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NDT Advance Access published online on June 20, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn321
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Use of ACE inhibitors or angiotensin receptor blockers and survival in patients on peritoneal dialysis*

Wei Fang1,2, Dimitrios G. Oreopoulos1 and Joanne M. Bargman1

1 Peritoneal Dialysis Program, University Health Network, Toronto, and University of Toronto, Toronto, Ontario, Canada 2 Renal Division, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Correspondence and offprint requests to: Joanne M. Bargman, University Health Network, Toronto, and University of Toronto, 200 Elizabeth Street 8N-840, Toronto, Ontario M5G 2C4, Canada. Tel: +1-416-340-4804; Fax: +1-416-340-4999; E-mail: joanne.bargman{at}uhn.on.ca



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve outcome in patients with renal failure not on dialysis therapy and patients on haemodialysis (HD). However, their effect on survival has not been studied in peritoneal dialysis (PD) patients. The present study examined the association between therapy with ACE inhibitor/ARB and mortality in patients undergoing chronic PD.

Methods. All patients who commenced PD between 1 January 2000 and 31 December 2005 at the University Health Network were included. Patients were grouped according to whether they had been treated with ACE inhibitor/ARB. They were followed up from the date of PD initiation until death, cessation of PD, transfer to other centres or to the end of the study (31 December 2006).

Results. A total of 306 patients were included in the study. One hundred and sixty-five were treated with ACE inhibitors/ARB (treated group) and 141 were not (untreated group). The treated group patients were younger (56.9 ± 16.6 versus 62.3 ± 17.8 years, P < 0.01) and more likely to have a history of hypertension than the untreated group. At the initiation of PD, systolic and diastolic blood pressures were higher in the treated than the untreated group (138.8 ± 21.8 versus 128.6 ± 22.4 mmHg, P < 0.001; 79.8 ± 14.1 versus 74.5 ± 12.5 mmHg, P = 0.001) and remained significantly higher during the follow-up (133.5 ± 16.4 versus 125.1 ± 16.7 mmHg; 77.3 ± 9.8 versus 73.2 ± 9.7 mmHg, both P < 0.001). The treated group had a significantly longer survival compared to the untreated group (log rank 19.191, P < 0.001). After adjusting for age, blood pressure and other demographic and clinical parameters, multivariable Cox proportional hazards modelling showed that the use of ACE inhibitor/ARB was associated with 62% reduced risk for death (HR 0.382, 95% CI 0.232–0.631, P < 0.001).

Conclusion. In this retrospective analysis, ACE inhibitor/ARB therapy was associated with a dramatically reduced mortality in patients on peritoneal dialysis independent of blood pressure and other clinical and demographic variables.

Keywords: angiotensin II type 1 receptor blockers (ARB); angiotensin-converting enzyme (ACE) inhibitors; end-stage renal disease (ESRD); peritoneal dialysis (PD); survival



   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Cardiovascular disease is a frequent and important cause of morbidity and mortality in patients with end-stage renal disease (ESRD). It is present in as many as 50–60% of ESRD patients and remains the leading cause of mortality [1]. Dialysis patients have a greater than 10- to 20-fold increase in cardiovascular mortality compared with age- and sex-matched populations without renal disease [2,3]. Hypertension is a major risk factor for cardiovascular complications in both the general population and patients with ESRD. An increase in the renin–angiotensin–aldosterone activity is one of the major factors contributing to the hypertension in ESRD patients. Furthermore, epidemiological and experimental data suggest that the activation of the renin–angiotensin–aldosterone system has an important role in increasing the risk of cardiovascular events [4]. In the general population, antihypertensive medications of various groups improve the prognosis of patients with hypertension [5], but the use of angiotensin-converting enzyme (ACE) inhibitors may have additional positive effects on high-risk patients [6].

ACE inhibitors have been shown to improve survival and confer substantial renal benefits in patients with renal failure not on dialysis [7,8]. In haemodialysis (HD) patients, Efrati et al. reported that treatment with ACE inhibitors, independent of their effect on blood pressure, was associated with 52% reduced mortality [9]. However, the effect on survival has not been studied in peritoneal dialysis (PD) patients. The present study examined the association between therapy with ACE inhibitors or angiotensin II type 1 receptor blockers (ACE inhibitor/ARB) and mortality in patients undergoing chronic PD.



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All patients who commenced PD between 1 January 2000 and 31 December 2005 at the University Health Network, University of Toronto, Toronto, Canada, were included. Clinical data and details of medical treatment were extracted from charts. Patients with hypertension had been treated with hypertensives as warranted by their clinical status. Patients treated with ACE inhibitor/ARB for at least 6 months were included in the ACE inhibitor/ARB-treated group.

