|Year : 1999 | Volume
| Issue : 4 | Page : 455-463
|Cardiovascular Disease and Survival in ESRD
Robert N Foley
The Division of Nephrology and Clinical Epidemiology, The Health Sciences Center, Memorial University, St. John's Newfoundland, Canada
Click here for correspondence address and email
|How to cite this article:|
Foley RN. Cardiovascular Disease and Survival in ESRD. Saudi J Kidney Dis Transpl 1999;10:455-63
It became apparent early in the history of chronic dialysis therapy that patient survival was much shorter than in a general population sample of similar age. Cardiovascular disease was the attributed cause of death in an unexpectedly large proportion of patients. In 1974, Lindner et al published the Seattle experience, in which 60% of deaths in their dialysis patients were due to cardiovascular diseases.  Approximately half of all deaths in dialysis patients are reported to be due to cardiovascular diseases. , It is likely that cardiovascular disease leads to uremia and that uremia leads to cardiovascular disease, a classic "vicious circle".
Mortality from cardiovascular disease is an order of magnitude higher in dialysis patients. Transplant patients appear to have rates that are intermediate, though still excessive.  The incidence rates of coronary artery disease and cardiac failure are considerably higher in dialysis patients than in the age-matched general population. For example, in the Canadian Hemodialysis Morbidity Study the admission rates for ischemic heart disease and cardiac failure were 10% per year for each condition.  In the Western World, most patients starting dialysis therapy have clinical manifestations of heart disease. For example, in the ongoing, prospective, USRDS Wave 2 study, the prevalence of ischemic heart disease and cardiac failure in patients starting dialysis therapy is 40% for both conditions.  Our group performed a 10-yer study from the inception of dialysis therapy in 433 end-stage renal disease (ESRD) patients. Abnormal left ventricular morphology and function were very common at inception of dialysis therapy; 74% had left ventricular hypertrophy, 32% had left ventricular dilatation and 15% had systolic dysfunction.  Several echocardiographic studies have had similar findings.
It is improbable that the large burden of already-established cardiac disease in patients starting dialysis therapy accounts for the very high subsequent incidence rates. In our study the incidence rates of new ischemic heart diseases and new cardiac failure were approximately 5% and 11% per year of dialysis therapy. , Cardiovacular disease clearly shortens survival in ESRD patients. Cardiac failure has been consistently associated with mortality in dialysis patients. The association has not been as consistent for ischemic heart disease, especially when the possibility of concomitant cardiac failure is taken into account in survival analysis. We found that patients with ischemic heart diseases starting dialysis therapy had shorter survival than those who did not. Much of the mortality effect of ischemic heart disease appeared dependent on the presence of cardiac failure. The presence of both ischemic heart disease and cardiac failure conditions was especially lethal. 
In our study, left ventricular (LV) disorders present on echrocardiography represented a hierarchy of risk as follows: normal LV, concentric LV hypertrophy, LV dilatation and systolic dysfunction. This risk grading strongly predicted the development of ischemic heart disease, cardiac failure and death. The relationship between echo cardiographic abnormalities and death came into effect after approximately two years on dialysis therapy, suggesting that the most effective time for intervention may be before this. ,
In a recent analysis, we found that regression of LV hypertrophy and systolic dysfunction between baseline and one year dialysis was associated with a lower risk of new-onset cardiac failure. 
Although the clinical epidemiology of cardiovascular disease in chronic renal disease has received much more attention in recent years, there are large gaps in our knowledge, Intuitively, it would seem logical that early risk factor intervention would gain more than late intervention. Regrettably, our information on the incidence and risk factors of cardiovascular disease in those with non-end-stage renal failure, To do this judiciously, we need accurate information about rates of cardiovascular events and reversible risk factors from large-scale prospective studies, in all the major sub-groups of patients with renal dysfunction.
The 1990's have been remarkable for the number of large trials showing that intervention in risk factors derived from observational studies translate into clinical benefit. These trials have shown repeatedly that those already at higher risk gain relatively more from intervention in a specific risk factor. For example, the benefits of treating blood pressure are very clear in older subjects.  Similarly, aggressive strategies of control of lipid disorders are most clearly advantageous in survivors of myocardial infarction, ,, while aspirin therapy is most clearly indicated in those with coronary artery disease ,,,, or in older diabetic patients.  These results are difficult to ignore and the interventions employed are easily applicable on ESRD patients, a group in which classical cardiovascular risk factors like hypertension, hypercholesterolemia and hyperglycemia are highly prevalent. It is impossible to disprove the hypothesis that these patients have risk factors unique to uremia and its therapies that could over-shadow the impact of classical risk factors. It is the opinion of this author that intervention trials in classic cardiovascular risk factors need to be repeated in ESRD patients if rational treatment algorithms are to be designed for ESRD patients.
