The association between BP and mortality in patients on chronic peritoneal dialysis

Alexander S. Goldfarb-Rumyantzev1, Bradley C. Baird1, John K. Leypoldt1,2 and Alfred K. Cheung1,2

1 Division of Nephrology and Hypertension, University of Utah School of Medicine and 2 Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT, USA

Correspondence and offprint requests to: Alexander Goldfarb-Rumyantzev, MD, PhD, Dialysis Program, University of Utah School of Medicine, 85 North Medical Drive, East Rm. 201, Salt Lake City, UT 84112-5350, USA. Email: alex.goldfarb{at}hsc.utah.edu



   Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. The relationship between blood pressure (BP) and mortality in haemodialysis patients is unconventional. It is not clear if this is the consequence of uraemia or related to the dialysis type. The goal of this project was to identify the relationship between BP and mortality in patients on chronic peritoneal dialysis (PD).

Methods. Patients on PD (n = 1053) from the USRDS prospective DMMS Wave 2 study were analysed. Primary outcomes were all-cause and cardiovascular mortality and duration of hospitalization.

Results. Low systolic BP categories, <100 mmHg [hazard ratio (HR), 2.71, P<0.001; and HR 3.83, P<0.001, respectively] and 101–110 mmHg (HR 1.85, P<0.05; and HR 2.92, P<0.005, respectively), but not high systolic BP, increased the risk of all-cause and cardiovascular mortality, with systolic BP 111–120 mmHg as the reference. Pulse BP, but not diastolic BP, followed a similar trend. In subgroup analysis, this association was demonstrated only in patients with a history of heart failure, in patients with diabetes and in those treated with antihypertensive medications.

Conclusion. Systolic BP <111 mmHg in PD patients is associated with higher mortality risk, while systolic BP >120 mmHg is associated with fewer hospital days. Aggressive treatment of hypertension in the PD population should be cautioned.

Keywords: blood pressure; cardiovascular; end-stage renal disease; epidemiology; mortality; peritoneal dialysis



   Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Blood pressure (BP) in haemodialysis (HD) patients has been found to bear a non-linear relationship with patient survival. There is an association between systolic BP (SBP) and pulse BP (PBP) with the risk of death in haemodialysis patients [1]. Low pre-dialysis SBP was associated with an elevated mortality risk in a random sample of HD patients from the United States Renal Data System (USRDS) [2]. Both high and low post-dialysis SBP were associated with an elevated mortality risk. Zager et al. [3] retrospectively studied 5433 HD patients and found a ‘U’ curve relationship between post-dialysis SBP and cardiovascular (CV) mortality. Post-dialysis hypertension, as well as low SBP, were associated with increased CV mortality. This phenomenon might be attributed either to end-stage renal disease (ESRD) or to the HD procedure itself. If the latter is true, peritoneal dialysis (PD) patients should not have this ‘paradoxical’ association between BP and mortality. Although BP has been reported to be an independent predictor of mortality [4], the relationship between BP and survival and the optimal BP in PD patients have not been adequately studied.

The goals of the present study were to test if BP is an independent risk factor for mortality in a large PD population, and to evaluate the nature of the association of BP with all-cause and CV mortality as well as the duration of hospitalization.



   Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Source of data
Data from the USRDS database collected during the prospective Dialysis Morbidity and Mortality (DMMS) Wave 2 study (n = 4500) were used for this project. The DMMS Wave 2 study started at the beginning of 1996 with patients being enrolled in 1996 and 1997, with a mean follow-up of the patient population at 23±14 months. Patient records were censored by death, transplant, last dialysis or the end of the study (December 31, 1999), whichever was earliest; 1788 patients treated with PD at the beginning of the study were identified. After applying the inclusion and exclusion criteria described below, and eliminating records with a missing study start date, 1053 patients remained in the final data set.

Inclusion criteria
Patients with ESRD at the time of initiation of the DMMS Wave 2 study, who survived >90 days since the onset of ESRD, were included in this analysis (time at risk for survival analysis therefore begins 90 days after starting dialysis).

Exclusion criteria
The following exclusion criteria were applied: (i) patients <18 years of age at the study start [2]; (ii) those who recovered renal function and no longer required dialysis; and (iii) patients for whom BP measurements were not available.

