Baseline blood pressure and other variables influencing survival on haemodialysis of patients without overt cardiovascular disease
Jose Jayme Galvão De Lima,
Marcelo Luis Campos Vieira,
Henry Abensur and
Eduardo M. Krieger
Unit of Hypertension and Division of Echocardiography, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
 |
Abstract
|
---|
Background. Age, diabetes and concomitant cardiovascular disease, recorded at the initiation of dialysis, allows the identification of patients with a high probability of early mortality. When all of these factors are taken into account the mortality rate of dialysis patients is still 3.5 times higher than for the general population. Information on the factors that increase the mortality of patients lacking the major cardiovascular risk factors is important because these are likely to be correctable, especially if detected early.
Methods. We investigated prospectively the relevance of blood pressure and other variables recorded at the initiation of dialysis treatment on the survival of a group of 103 relatively young adult haemodialysis patients (mean age 44.3 years ±13 SD), with a low prevalence of comorbidity and a median follow-up period of 79 months. Data were analysed by the Cox proportional regression model and survival curves were constructed by the KaplanMeier method.
Results. Forty-four patients died, 20 (46%) of whom as a result of cardiovascular causes. Multivariate analysis showed that mortality was associated with age (P=0.0001), serum creatinine (P=0.005, negative association), left ventricular (LV) mass (P=0.003) and hypertension (P=0.03). Mortality was increased by 7% for each additional year of age, by 0.7% for each 1 g increase in LV mass, and was reduced by 23% for each additional mg/dl of serum creatinine. Hypertensive patients had a higher probability (x2.2) of dying compared with normotensive patients.
Conclusions. In addition to age and conditions of occult malnutrition, hypertension and LV hypertrophy, when present at the initiation of dialysis, play a major role in the mortality of low risk, relatively young dialysis patients. These potentially correctable factors should be actively sought and treated during the early stage of renal insufficiency to improve prognosis.
Keywords: blood pressure; haemodialysis; hypertension; left ventricular hypertrophy; renal failure; survival on dialysis
 |
Introduction
|
---|
Mortality rates are much higher in dialysis patients than in the non-uraemic population [1]. Comorbidity, advanced age and increased frequency of cardiovascular risk factors all contribute to outcome. It is now generally accepted that many factors leading to premature death in dialysis patients are already present when patients are started on renal replacement therapy. Among these, baseline congestive heart failure [2], diabetes [3] and malnutrition [4,5] have particularly strong impacts on prognosis. Even when these factors are taken into account, survival is still shorter in this particular group of individuals than in the normal population. It is of interest to identify during the early phases of dialysis patients who, despite the lack of significant comorbidity, are at risk of premature death. This could be achieved by studying the relationship between baseline characteristics and outcome of low-risk dialysis patients. Information in the literature is scant. This is an important area of research because unlike advanced age, established cardiovascular disease and diabetes, the factors interfering with survival of low-risk patients are likely to be correctable, especially if they are detected early.
Arterial hypertension is very common among dialysis patients but its relation to survival in this population is controversial. Effective blood pressure control was found to be associated with increased survival by some authors [6]. Others, however, have reported that hypertension does not increase mortality [712] and may even be associated with extended survival [9]. Moreover, low blood pressure is frequently an expression of systolic dysfunction and malnutrition, and individuals with these characteristics have a particularly poor prognosis on dialysis [11,13]. Most of the above-mentioned studies, however, were retrospective and/or covered a relatively short period of observation precluding the assessment of the real long-term impact of high blood pressure on survival.
In 1987 we began a prospective study on a low-risk and relatively young haemodialysis population, intended to determine baseline factors that would adversely affect mortality, independent of the presence of serious associated (especially cardiovascular) diseases. Preliminary results of this study have been published previously [14]. In the present investigation, we report our observations of >12 years. In addition, we have analysed the predictive value of blood pressure levels at the inception of the study on prognosis.
 |
Subjects and methods
|
---|
The demographic and clinical characteristics of the patients were reported previously [14,15]. Briefly, 103 subjects (51 males, 52 females) were selected from an original cohort of 432 haemodialysis patients on the basis of the following characteristics: (i) age >20 years at the initiation of dialysis; (ii) dialysis duration of >8 months; (iii) low prevalence of comorbidity; and (iv) no evidence of overt cardiovascular disease (defined as heart failure, myocardial infarction, cerebrovascular accident and vasculopathy). All individuals were admitted to the study between April 1987 and September 1992. Patients were treated at four dialysis centres located in the same geographic area and employing similar dialysis routines. Haemodialysis was performed three times a week for at least 4 h per session, using a hollow fibre dialyser and a bicarbonate bath. A Kt/V>1.2 was considered adequate. Mean (±SD) age was 44.3±13 years (range: 2173 years; median: 43 years). Seventy-five patients were white, 25 black and three oriental. Chronic glomerulonephritis (22%), nephrosclerosis (24%), interstitial nephritis (15%) and polycystic kidney disease (10%) were the most common causes of renal failure. Three patients were diabetic. The causes of death were classified as cardiovascular, non-cardiovascular and other.