Smoking doubles the risk of cardiovascular disease in the general population. It is rarely seriously entertained in the search for reversible risk factors in ESRD patients. Relatively little is known about the impact of smoking on ESRD patients. In the USRDS Special Study of case Mix Severity, smoking increased mortality by 26% in hemodialysis patients.  In another study it was associated with a doubling of mortality rates in diabetic ESRD patients. 
Until recently, a nephrologists "know", from intuition, that hypertension is one of the main cardiovascular risk factors in dialysis patients. Recent observation data examining the relationship between blood pressure levels and ESRD mortality have been inconsistent. For example, in the wellknown study of Charra et al, patients who received long-duration hemodialysis, with an achieved mean KT/V of 1.67, had five year survival rates were extremely good. Almost all of these patients had "normal" blood pressure levels, without antihypertensive medications, Even within this normotensive range, higher blood pressures were directly associated with mortality.  In contrast, several epidemiological studies have suggested that low blood pressure is associated with mortality in ESRD. , If a true cause effect relationship is present, these latter results suggest that high blood pressure is protective in dialysis patients. In patients with progressive renal disease, it is hard to imagine how blood pressure levels could suddenly switch from being harmful immediately before, to beneficial immediately after starting dialysis therapy. Another recent study suggested that prehemodialysis blood pressure was unrelated to cardiovascular mortality. A U-curve association between post dialysis blood pressure and mortality was seen, with systolic blood pressure greater than 180 mmHg, diastolic blood pressure greater than 90 mmHg and systolic blood pressure less than 110 mmHg associated with increased cardiovascular mortality.  In our study, mean arterial blood pressure levels were 101 mmHg. An inverse relationship between blood pressure levels and mortality was seen. High blood pressure, however, was independently associated with an increase in LV mass index and cavity volume over time, as well as with new onset ischemic heart disease and cardiac failure. These data produce conclusions that appear to be internally irreconcilable: high blood pressure may have caused the conditions that caused death in these patients, while lower average blood pressure was associated with shorter survival. It is worth highlighting several results from our study.
Admission for cardiac failure predated most deaths. High blood pressure was very strongly predictive of the development of cardiac failure. Blood pressure fell following the development of cardiac failure. Low blood pressure strongly predicted mortality after the development of cardiac failure.  These data suggest, at the very least, that high blood pressure is harmful for dialysis patients without established cardiac disease. There are very few randomized trials examining antihypertensive therapy in ESRD patients. London and colleagues assigned 24 hypertensive dialysis patients with LV hypertrophy to either the ACE inhibitor perindopril or the calcium channel blocker nitrendipine. The blood pressure reductions seen were similar in both groups. However there was a greater reduction in LV mass index in those randomly assigned to receive perindopril, suggesting that blood pressure reduction is beneficial and that ACEinhibitors may have an impact that is independent of their blood pressure lowering effect.  The huge prevalence of hypertension in ESRD populations and the lack of uniformity in the blood pressure mortality relationship underscore the need for a large randomized trial of blood pressure targets in dialysis patients.
High triglycerides levels, decreased HDL and high Lp (a) levels are frequently observed in both hemodialysis and peritoneal dialysis, while peritoneal dialysis patients also have higher LDL levels. The associations between quantitative lipid abnormalities and outcome in ESRD are not as consistent as seen in the general population. Lowrie and colleagues found an inverse association between cholesterol levels and mortality, possibly because low cholesterol reflects malnutrition. Some studies, however, have reported that dyslipdemia may be association with cardiac mortality in diabetic hemodialysis patients,  and that lipoprotein (a) elelvated level is associated with cardiovascular disease in a mixed population of hemodialysis patients.  A recent crosssectional study reported that high apo (b) level, low-molecular weight apo (a) phenotype and low HDL levels were associated with the presence of coronary artery disease. 
Hyperhomocysteinemia appears to be a reversible cardiovascular risk factor in the general population. Very high homocysteine levels are found in ESRD patients. Several studies have reported that high homocysteine levels are associated with vascular disease in uremic patients. ,,,,, This risk factor may be abrogated with high dose B-vitamin therapy, even in patients with chronic renal disease. Boston and colleagues demonstrated that Vitamin B6 and a combination of folic acid plus Vitamin B12 have additive effects in reducing homocysteine levels in renal transplant patients.  Perma et al, have recently shown that oral methyltetraphydrofolate can lead to dramatic reductions of homocysteine levels in hemodialysis patients.  The cardiovascular benefit of interventions like this has yet to be established.
