No effect of enalapril on progression in autosomal dominant polycystic kidney disease

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1 Nephrol Dial Transplant (2003) 18: DOI: /ndt/gfg417 Original Article No effect of enalapril on progression in autosomal dominant polycystic kidney disease Marjan A. van Dijk 1, Martijn H. Breuning 2, Rik Duiser 3, Leendert A. van Es 1 and Rudi G. J. Westendorp 4 1 Department of Nephrology, 2 Clinical Genetic Center, 3 Clinical Chemical Laboratory and 4 Department of General Internal Medicine and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands Abstract Background. Angiotensin-converting enzyme (ACE) inhibitors are capable of reducing proteinuria and microalbuminuria with preservation of renal function in diabetic and non-diabetic renal disease. We designed a study investigating the effect of enalapril on the protection of renal function in autosomal dominant polycystic kidney disease (ADPKD). Methods. We studied 61 normotensive and 28 hypertensive ADPKD patients. The normotensive group participated in a randomized double-blind placebocontrolled study, using enalapril. The hypertensive group was randomized for open label treatment with enalapril or the -blocker atenolol. The follow-up was 3 years, and renal function was established repetitively by measuring the clearance of inulin. Results. In the normotensive group, renal function at baseline was 112 ± 3 ml/min and decreased by 8 ± 2 ml/min (P < 0.001). The loss of renal function in the patients treated with enalapril or placebo was similar ( 7±3 vs 9 ± 1 ml/min; P ¼ 0.4). Although blood pressure significantly decreased with enalapril treatment, it had no effect on microalbuminuria. In the hypertensive group, renal function at baseline was 89 ± 2 ml/min. The mean decline in renal function was 12 ± 2 ml/min (P < 0.001), and was equal in patients treated with enalapril and those treated with atenolol. The patients treated with atenolol required more additional treatment to control blood pressure, but no difference on microalbuminuria was observed between the two treatments. Conclusion. This study was unable to detect a beneficial effect of ACE inhibition on loss of renal function in ADPKD patients. Correspondence and offprint requests to: Professor M. H. Breuning, Clinical Genetic Center, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands. M.H.Breuning@lumc.nl Keywords: ACE inhibition; ADPKD; GFR; progression; randomized trial Introduction With a prevalence of 1 per 1000 population, autosomal dominant polycystic kidney disease (ADPKD) significantly contributes to the burden of renal failure. End-stage renal failure in ADPKD typically occurs in the fifth decade of life [1]. In order to avoid chronic dialysis or transplantation, it is important to identify, and eventually modify the determinants of decline in renal function. Among the determinants of renal failure in ADPKD are hypertension, renal volume, proteinuria and microalbuminuria [2,3]. A crucial breakthrough in the preservation of renal function has been the discovery of the renoprotective effect of inhibitors of the renin angiotensin system. Treatment with angiotensin-converting enzyme (ACE) inhibitors, which block the conversion from angiotensin I to angiotensin II, has been shown to reduce the decline in renal function in diabetic nephropathy and non-diabetic renal diseases [4,5]. In patients with ADPKD, the renin angiotensin system functions at a higher level and leads to increased renal vascular resistance [6,7]. This may explain the greater fall in renal vascular resistance and blood pressure in patients with ADPKD who are treated with ACE inhibitors [8]. Evidence has also been provided that angiotensin II is able to stimulate cyst growth, and tissue proliferation [9,10]. In an animal model of ADPKD, deterioration of renal function was diminished with treatment of an ACE inhibitor [11]. ACE inhibitors slow down the progression of renal failure in patients with diabetes and patients with IgA nephropathy, independently of its effect on blood pressure [4,5]. In these studies, ACE inhibition also reduced microalbuminuria significantly, which is