Upon admission to the study, an echocardiogram was obtained from each patient 2436 h after dialysis and analysed by two of the authors (H.A. and M.L.C.V.), who were unaware of the hypothesis of the study at that time. Left ventricular (LV) mass was measured using the cube function formula, as reported previously [16]. Pre-dialysis serum creatinine and haematocrit was also determined. Body mass index (BMI) was calculated using the average of 30 consecutive post-dialysis body weights during the weeks preceding the tests. Standing systolic and diastolic blood pressures were the average of 3438 consecutive pre-dialysis determinations obtained during the 3 months before the initiation of the study. Hypertension was defined as systolic blood pressure>160 mmHg or diastolic blood pressure >94 mmHg, or both. Patients were classified as hypertensive (n=37) or normotensive (n=66) according to their blood pressure profile. Fifty-seven patients (30 hypertensive, 27 normotensive) were receiving at least one type of antihypertensive medication, consisting of centrally acting drugs, angiotensin-converting enzyme inhibitors, calcium channel blockers and beta-blockers, either alone or in combination. Patients gave informed consent to participate in the study, which was approved by the Scientific and Ethics Committee of the Heart Institute.
Statistics
Values are expressed as means±SD, unless indicated otherwise. The main outcome variable studied was global mortality. Patient survival was calculated from the date of baseline examination to the corresponding date of death. If death did not occur during the study period, patients were censored on their last date of contact. The observation period ended on 30 April 1999. Survival curves were constructed by the KaplanMeier method [17] and compared with the log-rank method. We used the Cox proportional hazards regression model [18] to assess relative risks of death in univariate and multivariate analysis. A P value <0.05 was considered significant. Calculations were performed using the SAS statistical package (Version 8, 2000).
 |
Results
|
---|
Table 1
shows the clinical characteristics of the group as a whole and of living and deceased patients. The median follow-up period was 79.2 months (range: 10140.4 months). There were no losses to follow-up. At the end of follow-up, 19 patients were still on dialysis, 40 had been transplanted and 44 had died. Of note, 70% of the transplanted patients received their kidney graft during the first 3 years after starting dialysis.
View this table:
[in this window]
[in a new window]
|
Table 1. Baseline variables (mean±SD) for the study population as a whole and for the patients who died and survived, respectively
|
|
The causes of death are listed in Table 2
. Forty-six per cent of deaths were cardiovascular and 54% were due to other causes or not determined. Sudden death, cerebrovascular accident and infections were the most common causes of death.
Overall, survival was 93, 64 and 30% at 1, 5 and 12 years, respectively. At the end of follow-up, 57% of the hypertensive patients had died versus 35% of normotensive patients (P=0.016; Figure 1
). Univariate analysis showed that hypertension (P=0.02), age (P=0.001) and LV mass index (P=0.015) (Table 3
) were positively associated with death by all causes. Serum creatinine (P=0.02) was negatively associated with mortality. Race, gender, dialysis duration, BMI, haematocrit and antihypertensive medication did not influence outcome. In the multivariate analysis, mortality was independently influenced by hypertension, age, serum creatinine and LV mass index (Table 4
). The risk of dying was 2.2 times higher in hypertensive patients, and increased by 7% for each additional year of age and by 0.7% for each 1 g increase in LV mass index, and was reduced by 23% for each additional 1 mg of serum creatinine.
 |
Discussion
|
---|
Diabetes, heart disease and overt malnutrition are strong predictors of outcome in dialysis and, when present at the initiation of treatment, herald a poor prognosis. The identification of these factors, however, has limited implications for treatment, since they are not usually reversible. On the other hand early diagnosis of baseline risk factors that may be amenable to therapeutic intervention has a greater practical interest because their correction may reduce dialysis mortality. Information regarding the factors that increase mortality of patients lacking major risk factors is scant in the literature because the majority of individuals currently starting dialysis belong to high-risk groups.