At the initiation of PD, the following demographic and comorbidity characteristics were collected: age, gender, underlying cause of ESRD, height, weight, presence of diabetes mellitus (defined either as a comorbid condition or as the aetiology of ESRD), details about transplantation, history of hypertension, previous congestive heart failure (defined as an episode of congestive heart failure during the 6 months before PD commencement) and cardiovascular disease (CVD). CVD was defined as a previous history of coronary artery disease, peripheral vascular disease or cerebrovascular disease. Body mass index (BMI) was calculated as the weight (kg) divided by the square of height (in metres). The following laboratory parameters were collected: haemoglobin, serum albumin, electrolytes, calcium, phosphate, intact parathyroid hormone (iPTH) and lipids. Other clinical data collected at the initiation of PD included the presence of left ventricular hypertrophy (LVH), systolic and diastolic blood pressure, antihypertensive treatment, use of statins, residual renal function (RRF), urine output, PD prescription, peritoneal transport characteristics measured by the dialysate to plasma creatinine ratio (D/Pcr) at 4 h in a standard peritoneal equilibration test and total Kt/V urea. LVH was defined by mass indexed to the body surface area of >131 g/m2 in men and 100 g/m2 in women or by electrocardiographic criteria if echocardiography data were not available. Blood pressure was measured by trained nurses with a standard mercury sphygmomanometer in the supine position in the PD clinic. During the follow-up, data on systolic and diastolic blood pressures were collected serially every 2–3 months. Laboratory measures were collected serially at 6 months, 1 year and annually thereafter. All patients were followed up from the date of PD initiation until death, cessation of PD, transfer to other centres or to the end of the study (31 December 2006).

Statistical analyses
All results were expressed as mean ± SD for normally distributed data, median and range for skewed data and frequency (%) for categorical data. Differences in patient demographics, clinical and laboratory parameters between the treated group and untreated group were evaluated by Student's t-test for parametric data and the Mann–Whitney test for nonparametric data. Comparisons of percentages between the groups were made with the chi-squared test ({chi}2) or Fisher's exact test, as appropriate.

The outcome event was all-cause mortality. Survival curves were generated by the Kaplan–Meier method and compared by the log-rank test. The association between ACE inhibitor/ARB treatment and mortality was analysed by univariate and then by the multivariate Cox proportional hazards model. The following covariates were used in the modelling process: treatment with ACE inhibitor/ARB, age, sex, diabetes mellitus, CVD, previous congestive heart failure, systolic and diastolic blood pressures, treatment with calcium channel blockers, beta blockers and statins, haemoglobin, serum albumin, calcium, phosphate, lipids, residual renal function and Kt/V urea. Covariates with P-value <0.2 in the univariate analysis were present further to the multivariate Cox model. A backward stepwise elimination multivariate Cox modelling analysis was performed to determine the independent association between treatment with ACE inhibitor/ARB and other covariates, and only covariates that remained significant (P < 0.05) were kept in the model. Statistical analysis was performed using SPSS for Windows software, version 13.0 (SPSS Inc., Chicago, IL, USA). A P-value < 0.05 was considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
A total of 306 patients who started PD between 1 January 2000 and 31 December 2005 were included in the study. Among them, 165 (53.6%) were treated with ACE inhibitor/ARB (treated group) and 141 (46.4%) were not (untreated group). Patients in the treated group were younger (56.9 ± 16.6 versus 62.3 ± 17.8 years, P < 0.01), tended more often to have diabetic nephropathy as the aetiology of ESRD (33.3% versus 23.4%, P = 0.056) and were more likely to have a history of hypertension than the untreated group (93.3% versus 81.6%, P = 0.003). There was no significant difference in other comorbidities between the treated and untreated groups including CVD, history of congestive heart failure and LVH (Table 1).


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  		Table 1 Baseline demographic characteristics of patients treated or untreated with ACEI/ARB

 
At the beginning of PD, systolic and diastolic blood pressures were higher in the treated than the untreated group (138.8 ± 21.8 versus 128.6 ± 22.4 mmHg, P < 0.001; 79.8 ± 14.1 versus 74.5 ± 12.5 mmHg, P = 0.001) and remained significantly higher during follow-up (133.5 ± 16.4 versus 125.1 ± 16.7 mmHg; 77.3 ± 9.8 versus 73.2 ± 9.7 mmHg, both P < 0.001). The treated group took more hypertensive medications, and more patients in this group were prescribed calcium channel blockers and statins. Baseline serum albumin was higher in the treated group (37.1 ± 4.5 versus 35.8 ± 5.2 g/l, P = 0.032) and remained higher during the follow-up period (36.8 ± 3.4 versus 35.4 ± 4.6 g/l, P = 0.002). There was no statistically significant difference between the treated and untreated groups with regard to other laboratory parameters, RRF, peritoneal membrane transport status and small solute clearance (Tables 2 and 3).