2 No effect of enalapril on progression in ADPKD 2315 a marker for progression to renal failure in patients with diabetic and IgA nephropathy, and in patients with ADPKD [3]. Here we present in a randomized, double-blind, placebo-controlled trial: the effect of ACE inhibition on the progression of renal failure in ADPKD patients. assessment, blood pressure measurement (three measurements with a random-zero sphygmomanometer) and routine laboratory tests. Determination of the GFR and effective renal plasma flow was performed twice at baseline, 3 months after randomization, at the end of the first and second year, and twice at the end of the 3 year treatment period. The physical examination was repeated at one of the last visits. Subjects and methods Subjects Patients with ADPKD were recruited from our Nephrology department and from neighbouring hospitals, through family investigation of ADPKD patients and through advertisements from January 1994 to September ADPKD was defined by the ultrasonographic criteria described by Ravine et al. [12]. Inclusion criteria for the trial were: ADPKD, age between 18 and 70 years, and plasma creatinine <225 mmol/l. Hypertension was defined as diastolic blood pressure >95 mmhg and systolic blood pressure >160 mmhg or the use of antihypertensive medication. Exclusion criteria were: presence of other renal disease (excluding nephrolithiasis); presence or history of diabetes mellitus, congestive heart failure, myocardial infarction or cerebrovascular accident in the past 6 months; peripheral vascular disease; pregnancy; evidence of significant hepatic dysfunction; chronic (>3 months) use of immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), uricosurics and levodopa; and previous adverse reactions to ACE inhibitors. The Medical Ethics Committee of Leiden University Medical Center approved the protocol of the study, and informed consent was obtained from all patients. All investigations were conducted in accordance with the guidelines proposed in the Declaration of Helsinki. Study design Two baseline visits were scheduled. At each visit, blood pressure was measured three times with a random-zero sphygmomanometer and averaged. The glomerular filtration rate (GFR) was measured by continuous infusion of inulin, and the effective renal plasma flow by continuous infusion of p-aminohippurate (PAH). Twenty-four hour urine samples were collected for determination of creatinine clearance and urine portions to establish the microalbumin/creatinine ratio. Microalbuminuria was defined as a ratio of >2.5 mg/mmol. Blood was sampled for routine laboratory investigation. At one of the visits, a routine physical examination was performed. After the patient fulfilled the enrolment criteria, he/she was randomized. Patients who were normotensive were assigned randomly to placebo or enalapril in a double-blind fashion. Patients who were hypertensive were randomized for open treatment with enalapril or atenolol, after previous antihypertensive medication had been discontinued for at least 4 weeks. Randomization was performed for each patient in the pharmacy of our hospital, which also provided the blinded medication. Follow-up visits were scheduled at 3 month intervals. The measurements at the follow-up visits included clinical GFR and effective renal plasma flow GFR and effective renal plasma flow were measured after an overnight fast, by infusion of inulin and PAH. A loading dose was given in 10 min, followed by 3 h of continuous infusion. During the infusion, patients stayed in the resting position and maintained hydration by oral water intake. After 1.5 h, three urine samples were obtained over 30 min periods, with blood samples before and at the end of each collection period, for determination of inulin and PAH concentrations. For each urine portion and corresponding blood sample, the GFR was calculated and then averaged. GFR was not calculated for urine portions <100 ml. Calculation of the GFR was performed during the double-blind phase. Effective renal plasma flow was calculated in the same manner. To investigate whether the measurements of GFR were accurate and reproducible, we plotted the mean difference in GFR between the first and second visit (see Figure 1). The mean difference was 0.5 ml/min, excluding systemic variation. Intervention and end points Patients who were normotensive were treated with 10 mg of enalapril or placebo in a two-step dosage regime. When after the first step (5 mg enalapril or placebo) diastolic blood pressure decreased >10 mmhg, or was below 70 mmhg, the second step (10 mg of enalapril or placebo) was cancelled. Patients who were hypertensive were treated in a variable step-up dosage regime with a maximum of 20 mg of enalapril or 100 mg of atenolol to achieve a diastolic blood pressure of Fig. 1. Intra-individual differences in GFR. GFR was measured twice within 2 months. Differences are depicted as a function of the mean value. The horizontal dashed line represents the mean of the differences in GFR ( 0.7 ml/min).