In the present investigation LV mass, hypertension and reduced levels of serum creatinine were the main factors besides age affecting survival of low-risk dialysis patients. The marked effect of increased LV mass as measured at the initiation of the study, on prognosis, suggests that this factor persisted during follow-up and confirms the view that ventricular hypertrophy does not usually regress in dialysis [1921]. The high proportion of patients who died of cardiovascular causes (46%) despite the absence of overt myocardial, coronary or cerebrovascular diseases coupled with the low prevalence of diabetes at the inception of the study is intriguing and suggests that LV hypertrophy may have more serious implications for prognosis in patients with chronic uraemia and on dialysis compared with the general population. Indeed, half of the cardiovascular deaths of our patients were sudden, and sudden death is a well known consequence of LV hypertrophy. Because of the high frequency of complex arrhythmia in dialysis patients [22] it is tempting to speculate that sudden death in our patients was mainly due to lethal arrhythmia secondary to LV hypertrophy. Alternatively, occult or de novo coronary artery disease or myocardiopathy could explain the elevated number of cardiac deaths [23]. In this regard, Parfrey et al. [24] observed that most of the adverse effects of ventricular hypertrophy in dialysis patients occur via congestive heart failure or coronary events. However, only one of our patients died of myocardial infarction and one other of heart failure during this extended follow-up, making this explanation less probable.
In the present prospective investigation, high blood pressure, recorded at the initiation of the study, was an independent predictor of overall mortality. Increased blood pressure is a risk factor for LV hypertrophy in dialysis patients [16], as it is in the general population [25], and has been shown to remain unchanged in the majority of dialysis patients [26,27]. Also, hypertension is a major cause of cerebrovascular accidents [28], the second most important cause of cardiovascular death in our study. It is possible that blood pressure may be relevant for survival only in those dialysis patients who survive long enough on dialysis to develop secondary target-organ damage, especially cardiac hypertrophy. Target-organ damage caused by non-malignant hypertension requires months or years to become established, and this could explain the lack of relevance of high blood pressure on survival documented in short-term studies. This interpretation is not only coherent with our results but also agrees with observations in the general population [2830]. It should be mentioned that we do not have data concerning blood pressure levels of patients during follow-up, since the purpose of the present investigation was to detect alterations at the initiation of dialysis that would be useful as predictors of long-term outcome. Therefore, we cannot exclude the possibility that blood pressure values during the entire follow-up period would correlate better still with prognosis.
Reduced levels of serum creatinine [5,31], albumin [13,32] and cholesterol [33] are associated with a poor prognosis on dialysis and are thought to reflect the degree of malnutrition. Our patients were relatively young and good clinical condition was a criterion for inclusion in the study. However, occult malnutrition, reflected by reduced serum creatinine, was probably present in some patients at the initiation of the study. The relatively high proportion of deaths caused by malnutrition (7%) agrees with this view.
In conclusion, among dialysis patients without overt cardiovascular disease at the initiation of treatment there was a high proportion of deaths related to LV hypertrophy, hypertension, occult malnutrition and age. With the exception of age, other factors are not only easily identifiable but are also amenable to correction. Early detection and correction of hypertension, LV hypertrophy and malnutrition should be high priorities in patients on maintenance dialysis.
 |
Acknowledgments
|
---|
We are grateful to Ms Mariana Curi for the statistical analysis and to Mrs Elettra Greene for editorial assistance. This investigation was supported by the E. J. Zerbini Foundation, São Paulo, Brazil.
 |
Notes
|
---|
Correspondence and offprint requests to: Jose J. G. De Lima, Unidade de Hipertensão, Instituto do Coração, Rua Eneas Carvalho Aguiar 44, 05403000, São Paulo, Brazil. 
 |
References
|
---|
-
Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis1998; 32(Suppl. 3): S112S119[ISI][Medline]
-
Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int1995; 47: 884890[ISI][Medline]
-
Chantrel F, Enache I, Bouiller M, Kolb I, Kunz K, Petitjean P, Moulin B, Hannedouche T. Abysmal prognosis of patients with type 2 diabetes entering dialysis. Nephrol Dial Transplant1999; 14: 129136[Abstract]
-
Greaves SC, Sharpe DN. Cardiovascular disease in patients with end-stage renal failure. Aus NZ J Med1992; 22: 153158[ISI][Medline]