Independent variables
Primary variables of interest. SBP, diastolic BP (DBP) and PBP were used as primary variables of interest. The BP readings reported in the DMMS Wave 2 file are both pre- and post-dialysis BP, since the population in the study is a mix of HD and PD patients. We used the average ‘pre-dialysis’ BP as the primary variable of interest. BP was analysed as both a continuous and a categorical variable. BP categories were established based on specific cut-off points using two separate approaches. First, we categorized BP into quintiles. Also, we used The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC-7) classification as a guide [5], but subdivided some of the SBP categories further: ≤100, 101–110, 111–120, 121–130, 131–140, 141–160, 161–180 and >180 mmHg. The DBP categories were based on the following cut-off points: ≤65, 66–75, 76–80, 81–85, 86–90, 91–100, 101–110 and >110 mmHg. Finally, the PBP was subdivided into the following categories: 15–39, 40–59, 60–79, 80–99 and ≥100 mmHg. Our primary focus was on systolic BP since the Framingham Heart Study and the JNC-7 noted an elevated SBP to be a more significant CV disease risk factor than DBP in the general population [5].

Covariates. The following variables were used in the Cox models as covariates: age, race, gender, weight, height, primary cause of ESRD (diabetes, hypertension, glomerulonephritis, others), haemoglobin, serum albumin, calcium x phosphate product, bicarbonate level and residual renal function (creatinine clearance). Also, the following PD parameters were included in the models: dialysate volume (l/24 h), dialysis creatinine clearance and peritoneal transport characteristics (D/P ratio at 4 h). Peritoneal transport characteristics were calculated from 24 h dialysate collection using a multivariate formula that has been empirically derived on a small set of patients at the University of Utah Dialysis Program, who had simultaneous measurement of 24 and 4 h dialysate creatinine and D/P ratio. Co-morbidity characteristics [congestive heart failure (CHF), peripheral vascular disease (PVD), diabetes mellitus, left ventricular hypertrophy, coronary artery disease (CAD) and cerebrovascular disease (CVD) were also included in the models. CHF data in the DMMS file were presented as either ‘positive’, ‘negative’ or ‘suspected’. For the purpose of this study, we included suspected CHF in the positive category. The number of antihypertensive medications was used as an indicator of the presence and severity of hypertension. The duration of ESRD prior to entry into the study was not used in the multivariate models since only incident PD patients were enrolled in the DMMS Wave 2 study.

The final models include those variables that (i) were shown to have a significant association with the outcome in the initial multivariate model; or (ii) were not found to be significant predictors, but could have a physiological confounding effect.

Eliminating unreliable data
The limits for specific variables were set a priori as follows. Drain volume between 2 and 40 l/24 h, haemoglobin between 4 and 20 mg/dl, height between 100 and 215 cm, weight between 23 and 180 kg, phosphate between 0 and 20 mg/dl, serum bicarbonate between 5 and 45 mg/dl, SBP between 70 and 220 mmHg, DBP between 30 and 125 mmHg, dialysate creatinine >0 and serum creatinine between 0.6 and 20 mg/dl.

Outcome
Primary outcome variables were mortality and survival time. Secondary outcome was duration of all-cause hospitalization during the study period. Deaths were classified as CV or non-CV related. CV-related deaths include hypertensive disease (ICD-9 401–405), ischaemic heart disease (IDC-9 410–414), other heart disease (IDC-9 420–429) and CVD (ICD-9 430–438).

Statistical analysis
Cox regression with fixed covariates was used to test if BP control is an independent predictor of mortality and to evaluate the relationship between these variables. A linear regression model was used to evaluate the duration of all-cause hospitalizations. The SAS statistical package (SAS Institute, Cary, NC) was used to perform the analysis in this study.



   Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Descriptive statistics
Baseline characteristics of the study population are presented in Table 1. Average age was 57.2±15.3 years, 72.2% of the patients were white, 18.7% were African American, 5.3% were Asian. Patients were treated with continuous ambulatory peritoneal dialysis (CAPD) in 66.5%, cycler in 29.8% and with combined modalities in 3.7%. According to the DMMS study design, baseline characteristics were collected in almost all of the patients at ~2 months after the onset of ESRD. Average SDP and DBP at baseline were 141.7±20.3 and 79.9±12.0 mmHg, respectively. The number and percentage of patients in each SBP category are presented in Figure 1.