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  		Table 2 Baseline clinical characteristics of patients treated or untreated with ACEI/ARB

 

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  		Table 3 Clinical characteristics during follow-up of patients treated or untreated with ACEI/ARB

 
After a total follow-up of 8422 patient-months, 74 patients died, including 49 (34.8%) in the untreated group and 25 (15.2%) in the treated group. Table 4 shows the outcomes of the study patients treated or untreated with ACE inhibitor/ARB. Kaplan–Meier survival curves for the treated or untreated groups are shown in Figure 1. Patients in the treated group survived longer compared to the untreated patients (log rank 19.191, P < 0.001). Table 5 shows the results of univariate analysis of baseline variables in relation to mortality. In the full Cox proportional hazards regression model, treatment with ACE inhibitor/ARB was independently associated with reduced all-cause mortality (HR 0.382, 95% CI 0.232–0.631, P < 0.001). Other parameters included in this model that were independently associated with mortality were advancing age (for every 10 year increase, HR 1.433, 95% CI 1.189–1.727, P < 0.001), low serum albumin (for every 1 g/l increase, HR 0.922, 95% CI 0.877–0.970, P = 0.002) and congestive heart failure (HR 1.707, 95% CI 1.029–2.830, P = 0.038).


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  		Table 4 Outcomes of study patients treated or untreated with ACE inhibitor/ARB

 

Figure 1
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  		Fig. 1 Kaplan–Meier survival curves of patients treated or untreated with ACE inhibitor/ARB.

 

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  		Table 5 Univariate Cox regression analysis of baseline variables in relation to mortality in study patients

 


   Discussion
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 Introduction
 Methods
 Results
 Discussion
References
 
To our knowledge, this study is the first to demonstrate the association between ACE inhibitor/ARB therapy and improved survival in ESRD patients receiving PD. Results of this study suggest that ACE inhibitor/ARB treatment reduced the risk for mortality in PD patients by 62%, independent of attained blood pressure.

Although no prospective, randomized clinical trials have been carried out to confirm that ESRD patients may benefit from ACE inhibitor/ARB therapy to a similar degree as patients without renal failure, several retrospective studies suggest that these medications may have a favourable prognostic effect on patients with renal failure. A retrospective analysis of the Heart Outcomes Prevention Evaluation (HOPE) trial evaluated the relationship between renal function and outcomes by analysing the effect of ramipril in the subset of patients with mild renal insufficiency. The risk reduction for all-cause mortality appeared to be higher in the renal insufficiency group as compared to those without renal insufficiency (HR 0.59 versus 0.9), and importantly, without increasing adverse events [7]. A retrospective analysis of the Survival And Ventricular Enlargement (SAVE) study also suggested that captopril was equally efficacious in patients with and without chronic kidney disease. This study showed that captopril was associated with a greater risk reduction in total mortality and cardiovascular morbidity/mortality in patients with eGFRs of <60 ml/min as compared to those with an eGFR above this level. The absolute benefit of captopril was greatest in the lowest eGFR quartiles [10]. Berger et al., using the ESRD database and the Cooperative Cardiovascular Project (CCP) database, conducted a retrospective analysis to study the effectiveness of post-MI therapies in elderly patients with ESRD. They reported that among dialysis patients, use of ACE inhibitors was associated with a significant reduction of 30-day mortality. After adjusting for baseline demographic and clinical risk factors, the association between ACE inhibitor use and lower mortality persisted (RR 0.58, 95% CI 0.42–0.77) [11]. Similar findings have been reported by McCullough et al., who analysed 386 ESRD patients admitted to a coronary care unit for heart failure or acute coronary syndromes. After adjustment for known confounders, this study demonstrated a 37% reduction in all-cause mortality in those who received ACE inhibitors versus those who did not during a 3-year follow-up period [12]. A retrospective study by Efrati et al. also reported that HD patients who were treated with ACE inhibitors had a significantly lower mortality risk as compared to those who were not treated (RR 0.48, 95% CI 0.25–0.91) [9]. In the Fosinopril in Dialysis (FOSIDIAL) study, a randomized, placebo-controlled trial to evaluate the effect of fosinopril on cardiovascular events in 397 HD patients, trends were observed suggesting fosinopril might be associated with a lower risk of cardiovascular events (RR 0.79, 95% CI 0.59–1.1, P = 0.099). Because the study population in the FOSIDIAL study was small, the investigators concluded that these trends might have become statistically significant had the sample size been adequate [13]. These data suggest that a survival benefit may be associated with ACE inhibitor/ARB therapy in patients with renal insufficiency and ESRD. The present study suggests that a similar favourable effect of ACE inhibitor/ARB could also be observed in PD patients.

