Morbidity

Kidney International (2000) 57, S100–S104; doi:10.1046/j.1523-1755.2000.07417.x

Comorbidities and their impact on outcome in patients with end-stage renal disease

Sarah S Prichard

Nephrology Division, Department of Medicine, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada

Correspondence: Sarah Prichard, M.D., Nephrology-R2.38, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. E-mail: sprichard@rvhmed.lan.mcgill.ca

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Abstract

Comorbidities and their impact on outcome in patients with end-stage renal disease. End-stage renal disease is associated with an increased mortality compared to age-matched controls. Increasing age, diabetes, cardiovascular disease and poor nutrition are the most important co-existing conditions that predict worse outcomes for patients with end-stage renal disease. Of the cardiovascular conditions that are associated with higher mortalities, ischemic heart disease and left ventricular hypertrophy have a high prevalence amongst the predialysis and dialysis population. There are multiple risk factors associated with uremia that predispose to these conditions. Congestive heart failure is also a strong predictor of poor outcome and often coexists with hypertension and ischemic heart disease. Although hypertension in the general population is associated with higher mortalities, in dialysis patients hypotension is a more accurate predictor of high mortality rates. Diabetes is now the most common cause of end-stage renal disease in many parts of the world. It has a strong negative impact on survival and is associated with the presence of vascular disease. Similarly, increasing age in the uremic population is associated with a high frequency of hypertension and vascular disease. Poor nutritional status, as indicated by a low serum albumin or subjective global assessment is a strong predictor of high mortality. This may in part indicate the coexistence of a chronic inflammatory state. The most important predictors of poor outcome in end-stage renal disease are increasing age, cardiovascular disease, diabetes and poor nutrition as reflected by hypoalbuminemia. Future studies need to be initiated which will assess the impact of interventions which modify directly these co-morbidities.

Keywords:

comorbidities, outcomes, ESRD

Renal replacement therapy has offered millions of patients an opportunity to prolong their lives. The success of the therapy has been undeniable, and outcomes continue to improve. In spite of these advances, patients with end-stage renal disease (ESRD) have a significantly reduced life expectancy compared to age-, gender-, and race-matched populations. In the United States, the mean expected life span for patients beginning dialysis at age 40 is 9.3 years, and is 4.3 years for patients beginning dialysis at the age of 591. Annual mortality rates reported in various registries for patients with end-stage renal disease range from 10% to over 20%1,2,3. Furthermore, as advances have been made in renal replacement therapy, the patient population initiating treatment has become older and often has a number of comorbid conditions that become the major determinants of survival. Improvements in outcome for patients with ESRD will depend in part on improvements in the renal replacement therapy itself, but also on the better understanding and management of those conditions which coexist and become the primary determinants of outcome. This article will review several of the major comorbidities, their prevalence, their impact on outcome, and their etiologies, which may give insight into treatment strategies.

In 1982 Hutchinson et al4 reported that the risk of death for a patient initiating renal replacement therapy doubled with each decade, with the coexistence of diabetes and with the occurrence of an episode of congestive heart failure. Although additional insights have been made with regard to understanding pathogenesis, age, diabetes and heart disease, together with nutritional status, remain the most important predictors of outcome for this patient population. Of these factors, cardiovascular disease, diabetic management, and nutritional status are potentially modifiable. Thus, it is important to concentrate our attention on these issues. There are additional conditions that have a strong impact on outcome, such as AIDS or malignancy, which affect a small percentage of the ESRD population. The management of AIDS patients is a good example of how improvement in the overall care of these patients has resulted in improvements in their outcome on dialysis5.

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CARDIOVASCULAR DISEASE

The most important cardiovascular abnormalities in ESRD are ischemic heart disease, left ventricular hypertrophy, congestive heart failure, hypertension, and peripheral vascular disease. Other conditions such as arrhythmias, vascular disease, and infiltrative disease represent a smaller clinical problem.