3 2316 M. A. van Dijk et al. 85 mmhg and a systolic blood pressure of 140 mmhg. When this goal was not obtained with the maximal dose, additional therapy was prescribed. Additional therapy consisted of a diuretic (hydrochlorothiazide, maximal 25 mg/day), followed by a calcium-entry blocker (felodipine, maximal 20 mg/day). The study was terminated prematurely in any of the patients if there was the occurrence of uncontrolled hypertension defined as an increase in diastolic blood pressure >100 mmhg despite study medication; serious side effects of the medication; a decrease in creatinine clearance of 30%; or occurrence of other diseases or medical treatment that may influence renal function. Medication Enalapril and placebo were provided by Merck, Sharp and Dohme. The pharmacy of our hospital distributed the medication to the participating patients. Statistical analysis We estimated the beneficial effect of ACE inhibition on the decline of GFR in normotensive and hypertensive ADPKD patients separately. The primary analysis was based on the patients who completed the whole follow-up of 3 years, thus excluding patients in whom the study was terminated prematurely. This analysis estimates the true pharmacological effect of ACE inhibition. As a secondary analysis, we included all patients who were randomized until the moment the study was closed. A power analysis was performed to calculate the number of patients needed for inclusion. A difference of 5 ml/min (±1.5 ml/min) in GFR after 3 years of follow-up was considered a beneficial effect. Twenty-four patients were needed in each group to detect such a difference, with a power of 0.90 and a significance of Student s t-tests were performed to compare the clinical parameters of patients at baseline. Analysis of variance was used to estimate the effect of treatment on GFR, effective renal plasma flow, microalbumin/creatinine ratio and blood pressure. All values are given as means ± SEM. A P-value <0.05 was considered statistically significant. Table 1. Baseline characteristics of patients with ADPKD Results Baseline characteristics in normotensive and hypertensive patients Of the 72 recruited patients who were normotensive, two did not meet the inclusion criteria, while one dropped out after randomization because of a drugrelated cough. Of the 69 randomized patients, 61 (88%) completed 3 years follow-up. Six patients dropped out because they became hypertensive (all six received placebo medication). Two patients on enalapril withdrew from the study after 2 years followup (one because of a desire to become pregnant, and the other because of increasing workload). The primary analysis was thus based on 61 patients. Of these patients, five were on a dose of 5 mg of enalapril or placebo, while all the others received 10 mg of enalapril or placebo. Baseline clinical characteristics of the patients are listed in Table 1. No significant differences were found between the two treatment groups (all P > 0.05). Of the 35 recruited patients who were hypertensive, 28 (80%) completed 3 years follow-up. Five patients randomized for treatment with atenolol dropped out. One patient dropped out because she became dialysis dependent; two patients because of uncontrollable hypertension; one patient because of a liver cyst infection requiring long-term antibiotic treatment; and one patient died after 2 years from subarachnoid haemorrhage. Two patients randomized for enalapril dropped out, one because of psychological problems, the other because of a massively enlarged polycystic liver, which required treatment with NSAIDs. The primary analysis was thus based on 28 patients. Four patients on enalapril and seven patients on atenolol needed additional treatment with diuretics (four patients on atenolol received the maximal dose of 25 mg daily). Two patients on atenolol required further treatment with felodipine. Clinical characteristics of the patients are also listed in Table 1. No significant differences were found between the two treatment groups (all P > 0.05). Normotensive Hypertensive Enalapril Placebo Enalapril Atenolol (n ¼ 32) (n ¼ 29) (n ¼ 13) (n ¼ 15) Age (years) 36±2 37±2 40±3 33±3 Males/females 11/21 14/15 5/8 5/10 Height (m) 1.73± ± ± ±0.02 Weight (kg) 78±4 79±5 78±3 77±3 Creatinine (mmol/l) 89±3 88±3 119±12 112±12 MA/creat ratio (mg/mmol) 0.46± ± ± ±0.28 SBP (mmhg) 133±2 133±2 144±3 144±3 DBP (mmhg) 88±2 88±1 98±2 96±1 MAP (mmhg) 103±2 103±1 113±2 107±2 MA/creat, microalbumin/creatinine ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure. Date are presented as means ± SEM.

