mean ± SD Mean ± SD Difference 95% CI p Total cholesterol Control 4.91 ± ± to Pravastatin 5.22 ± ± to LDL-C Control 3.08 ± ± to Pravastatin 3.52 ± ± to HDL-C Control 1.38 ± ± to Pravastatin 1.08 ± ± to Triglycerides Control 1.19 ± ± to Pravastatin 1.65 ± ± to a Means ± SD and difference of means estimated by repeated-measures mixed methods linear regression, with p values corrected for multiple comparisons by the Holm method. CI = confidence interval; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol.

4 Pravastatin in polycystic kidney disease 59 Table III. Blood pressures in patients with autosomal dominant polycystic kidney disease before and after taking pravastatin for 2 years and control patients. Pravastatin difference Control difference Pre Post Pre Post Comparison p value a Systolic BP (mmhg) ± ± 13.3 # 2.0 ± ± ± 14.8 # 3.3 ± Diastolic BP (mmhg) 87.8 ± ± 6.4 # 3.7 ± ± ± 7.8 " 2.1 ± a Means ± SD and difference of means estimated by repeated-measures mixed methods linear regression, with p values corrected for multiple comparisons by the Holm method. BP = blood pressure. Table IV. Estimated mean initial and rate of change in glomerular filtration rate, creatinine clearance and urinary protein excretion in patients with autosomal dominant polycystic kidney disease taking pravastatin or control for 2 years. different populations the subjects had similarities, both having normal kidney function, blood pressure and serum cholesterol at baseline. Pravastatin had no significant effect on urinary microalbumin concentrations or cardiovascular events in the PREVEND IT randomized controlled trial (RCT) study. Pravastatin had no significant effect on urinary microalbumin concentrations or cardiovascular events in the PRE- VEND IT RCT [28]. The finding that pravastatin 40 mg was ineffective in the PREVEND IT study is in keeping with the present results. The dose of pravastatin used in the PREVEND IT study was greater than in this study and had a more substantial effect on serum lipid concentrations. In this study the fall in serum cholesterol in pravastatin treated subjects was less than expected, although significant. The dose of 20 mg was considered adequate at the time the study started; however, it would be considered a low dose now. Other statin trials in kidney disease have also produced negative results. First, the ALERT study assessed the effect of fluvastatin 40 mg on both cardiovascular events and kidney function in renal transplant patients. While effective in reducing cardiovascular events when fluvastatin was started within the first 4 years of transplantation, there was no effect on kidney function [29]. Secondly, although it did not assess kidney function, the 4D study found that Control (n = 17) Pravastatin (n = 25) Comparison a Initial Rate of change (year 1 ) Initial Rate of change (year 1 ) Rate of change (year 1 ) Difference 95% CI egfr (ml/min/1.73 m 2 ) 49.9 ± ± ± ± ( 6.02 to 8.07) 0.78 Creatinine clearance (ml/s) 1.40 ± ± ± ± ( 0.18 to 0.05) 0.09 UPE (g/day) b 0.22 ± ± ± ± ( 0.32 to 0.33) 0.98 a Means ± SD and difference of means estimated by repeated-measures mixed methods linear regression, adjusted for age and gender. b Urinary protein excretion (UPE) showed a markedly skewed distribution, and mean ± SD are shown for illustrative purposes only: comparison is performed on a box-cox transformation of UPE, with the difference of this abstract number and 95% confidence interval (CI) shown. egfr = estimated glomerular filtration rate. atorvastatin 20 mg was ineffective at reducing cardiovascular events in haemodialysis patients [30]. A positive result was demonstrated in a small, 4 week study that assessed whether simvastatin 40 mg could improve kidney function and renal plasma flow in patients with ADPKD. Ten patients were randomized sequentially to simvastatin 40 mg or placebo [20]. Kidney function was measured using inulin clearance. Although this study specifically assessed ADPKD patients it was of short duration and included very small numbers. However, investigators in this study measured kidney function accurately as well as measuring renal plasma flow. The recent metaanalysis reported by Strippoli et al. also concluded that statins had no effect on kidney function [8]. Although, in the present study, pravastatin lowered circulating lipid concentrations (decreased total cholesterol by 7.2% and LDL-cholesterol by 5.8%), only the reduction in total cholesterol reached statistical significance. It is possible that an improvement in kidney function and urinary protein excretion may require a greater reduction in lipid concentrations that may require a higher dose of statin therapy or the use of a more potent statin. In addition, the changes in kidney function over 2 years were small (egfr decreased by 2.9% and creatinine clearance decreased by 0.1% in the control patients). For a positive effect of statins to be observed it may be necessary to recruit p

5 60 R. G. Fassett et al. a larger number of patients with a greater decline in kidney function at entry into the trial. This trial had several limitations, including the open-label design with the control group receiving no therapy and the fact that the markers of kidney function used were not the most sensitive available. In addition, the small sample size may have affected the findings. For example, owing to a large variability in the changes in urinary protein excretion within groups there was only a power of 0.17 (alpha = 0.05) to detect the observed difference in change in this variable between groups. To increase the power to 0.8 would have required 137 patients per group to detect a change of 50% between groups. The powers for the observed differences in egfr and creatinine clearance were 0.33 and 0.34, respectively. It is possible, therefore, that pravastatin treatment had no effect on the progression of polycystic kidney disease in this study. egfr and creatinine clearance are not as sensitive or valid as measures of kidney function such as isotopic GFR, iohexol or inulin clearance, and urinary microalbumin. Hence, a larger, double-blind, randomized, placebo-controlled trial with more accurate kidney function measures may be required to assess the role of statins in CKD caused specifically by ADPKD. A component of the Study of Heart and Renal Protection (SHARP) study, currently in progress, will assess whether 20 mg simvastatin and 10 mg ezetimibe can slow the progression of kidney disease, which may help to resolve some of the gaps in our understanding [31]. The present group is currently conducting the LORD (Lipid Lowering therapy in Renal Disease) trial, a double-blind, randomized, placebo-controlled trial comparing the effects of atorvastatin 10 mg compared with placebo in patients with chronic kidney disease with serum creatinine < 120 mmol/l [32,33]. While neither of these studies is specifically assessing patients with ADPKD, such patients will be included. In addition, these studies are assessing the effects of statins in more advanced kidney disease. In conclusion, this small, prospective, open-label, randomized clinical trial did not demonstrate any effect of taking pravastatin 20 mg for 2 years on kidney function or urinary protein excretion in patients with ADPKD. The small sample size achieved does not allow conclusions to be drawn from these data. Further, larger, longer RCTs using a potent statin in CKD and specifically ADPKD are required. 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