Ischemic heart disease

Diseases that cause ESRD often constitute a risk factor for ischemic heart disease, with diabetes, hypertension, and peripheral vascular disease causing renal artery stenosis being the most common examples. However, the onset of renal failure also adds new cardiovascular risk factors to these patients6. Lipoprotein abnormalities including low levels of high density lipoprotein (HDL), hypertriglyceridemia, and elevated low density lipoprotein (LDL) cholesterol abnormalities and Lp(a) are frequent. Homocysteine levels are virtually always significantly elevated and often are resistant to vitamin supplementation. Chronic inflammation, insulin resistance, elevated calcium, phosphate products and oxidative stress all constitute additional risk factors which are brought on by the condition of uremia. Conventional risk factors such as family history and smoking add to the list of atherosclerotic risk factors. Thus, it is not surprising that the prevalence of ischemic heart disease is very high within the dialysis population.

In data from the U.S. Case Mix study7, 40% of hemodialysis and peritoneal dialysis patients were reported to have clinical coronary artery disease. This may represent an underestimate of the incidence since many patients with congestive heart failure may have as their underlying etiology coronary ischemic heart disease which has not presented clinically as such. In a recent survey at the Royal Victoria Hospital in Montreal, 60% of the dialysis population patients prevalent on May 15th, 1998 had a diagnosis of ischemic heart disease.

In the 1998 Canadian Registry3, ischemic heart disease was present in 23.1 % of the diabetic and 5.2% of the nondiabetic patients starting analysis who were under the age of 45 years. In those over the age of 45 years, that increases to 56.6% of the diabetics and 45.8% of the nondiabetics. In this report, ischemic heart disease was defined as the presence of angina or a history of myocardial infarction. In chronic renal insufficiency, i.e., predialysis, the incidence of ischemic heart disease is less certain, but in a prospective study of 422 patients followed in Canada, 23% had had a coronary artery bypass, angioplasty, acute myocardial infarction, or angina (unpublished data). In the Canadian hemodialysis morbidity study8, 33.7% of the patients on dialysis had cardiovascular disease, of which the vast majority had ischemic heart disease. Thus, it is clear that patients with uremia have an extraordinarily high coexistence of ischemic heart disease.

The impact of the coexistence of ischemic heart disease on survival is important but is often confounded by the coexistence of left ventricular hypertrophy and congestive heart failure. In the Canadian morbidity study8, cardiovascular disease existed in 33.7% of the patients, yet this group accounted for 16.2% of the deaths as compared to those without cardiovascular disease (66.3%), who accounted for only 5.8% of the deaths. In a cohort of 433 patients from the Royal Victoria Hospital in Montreal, Quebec, and the Health Sciences Centre in St. John's, Newfoundland, the existence of ischemic heart disease at the initiation of dialysis had a significant negative impact on survival9. At 5 years, the survival rate in those with ischemic heart disease was approximately 22% compared to those without ischemic heart disease, in whom the survival rate was almost 50%. Using a Cox proportional hazards model, ischemic heart disease increased the odds ratio of death to 1.48 (P < 0.001). However, ischemic heart disease also predicted a greater likelihood of an episode of congestive heart failure. Using the same Cox proportional hazards model in which heart failure is entered into the analysis, ischemic heart disease did not add further risk to the outcome for the patients. In that analysis it appears that the impact of ischemic heart disease is in its contribution to causing heart failure, which then becomes a much more powerful predictor of death.

In summary, patients with ESRD have multiple risk factors for ischemic heart disease and the same systemic diseases that predisposed to renal failure also represent risk with respect to ischemic heart disease. The existence of ischemic heart disease in this patient population predisposes to a worse outcome after initiating renal replacement therapy.

Left ventricular hypertrophy

In the Framingham studies, left ventricular hypertrophy was found to be an independent risk factor for death in the general population10. The most important determinant of left ventricular hypertrophy (LVH) in the non-uremic patient is hypertension. There are similarities in the renal failure population.

LVH is extremely common in the uremic population. In a report by Levin et al11, the prevalence of LVH was 26.7% of patients with a creatinine clearance> 50 mL/min, 30.8% in those with clearance between 25 and 49 mL/min, and 45.2% in those with clearance <25 mL/min. LVH has been reported to be present in up to 75% of patients on hemodialysis and peritoneal dialysis. At the initiation of dialysis in a Canadian study, 39.4% of the patients had concentric LVH12. Risk factors for the development of LVH have consistently been shown to include age and blood pressure13,14. Anemia has often been shown to be a risk factor15, and its correction is associated with regression of LVH. Other factors, including the presence of fistulas, hyperparathyroidism, and certain antihypertensives, have been variably reported as an association.