It is likely that ACE inhibitor/ARB exert additional direct mechanisms on the heart and vasculature in addition to reducing blood pressure. These may include antagonizing the direct effects of angiotensin II on vasoconstriction, the proliferation of vascular smooth muscle cells and rupture of plaques, improving vascular endothelial function and enhancing fibrinolysis [4,14,15]. Recent research has revealed that the renin–angiotensin–aldosterone system is involved in the process of injury and remodelling of cardiovascular organs and tissues. Angiotensin II and aldosterone promote hypertrophy of cardiovascular cells and fibrosis of the cardiovascular tissues [16,17]. Therefore, antihypertensive medications suppressing the renin–angiotensin–aldosterone system, such as ACE inhibitors and ARB, are expected to have protective effects against hypertensive damage of cardiovascular organs beyond their hypotensive effects. Indeed, several studies have reported that the regression of LVH by ACE inhibitors or ARB reduced left ventricular mass in ESRD patients on chronic HD [18–21]. Furthermore, clinical trials in patients both with and without diabetes indicate a favourable effect of ACE inhibitors in slowing the progression of renal disease [22]. In patients with advanced renal failure not on dialysis and patients on PD, treatment with ACE inhibitors also had substantial renal benefits [8,23]. Marked reduction in the incidence of complications related to diabetes and new cases of diabetes with ACE inhibitor treatment has been reported [6,24]. These effects may be mediated by preservation of beta-cell function and/or an enhancement of insulin sensitivity, a decrease in hepatic clearance of insulin, an anti-inflammation effect, improved blood flow to the pancreas or an effect on adipocyte turnover [25,26]. Treatment with ACE inhibitors could also increase antioxidant defences in animal experiments and HD patients [27,28]. Beneficial effects of ACE inhibitors on the development of morphological peritoneal alterations and peritoneal membrane function have been reported in experimental models, showing decreased angiogenesis and fibrosis and preservation of ultrafiltration [29–31]. The protective effects on the peritoneal membrane may be mediated by inhibiting the overexpression of angiogenic and fibrotic cytokines such as VEGF and TGF-β1 [32]. Duman et al., using rat models, compared the effects of an ACE inhibitor (lisinopril) and an ARB (valsartan) on peritoneal alterations induced by hypertonic PD solutions and found that both have equally favourable effects on peritoneal function and morphology [33]. In accordance with the results of animal models, recently Kolesnyk et al. investigated the effects of ACE inhibitor/ARB in PD patients and reported that use of ACE inhibitor/ARB could prevent the increase in the mass transfer area coefficient that occurs in long-term PD [34]. Therefore, ACE inhibitor/ARB might preserve the viability of peritoneum in PD patients over the long term. All these beneficial effects might contribute to the markedly reduced mortality associated with ACE inhibitor/ARB therapy observed in the present study.

Hyperkalaemia is an important concern with the use of ACE inhibitors in ESRD population. Patients on HD receiving either ACE inhibitors or angiotensin receptor blockers have a significantly higher risk of developing hyperkalaemia compared with ESRD patients not receiving these drugs, even after adjusting for other risk factors [35]. However, in CAPD patients, Phakdeekitcharoen et al. reported that the standard doses of the ACE inhibitors or ARB have little effect on serum potassium [36]. The present study also found that the change in serum potassium was minimal. However, use of ACE inhibitor/ARB still requires caution for hyperkalaemia in patients with inadequate dialysis, low solute transporters and those who are noncompliant with dietary potassium restriction.

Our study has several limitations. The study population is relatively small and its design is retrospective; therefore, patients were not randomized and there was no standardization in the treatment protocol. Because of the retrospective nature, no conclusion about causation can be drawn. We do not have the data about why the untreated group was not prescribed ACEI/ARB. We do not know whether there were more late referral patients in the untreated group and whether such factors may have had a negative impact on patient survival. Nor do we know whether the apparent effect of ACEI/ARB was due to selection of patients with a high diastolic blood pressure, a factor which in both this and previous studies is a marker of good prognosis [37]. Also, we could not exclude completely those patients who had been treated with ACEI/ARB for a long time before initiation of PD in the untreated group. Furthermore, other unknown confounders may also exist. ACE inhibitor/ARB and other antihypertensive medications are analysed as classes of medications, rather than individual drugs. In addition, no data are available for other potentially important end points such as deterioration of residual renal function, progression of LVH, congestive heart failure or number of hospitalizations. Clearly prospective randomized controlled trials are needed to study the effects of ACE inhibitor/ARB therapy in PD patients.

In conclusion, this retrospective analysis showed that ACE inhibitor/ARB therapy was associated with a dramatically reduced mortality in patients on peritoneal dialysis independent of blood pressure and other clinical and demographic variables.

Conflict of interest statement. None declared.



   Notes
 
* Presented in part at the 40th Congress of the American Society of Nephrology, 2007. Back



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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 27.12.07
Accepted in revised form: 19. 5.08


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