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Table 1. Baseline characteristics of the study populationa

 


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Fig. 1. Repartition of patients according to the systolic blood pressure categories.

 
Factors associated with low SBP
Factors predicting low BP (<100–110 mmHg) were evaluated by logistic regression. The following factors were found to be associated with low BP: history of CAD [odds ratio (OR) 2.64, P<0.05], history of PVD (OR 2.19, P<0.05), history of CHF (OR 2.35, P<0.05) and number of antihypertensive medications (OR 0.51, P<0.001). Residual renal function does not predict low BP in our logistic regression model (P = 0.438).

BP control and patient survival
The correlation coefficient between SBP and DBP was 0.26, therefore they were not considered collinear and were evaluated in the same Cox model. PBP was evaluated in a separate Cox model. Neither systolic (HR 0.996, P = 0.153) nor diastolic (HR 0.994, P = 0.296) BP was significantly associated with all-cause mortality when studied as a continuous variable.

BP categories were evaluated in a proportional hazard model (Table 2) using the SBP of 111–120 mmHg and DBP of 76–80 mmHg as reference groups. Both categories of low SBP: <100 mmHg (HR 2.71, P<0.001) and 101–110 mmHg (HR 1.85, P<0.05) substantially increased the risk of all-cause mortality compared with the reference group. None of the high BP categories were associated with a significant increase in mortality (Figure 2). This is further illustrated by Kaplan–Meier plots for SDP and DBP (Figure 3).


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Table 2. Proportional hazard model evaluating the hazard ratio of all-cause and cardiovascular mortality in various blood pressure categories (n = 1053)a

 


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Fig. 2. The association of systolic blood pressure categories with all-cause mortality evaluated in a proportional hazard model using the 111–120 mmHg group as a reference group. Both categories of low SBP, i.e. <100 mmHg (HR 2.71, P<0.001) and 101–110 mmHg (HR 1.85, P<0.05), substantially increased the risk of all-cause mortality. None of the high blood pressure categories was associated with a significant increase in mortality.

 


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Fig. 3. Kaplan–Meier plots illustrating the association of systolic (A) and diastolic (B) blood pressure and all-cause mortality.

 
To evaluate if the effect of low BP is confounded by infection, we have also performed additional analysis that limits the outcome of interest only to CV mortality. A total of 339 CV deaths were observed in the study population. We observed similar results where the two lowest categories of systolic BP <100 mmHg (HR 3.83, P<0.001) and 101–110 mmHg (HR 2.92, P<0.005) were associated with substantial and statistically significant risk of CV mortality. DBP showed no significant association with all-cause or CV mortality, though the highest DBP category was associated with substantially higher HR for all-cause (HR 2.51, P = 0.094) and CV (HR 2.82, P = 0.106) mortality. PBP was associated with all-cause mortality similar to SBP, where, using the 40–59 mmHg category as a reference, the lowest PBP category of 15–39 mmHg was associated with an HR of 1.49 (P<0.05), while 60–79 mmHg had a protective effect (HR 0.77, P<0.05) and the rest of the categories were not significant. Residual renal function has a significant protective effect for all-cause mortality (HR 0.96, P<0.05) but not CV mortality (HR 0.97, P = 0.194). Conversely, increased dialysis creatinine clearance was associated with greater all-cause and CV mortality.

Subgroup analysis: patients with and without CHF, patients using or not using antihypertensive medications, patients with and without diabetes
To evaluate if the effect of low BP is confounded by CHF, in addition to adjusting multivariate models for underlying history of CHF, we used the following two approaches: (i) we performed analysis stratified by the presence of CHF to reduce potential residual confounding; and (ii) recognizing that low BP may indicate either baseline hypotension or overtreatment of the patient with antihypertensive medications, we stratified analysis by the use of antihypertensive medication.

In the analysis stratified by CHF, in patients without CHF (n = 339), none of the associations between SBP, DBP, PBP and mortality were statistically significant. In patients with CHF (n = 708), using SBP 111–120 mmHg as a reference, the two groups of low BP were associated with significantly greater risk (HR 3.13 and 3.46, P<0.01 and P<0.005 for SBP categories ≤100 and 101–110 mmHg, respectively) as well as the group of patients with SBP 121–130 mmHg (HR 2.16, P<0.05) (Figure 4).