4 No effect of enalapril on progression in ADPKD 2317 Treatment of normotensive patients Mean arterial pressure remained stable during 3 years follow-up, with an average decline of 1 ± 2 mmhg. Mean arterial pressure decreased in the patients treated with enalapril ( 3 ± 2 mmhg) and slightly increased in the patients treated with placebo (2 ± 2 mmhg), but this difference did not reach statistical significance (Table 2). GFR significantly decreased during follow-up, with an average of 8 ± 2 ml/min (P < 0.001). Although the baseline GFR in patients treated with enalapril was slightly lower, the decline in GFR was similar to the decline observed in patients treated with placebo, 9 ± 1 ml/min vs 7 ± 3 ml/min; P ¼ 0.4 (Table 2). In the enalapril-treated group, three patients had a decline in GFR of >20% after they had started their medication. In the placebo-treated group, one patient had a decline in GFR of >20%. These were the four patients who had a renal function below 60 ml/min at the start of the trial. The other patients showed no significant decline in GFR after starting treatment with enalapril. The yearly drop in GFR did not differ significantly between the two treatment groups. Nine patients on enalapril were willing to undergo a GFR measurement 1 month after discontinuation of medication. None of these patients showed amelioration of their GFR. Analogously to the GFR, the effective renal plasma flow decreased during the 3 years follow-up, whereas no significant difference in decline between the two groups was observed (Table 2). Patients receiving placebo showed a slight increase in microalbumin/creatinine ratio from 0.39 ± 0.50 to 0.68 ± 1.01 compared with patients treated with enalapril (from 0.46 ± 0.68 to 0.42 ± 0.48), but this effect was not significant. Only two patients treated with placebo fulfilled the criteria for microalbuminuria after 3 years follow-up. As a secondary analysis, we studied the decline in GFR of all randomized patients until the time they were withdrawn from the study. Figure 2 shows repetitive measurements of GFR for the 69 normotensive patients. The slope of the decline in GFR was highly significant (P < 0.001) but not different between the groups (P > 0.05). Treatment of hypertensive patients Mean arterial pressure in patients with hypertension was significantly higher compared with patients who were normotensive (110 ± 2 vs 103 ± 1 mmhg; P < 0.001). Antihypertensive treatment significantly decreased mean arterial pressure, with an average of 7±2mmHg (P < 0.01). Although the decline in mean arterial pressure was larger in the enalapriltreated group compared with the atenolol-treated Fig. 2. GFR of ADPKD patients who were normotensive. This graphical representation includes the patients who were withdrawn during follow-up. The numbers in the plot represent the number of participating patients. The solid symbols represent patients treated with enalapril; the open symbols represent patients treated with placebo. There were no significant differences in the decline of GFR (ANOVA; P > 0.05) between the two groups. Table 2. Blood pressure, glomerular filtration rate and effective renal plasma flow in normotensive ADPKD patients treated with enalapril or placebo Enalapril Placebo P-value (n ¼ 32) (n ¼ 29) (comparison between groups) Mean arterial pressure (mmhg) at baseline 103±2 103± after 3 years follow-up 100±2 105± decrease 3±2 2± Glomerular filtration rate (ml/min) at baseline 106±4 112± after 3 years follow-up 97±5 105± decrease 9±1* 7±3* 0.40 Effective renal plasma flow (ml/min) at baseline 437±24 439± after 3 years follow-up 393±22 406± decrease 44±11 33± Data are presented as means ± SEM. Student s t-test. P-values indicate comparison between enalapril and placebo. *P < compared with baseline.