-
De Lima JJG, Fonseca JA, Godoy AD. Baseline variables associated with early death and extended survival on dialysis. Renal Failure1998; 20: 581587[ISI][Medline]
-
Charra B, Calemard E, Cuche M, Lurent G. Control of hypertension and prolonged survival on maintenance hemodialysis. Nephron1983; 33: 9699[ISI][Medline]
-
Churchill DN, Taylor W, Cook RJ, et al. Canadian hemodialysis morbidity study. Am J Kidney Dis1992; 19: 214234[ISI][Medline]
-
Ritz E, Koch M. Morbidity and mortality due to hypertension in patients with renal failure. Am J Kidney Dis1993; 21(Suppl. 2): 113118[ISI][Medline]
-
Salem MM, Bower JD. Hypertension in the hemodialysis population: any relation to 2-years survival? Nephrol Dial Transplant1999; 14: 125128[Abstract]
-
Klefter R, Lokkegaard H. Risk factors in haemodialysis patients: evaluation of commonly measured variables on death rate. Scand J Urol Nephrol1998; 32: 127131[ISI][Medline]
-
Port FK, Hulbert-Shearon TE, Wolfe RA, Bloemberg WE, Golper TA, Agodoa LY, Young EW. Predialysis blood pressure and mortality risk in a national sample of maintenance hemodialysis patients. Am J Kidney Dis1999; 33: 507517[ISI][Medline]
-
Duranti E, Imperiali P, Sasdelli M. Is hypertension a mortality risk factor in dialysis? Kidney Int Suppl1996; 55: S173S174[Medline]
-
Iseki K, Miyasato F, Tokuyama K et al. Low diastolic blood pressure, hypoalbuminemia, and risk of death in a cohort of chronic hemodialysis patients. Kidney Int1997; 51: 12121217[ISI][Medline]
-
De Lima JJG, Sesso R, Abensur H, Lopes HF, Giorgi MCP, Krieger EM, Pileggi F. Predictors of mortality in long-term hemodialysis patients with a low prevalence of comorbid conditions. Nephrol Dial Transplant1995; 10: 17081713[Abstract]
-
De Lima JJG, Abensur H, Krieger EM, Pileggi F. Arterial hypertension and left ventricular hypertrophy in hemodialysis patients. J Hypertens1996; 14: 10191024[ISI][Medline]
-
De Lima JJG, Abensur H, Bernardes-Silva H, Bellotti G, Pileggi F. Role of arterial hypertension in left ventricular hypertrophy in hemodialysis patients: an echocardiographic study. Cardiology1992; 80: 161167[ISI][Medline]
-
Kaplan EL, Meir P. Non-parametric estimation from incomplete observations. J Am Statist Assoc1958; 53: 457481[ISI]
-
Cox DR. Regression models and life tables. J R Statist Soc (Series B)1972; 34: 187219
-
Locatelli F, Del Vecchio L, Manzoni C. Morbidity and mortality on maintenance hemodialysis. Nephron1998; 80: 380400[ISI][Medline]
-
Hüting J, Kramer W, Schutterle G, Wizemann V. Analysis of left ventricular changes associated with chronic hemodialysis. Nephron1988; 49: 284290[ISI][Medline]
-
De Lima JJG, Abensur H, Fonseca JA, Krieger EM, Pileggi F. Comparison of echocardiographic changes associated with hemodialysis and renal transplantation. Artif Organs1995; 19: 245250[ISI][Medline]
-
De Lima JJG, Vieira MLC, Lopes HF, Guppi CJ, Medeiros CJ, Ianhez LE, Krieger EM. Blood pressure and the risk of complex arrhythmia in renal insufficiency, hemodialysis, and renal transplantation. Am J Hypertens1999; 12: 204208[ISI][Medline]
-
Bleyer AJ, Russell GB, Satko SG. Sudden and cardiac death rates in hemodialysis patients. Kidney Int1999; 55: 15531559[ISI][Medline]
-
Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray DC, Barre PE. Outcome and risk factors for left ventricular disorders in chronic uremia. Nephrol Dial Transplant1996; 11: 12771285[Abstract]
-
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographic determined left ventricular mass in the Framingham heart study. N Engl J Med1990; 322: 15611566[Abstract]
-
Mittal SK, Kowalski E, Trenkle J et al. Prevalence of hypertension in a hemodialysis population. Clin Nephrol1999; 51: 7782[ISI][Medline]
-
Rahman M, Dixit A, Donley V, Gupta S, Hanslik T, Lacson E, Ogundipe A, Weigel K, Smith MC. Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients. Am J Kidney Dis1999; 33: 498506[ISI][Medline]
-
MacMahon S, Rodgers A. The epidemiological association between blood pressure and stroke: implications for primary and secondary prevention. Hypertens Res1994; 17(Suppl. I): S23S32
-
Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med1991; 114: 345352[ISI][Medline]
-
Shigematsu Y, Hamada M, Mukai M, Matsuoka H, Sumitomo T, Hiwada K. Clinical evidence for the association between left ventricular geometric adaptation and extracardiac target organ damage in essential hypertension. J Hypertens1995; 13: 155160[ISI][Medline]
-
Fink JC, Burdick RA, Kurth SJ, Blahut SA, Armistead NC, Turner MS, Shickle LM, Light PD. Significance of serum creatinine values in new end-stage renal disease patients. Am J Kidney Dis1999; 34: 694701[ISI][Medline]
-
Lowrie EG, Lew HL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis1990; 15: 458482[ISI][Medline]
-
Degoulet P, Legrain M, Reach I, Devries C, Rojas P, Jacobs C. Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron1982; 31: 103110[ISI][Medline]
Received for publication: 6.10.99
Revision received 18. 6.00.