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Fig. 4. The association of systolic blood pressure categories with all-cause mortality evaluated in a proportional hazard model using the 111–120 mmHg group as a reference group. Patients without CHF (CHF–) and with CHF (CHF+) were analysed separately.

 
PBP had a similar trend, where, using the 40–59 mmHg category as a reference, the lowest PBP category (15–39 mmHg) was associated with increased mortality (HR 1.82, P<0.05), while PBP 60–79 mmHg was protective (HR 0.61, P<0.005); the rest of the PBP categories did not have any significant association with the outcome.

In patients on no antihypertensive medications (n = 190), there were no associations between low or higher BP and mortality. In those who were taking antihypertensive medications (n = 857), the association between low BP and mortality was the same as in the whole patient group (HR 4.38 and 3.79, P<0.001 and P<0.005 for SBP categories ≤100 and 101–110 mmHg, respectively).

In patients without diabetes, we did not find any significant association between BP and mortality. In patients with diabetes, low SBP found to be hazardous (HR 2.74, P<0.01).

BP control and hospitalization
The association between BP and total duration of patient hospitalization during the follow-up period was evaluated in a multiple linear regression model. Using backward selection on the complete set of independent variables described above, we evaluated SBP and DBP as continuous variables with the number of days of hospital stay as an outcome. We used duration of hospitalization on a logarithmic scale to adjust for extremely long duration in a few patients (18 patients were hospitalized for >100 days during the follow-up period). Neither SBP nor DBP as continuous variables were significantly associated with the duration of the hospital stay. Low BP categories had no significant association with the outcome; however, higher BP categories were associated with the duration of hospitalization: for SPB category 121–130 mmHg, the regression coefficient was –0.52 (P<0.05); for SBP 131–40 mmHg, the regression coefficient was –0.59 (P<0.05); and for SBP 141–160 mmHg, the regression coefficient was –0.83 (P<0.05) (Table 3). Negative regression coefficients suggest a protective effect of higher BP on duration of hospitalization. None of the diastolic BP categories had a significant association with the duration of hospitalization.


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Table 3. Multiple linear regression model evaluating the association of blood pressure categories and other baseline variables with the total number of hospital days (log-transformed) during the follow-up perioda

 


   Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The prevalence of hypertension in PD patients is high and ranges from 29 to 88% [6,7], while the prevalence of hypotension is 12% in the CAPD population [8]. BP decreases early in the PD course, but increases after 6–12 months [9]. Among the home dialysis patients (both on HD and on PD), most of whom did not require antihypertensive drugs, hypertension was a risk factor for survival; patients with mid-range BP values survived the longest [10]. Elevated BP in PD patients on background therapy was postulated to contribute to left ventricular hypertrophy [11]. The risk of stroke [12], ischaemic heart disease, left ventricular hypertrophy and cardiac failure [13,14] has been associated with elevated BP in patients with ESRD (both on HD and on PD). Hypertension has been shown to be an independent factor affecting mortality of patients on PD [4,15,16], which is primarily associated with systolic hypertension caused by increased arterial stiffness and fluid overload [17].

However, in previous retrospective studies in patients on HD, BP has been demonstrated to have a paradoxical association with clinical outcome. The association of a low pre-dialysis systolic BP with an elevated mortality risk has been shown in a random sample of HD patients from the USRDS [2]. Post-dialysis systolic BP was associated with an elevated mortality risk for both low and high BP levels as compared with mid-range BP [3]. Analysing data from PD, where there are no fluctuations of BP associated with dialysis treatment, might help to establish if this apparently paradoxical relationship between BP and clinical outcome is related to the ESRD per se, rather than the specific type of dialysis. If the former is correct, the data might potentially be applicable to patients with advanced chronic kidney disease not requiring dialysis.

In the previous studies, the incidence of hypotension was 12% in the CAPD population and the mortality rate was higher among hypotensive patients than among the non-hypotensives on CAPD [8]. In this study, we performed the analysis of mortality associated with several categories of BP adjusted for other covariates using the Cox model. We demonstrated that the two lowest categories of BP (SBP <100 and SBP 101–110 mmHg) were associated with increased all-cause mortality and CV mortality. There was no such trend for diastolic BP. PBP (unadjusted for SBP) followed a trend similar to the SBP. Klassen et al. [1] evaluated the role of PBP with and without adjusting for SBP. Unadjusted for SBP, PBP had an inverse association with mortality (similar to our results). However, when the authors adjusted for SBP, higher PBP had a significant association with mortality (12% increase per 10 mmHg of PBP) [1]. We did not perform analysis of PBP adjusted for SBP due to collinearity of these two variables.