Anemia has been shown consistently to be a risk factor for the cardiac abnormalities seen in ESRD. Hemoglobin levels averaged 8.8 g/dl in our study. Anemia was associated with progressive LV dilatation on echocardiography, the development of denovo cardiac failure, and overall mortality.  More recently, a number of large studies have shown associations between anemia and mortality, with the mortality risk increasing as hematocrit falls below 33%. ,,
Many studies have examined the effect of partial correction of anemia with erythropoietin on echocardiographic abnormalities. Partial correction of anemia partially reverses left ventricular dilatation and hypertrophy. ,, Several observational studies in chronic renal impairment have shown that cardiac enlargement progress rapidly as glomerular filtration rate falls; the development of renal anemia has been associated with this cardiac enlargement in the studies reported thus far. , Our group has recently examined the annual evolution of patients from inception up to three years on dialysis therapy. LV dilatation with compensatory LV wall thickening occurred over time. Most of the cardiac enlargement took place in the first year. Risk factors (anemia and hemodialysis compared to peritoneal dialysis) could only be identified in the first year. The cardiac enlargement observed after this was autonomous of several standard risk factors.  these data suggest that earlier intervention to prevent anemia might achieve more than late intervention.
Three randomised clinical trials comparing partial to complete correction of anemia have recently been completed. In the US trial, 1233 patients (of whom 56% were diabetic) were randomly assigned to target hematocrit of 30% or 42%. The presence of congestive heart failure or ischemic heart disease was a mandatory inclusion criterion for the trial. After 2.4 years of follow-up, there were 183 deaths and 19 had first nonfatal myocardial infarctions in the highhematocrit group, compared to 150 deaths and 14 with nonfatal myocardial infarctions in the low-hematocrit group. This represented a risk ratio of 1.3 for the normal hematocrit group compared to the lowhematocrit group, with a 95 percent confidence interval of 0.9 to 1.9. the patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group. In particular, there was an excess of vascular access thrombosis, with rates of 39% vs 29% respectively,  translating into an increase of relative risk of approximately one-third in those in the high-hematocrit group. It appears, therefore, that in hemodialysis patients with advanced cardiac disease, the conservative target hematocrit Canadian Multicenter trial in hemodialysis patients without symptoms of cardiac disease. The principal objectives were to compare target hemoglobin levels of 100 and 135 g/l with respect to regression of concentric LV hepertrophy and LV dilatation. The results of this trial are being analysed at the time of writing. Furthermore, a Swedish trial has recently been completed in which partial versus complete correction of renal anemia were compared in patients with advancing chronic renal failure, dialysis patients and renal transplant recipients.
We found that chronic hypocalcemia in dialysis patients was associated with ischemic heart disease and death.  Hypocalcemia is known to lead to hyperparathyroidism, which may lead to intracellular calium overload, altered myocardial bioenergetics and myocardial ischemia.  Hyperparathyroidism has been associated with LV abnormalities and arterial thickening in dialysis patients. , A recent USRDS study suggested that phosphorus levels above 6.5 mg/dl (1.8 mmol/L) and hyperparathyroidism were both associated with mortality in hemodialysis patients.  The target levels of calcium, phosphate and parathyroid hormone that minimize cardiovascular risk in ESRD are unknown.
Hypoalbuminemia and dialysis intensity are predominant outcome predictors in ESRD. , The contribution of acute phase reaction and actual malnutrition to the hypoalbuminemia of ESRD is not fully known. The consistent observation that cardiovascular disease far outpaces any other cause of death in ESRD suggests that hypoalbuminemia and cardiac disease in dialysis patients may be inter-related. In our prospective cohort study hypoalbuminemia was strongly associated with the development of de novo and recurrent cardiac failure, do novo and recurrent ischemic heart disease, cardiac mortality and overall mortality in hemodialysis patients. Among peritoneal dialysis patients hypoalbuminemia was independently associated with progressive LV dilatation on serial echocardiograms, de novo cardiac failure and over all mortality.  The biological pathways connecting hypoalbuminemia to coronary artery disease and cardiomyopathy in dialysis patients are not know. Several are theoretically possible, including hypercoagulability, as in the nephrotic syndrome, direct effects related to inadequate protein stores, and as a surrogate marker for the pathogenic effects of a chronic inflammatory state.
Animal studies show the uremia leads to myocardial collagen deposition, fibrosis and a reduction in capillary surface density. , Uremic serum directly depresses myocardial contractility.  Uremia has been shown to cause chronic activation of the vascular endothelium.  The evidence that uremia leads to clinical cardiovascular disease in human ESRD is indirect. In the National Co-operative Dialysis Study there were more cardiac events in patients who received less intensive dialysis therapy.  It is known that renal transplantation leads to an improvement in many of the echocardiographic abnormalities seen in dialysis patients.  The ongoing HEMO study, a very large multicenter trial testing the effects of dialysis dosage and membrane flux on morbidity and mortality, should enlighten us considerably.
The last decade has seen an explosive increase in the volume of work trying to define the clinical epidemiology of cardiac disease in chronic uremia. Classis cardiac risk factors are common in ESRD but need to be rigorously tested for clinical benefit in uremic populations. In addition, there appear to be several modifiable cardiovascular risk factors that directly related to the uremic state. High quality, prospective epidemiological data, as well as randomised controlled clinical trials are needed in ESRD.
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Robert N Foley
The Division of Nephrology and Clinical Epidemiology, The Health Sciences Center, Memorial University, St. John's Newfoundland, A1B3V6
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