5 2318 M. A. van Dijk et al. Table 3. Blood pressure, glomerular filtration rate and effective renal plasma flow in hypertensive ADPKD patients treated with enalapril or atenolol Enalapril Atenolol P-value (n ¼ 13) (n ¼ 15) comparison between groups Mean arterial pressure (mmhg) at baseline 113±2 108± at 3 years follow-up 102±3 105± decrease 11±3* 3±3* 0.09 Glomerular filtration rate (ml/min) at baseline 80±9 92± at 3 years follow-up 64±9 83± decrease 12±2** 12±3** 0.81 Effective renal plasma rate (ml/min) at baseline 316± ± at 3 years follow-up 249± ± decrease 67±47 67± Data are presented as means±sem. Student s t-test. P-values indicate comparison between enalapril and atenolol. *P < and **P < 0.001compared with baseline. group, 11 ± 3 vs 3 ± 3 mmhg, this difference did not reach significance (Table 3). ADPKD patients who were hypertensive had a significantly lower renal function (plasma creatinine 89 ± 2 in normotensives vs 112 ± 3 mmol/l in hypertensives; P < 0.005). Baseline GFR was lower in the enalapril-treated group. The decline in GFR for patients treated with enalapril was similar to the decline for patients treated with atenolol, 12 ± 2 ml/min vs 12 ± 3 ml/min (Table 3). In the group treated with enalapril, one patient had a decline in GFR of >20% after starting the medication. In the atenolol-treated group, four patients had a decrease in GFR of >20%. These were the patients who had a renal function below 60 ml/min at the beginning of the trial. The decrease in effective renal plasma flow was similar in both groups (Table 3). There were no significant differences between the two treatment groups in microalbumin/creatinine ratio (enalapril, 0.39 ± 0.31 to 1.18 ± 1.45; atenolol, 0.33 ± 0.28 to 0.49 ± 0.59). One patient treated with enalapril fulfilled the criteria of microalbuminuria after 3 years follow-up. A secondary analysis was performed to determine the decline in GFR of all randomized patients until the time they were withdrawn from the study. Figure 3 shows repetitive measurements of GFR for the 35 hypertensive patients. The slope of the decline in GFR was highly significant (P < 0.001) but not different between the groups (P > 0.05). The apparent increase in GFR at the end of the study in patients treated with atenolol is due to the withdrawal of four patients who became dependent on dialysis, or had GFRs <40 ml/min in the atenolol treatment group. Discussion In this randomized study with 3 years follow-up, we were unable to demonstrate a beneficial effect of Fig. 3. GFR of ADPKD patients who were hypertensive. This graphical representation includes the patients who were withdrawn from the study. The numbers in the plot represent the number of participating patients. The solid symbols represent patients treated with enalapril; the open symbols represent patients treated with atenolol. There were no significant differences in the decline of GFR (ANOVA; P > 0.05) during the 3 years of follow-up between the two groups. the ACE inhibitor enalapril on the deterioration of renal function in patients with ADPKD. A renoprotective effect was not found, neither in patients who were normotensive nor in patients who were hypertensive. There was no indication for an important haemodynamic effect of enalapril, as there was no initial decline in GFR after starting enalapril nor amelioration of GFR after discontinuation of enalapril. However, we were able to detect a mean annual decrease in GFR of as little as 3 4 ml/min, indicating that the study was sensitive enough to detect small differences between the groups.