In addition, in our study, higher BP categories were associated with lower total duration of hospitalization. We did not reveal any association between high BP and negative clinical outcome, possibly due to a relatively short follow-up period (mean follow-up of 23 months). Due to the latter, the potential negative effect of hypertension on CHF and left ventricular hypertrophy is uncertain from the results of this study.

Potential confounding and bias may distort the results of retrospective analysis. It has been proposed that the association of low BP with increased mortality is the reflection of ante-mortem heart failure [14], and low BP in PD patients was associated with hypovolaemia, CHF or excessive antihypertensive therapy [8,18]. Also, patients with heart failure and hypotension showed a poor prognosis in the previous reports [18]. We also demonstrated that CV co-morbidity and the number of antihypertensive medications have a strong association with low SBP; it is possible that low BP is a reflection of poor CV status, or overaggressive treatment of hypertension resulting in hypotension and hypoperfusion. To decrease residual confounding, the analysis was stratified by the presence of CHF and the usage of antihypertensive medications. In this stratified analysis, the association between low SBP and mortality was present in the subgroups of patients with baseline CHF and those who used the antihypertensive medications, but not the other subgroups. The presence of the association between low BP and mortality in patients with, but not in those without, CHF supports the notion that the relationship between low BP and high mortality is mediated through heart failure. Diabetic complications can cause hypotension in patients with autonomic neuropathy as well as increased patient mortality. It has been shown that the presence of autonomic neuropathy is associated with a more severe hypotension in HD patients [19]. To adjust for that, we stratified the analysis by the diabetic status and found an association between low BP and increased mortality in diabetics patients, with no significant association in non-diabetic patients. Infection during the follow-up period was another potential confounder. We did not have information about infections in the data set, but addressed potential confounding by examining all-cause and CV mortality separately; the latter outcome should not have been substantially affected by infection. Other potential confounders, such as malnutrition, anaemia and hypovolaemia, were addressed by including appropriate variables in the model.

Our study did not address the following caveats. If a patient developed CHF during the follow-up period, the model would not have accounted for that. There was a higher proportion of malignancies, non-insulin-dependent diabetes mellitus and chronic obstructive pulmonary disease in the hypotensive subgroup in patients on PD [8]. Our models did not adjust for any of these potential confounding factors, because not all of the necessary information was available in the original data set. In view of potential residual confounding by depressed cardiac function, prospectively assessing cardiac function in detail at both high and low ends of the BP spectrum would be helpful in understanding the mechanisms underlying these apparently paradoxical relationships. In addition, the results could be distorted by reverse causality and end-of-life bias, as described elsewhere [20]. Alternative explanations for the potential role of BP in mortality might be as a direct cause (BP causing mortality directly), an indirect cause (e.g. accelerated rate of decline in residual renal function in hypotensive patients on PD, depression, malnutrition, hypoperfusion/worsening PVD), or as a mediator of the effect of CHF or autonomic neuropathy in diabetics.

The optimal BP range for dialysis patients has never been established. Based on our survival analysis, high BP does not have any negative implications for survival, while low BP is associated with increased mortality. Analysis of the hospitalization data in fact suggests that higher BP is associated with shorter duration of hospitalization.

We conclude that pre-existing CV morbidity and the number of anti-hypertensive medications were associated with SBP <111 mmHg. SBP <111 mmHg in PD patients was associated with higher mortality risk. This association was present in patients with a history of CHF, those treated with antihypertensive medications and patients with diabetes. The association could possibly be explained by these three factors. Higher BP (SBP >120 mmHg) was paradoxically associated with shorter duration of hospitalization. Caveats of retrospective data analysis notwithstanding, the association of BP with clinical outcomes in PD patients appears to be unconventional. Clinical judgement should be exercised in treating hypertension in chronic PD patients, but, based on presented data, aggressive treatment of hypertension in this population should be cautioned.



   Acknowledgments
 
This study was supported by the Dialysis Research Foundation. The data reported here were provided by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as official policy or interpretation of the US government.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received for publication: 31. 1.05
Accepted in revised form: 1. 4.05