6 No effect of enalapril on progression in ADPKD 2319 The low annual loss of renal function means that most of our participating patients were in a more or less stable phase of their disease. Patients with ADPKD, as with many other renal diseases, do not show a linear decrease in GFR, but preserve their renal function for many years, followed by a second phase of rapid, almost linear impairment [13]. Only a few patients in our study demonstrated such a rapid decline in renal function. In the patients with ADPKD who were hypertensive, progression to renal failure was enhanced when compared with the patients who were normotensive, but nevertheless a beneficial effect of enalapril could not be demonstrated. Although not statistically significant, there were more women included in the normotensive enalapril group. Women have been reported to have a slower progression towards renal failure. Such slower progression could have concealed a beneficial effect of enalapril. However, since more women were present in the normotensive enalapril group, one would have expected a reinforcement of differences in decline of GFR in favour of the group treated with enalapril, which was in fact not observed. We were unable to assess the distribution of the two different ADPKD genotypes (PKD1 and PKD2) that are associated with different courses of progression [14]. If by chance the placebo group contained more patients with PKD2, the renoprotective effect of enalapril could be disguised. There were, however, no differences in the baseline characteristics that suggest an uneven distribution of the various genotypes. Our findings confirm earlier reports of ACE inhibition in patients with ADPKD, hypertension and mild to severe renal insufficiency in which a beneficial effect could also not be detected [15,16]. Two recent studies demonstrated a beneficial effect of ACE inhibition in hypertensive APDKD patients. First, in a group of hypertensive ADPKD patients, those treated with an ACE inhibitor without a diuretic showed less progression of renal failure than those treated with diuretics and no ACE inhibitors [17]. There can be two reasons for this observation: a nonrandomized study is prone to selection of individuals for specific treatments and in this study the patients on ACE inhibition appeared to be younger, more frequently male and had better renal function at the beginning. An alternative explanation is the use of diuretics in half of the patients that may even have had an adverse effect on renal function. The second study compared the effect of ACE inhibition and calcium channel blockade on the decay of renal function in 214 patients with primary renal disease, including 45 with ADPKD [18]. All patients in this randomized, open-label study exhibited a progressive increase in serum creatinine during the previous 2 years. The ADPKD patients were thus less likely to be in their stable phase. More importantly, control of systolic blood pressure was significantly better in those treated with ACE inhibition, and this may have contributed to the renal protective effect. In the randomized trial presented here, we were unable to show that treatment with enalapril had a beneficial effect on the microalbumin/creatinine ratio, microalbuminuria being a factor related to progression of renal failure in patients with ADPKD. This is probably due to the very low microalbumin/creatinine ratios in our patients (none of the patients showed microalbuminuria at the beginning of the trial), with their relatively preserved renal function. It has been demonstrated that the protection of renal function with ACE inhibitors can be observed in patients with nephrosclerosis or chronic glomerular diseases and proteinuria >2.0 g/24 h, but not in ADPKD patients [19]. ADPKD is not primarily a glomerular disease, and none of our patients had proteinuria >2.0 g/24 h. The virtual absence of signs of glomerular involvement or established nephrosclerosis in our patients may well explain the lack of a beneficial effect on the deterioration of renal function in our study. The lack of effect of ACE inhibition on renal function could also be due to the low doses of enalapril used, maximal 10 mg and in five patients 5 mg. This means that angiotensin I to angiotensin II conversion might not have been blocked effectively. Additionally, the role of endogenous mediators in angiotensin I to angiotensin II conversion has not been elucidated in ADPKD patients, and such mediators may have an important impact on the disease. The antiproliferative effect of ACE inhibition, which was assumed to be responsible for the reduction in cyst number and cyst size in the Han:SPRD rat [11], was not investigated in this study. Therefore, a beneficial effect of ACE inhibitors on cyst growth cannot be ruled out. The surplus of cells initiating cyst formation in renal tubules may be the result of an imbalance between cell growth and cell loss due to dysregulation of multiple homeostatic systems. If multiple systems are involved in cyst growth, it seems unlikely that ACE inhibition alone can contribute substantially to reduction of cyst growth in patients with ADPKD. If such a growth-reducing mechanism of ACE inhibition exists, however, we were unable to show an impact on the decline in renal function. In conclusion, in our study, we did not find a renoprotective effect of ACE inhibition in normotensive patients with ADPKD. This effect could also not be demonstrated in hypertensive ADPKD patients when compared with treatment with a -blocker. Acknowledgements. We would like to express our gratitude for the cooperation of all participating patients. We would like to thank M. van Tol for her support and help in managing this study, and Drs W. F. Florijn and B. L. Hogewind for their help with recruiting patients. This study was supported by the Dutch Prevention Found. Conflict of interest statement. None declared. References 1. Gonzalo A, Gallego A, Tato A et al. Age at renal replacement therapy in autosomal dominant polycystic kidney disease. Nephron 1996; 74: 620

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