As is true in the non-uremic population, LVH is a risk factor for mortality in the dialysis population. In comparing the upper and lower quintile for left ventricular mass index in a dialysis population, the adjusted relative risk for overall mortality was 2.9 and for cardiac death was 2.716. Furthermore, left ventricular abnormalities were associated with an increase in de novo ischemic heart disease and heart failure9.

In summary, LVH is common in patients initiating dialysis and becomes more common once the patients initiate renal replacement therapy. It is an independent risk factor for death as well as a predisposing factor for the development of heart failure and ischemic heart disease.

Hypertension

Hypertension can be both a cause of renal failure and a frequent complication of renal insufficiency. With respect to the impact of hypertension on outcome for renal failure patients, the data is somewhat paradoxical.

Hypertension is a predisposing factor for the development of left ventricular hypertrophy which is a risk factor for both death and the development of congestive heart failure17. These latter two effects have a negative impact on outcomes.

More recently, however, a number of studies have demonstrated that low blood pressure is an important risk factor for higher mortality in dialysis patients18,19. In order to reconcile these two sets of observations, one can develop a hypothesis that the existence of hypertension predisposes to both left ventricular hypertrophy and ischemic heart disease, which in turn predispose to heart failure. As the heart failure advances and pump failure follows, blood pressures might be expected to fall. Thus, the poor survival with low blood pressure may be a marker for cardiac failure rather than an indication that low blood pressure per se is an independent risk factor for mortality.

Congestive heart failure

As originally described by Hutchinson4, the occurrence of congestive heart failure has been demonstrated to have a negative impact on outcomes in patients with end-stage renal disease. In the U.S. Case Mix adequacy study, 40% of patients on hemo and peritoneal dialysis had clinical congestive heart failure7. In the Canadian study, 25.1% of the patients had LV dilation on echocardiography and a further 24.1% developed de novo cardiac failure in follow-up17. Heart failure gave an odds ratio of 1.93 of death using a Cox proportional hazard model. In the USRDS, cardiac failure independently predicted mortality in a cohort of 3,399 patients starting hemodialysis (relative risk 1.26). Finally, the observation that patients on peritoneal dialysis who are high transporters have a higher mortality rate despite better clearances has been interpreted as being an indication of chronic fluid overload and perhaps subclinical heart failure. No direct evidence for this linkage has been made, but it underlines the potential importance of aggressive management of volume status in improving outcomes for our patient population.

Peripheral vascular disease

Peripheral vascular disease is an important cause of morbidity in ESRD patients. The coexistence of ischemic heart disease and diabetes with peripheral disease is frequent. For example, in the U.S. study of high target hematocrits for patients with clinical cardiac disease, 38% of the patients had peripheral vascular disease20. In the Canadian Renal Failure Registry in 19983, in patients under the age of 45 years, 14.4% of the diabetics and 1% of the non-diabetics had peripheral vascular disease at the initiation of dialysis. In those over the age of 45 years those percentages increased to 28.8% and 15.5% for the diabetics and non-diabetics, respectively. In 1998, non-cardiac vascular disease was reported as a cause of death in 7% of all patients over the age of 45 years in Canada and in 8.2% of all patients under the age of 45.

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DIABETES

Diabetes has emerged as the leading cause of ESRD in many parts of the world. In all registries, the coexistence of diabetes is noted to have a negative impact on survival at all ages2,3. The majority of the diabetics included in such registries are type 2 diabetics, but the analyses are usually a mix of both type 1 and type 2 diabetics.

Diabetes has a particularly important impact on vascular disease. From the Canadian Renal Failure Registry3, diabetics under the age of 45 have a marked increase in incidence of angina, myocardial infarction, cerebral vascular accident and peripheral vascular disease, as shown in Table 1. In patients over the age of 45, the difference between diabetics and non-diabetics is not as great as in the younger group but the prevalence of all of these vascular co-morbidities is significantly higher. This translates into cardiovascular mortality rates for diabetic dialysis patients that exceed their age and gender matched comparison groups in all age groups. From the USRDS, diabetics over the age of 85 have an annual cardiovascular mortality rate in excess of 25%. In the Canadian morbidity study8, diabetes was present in 18.6% of the study group and yet accounted for 9.8% of the deaths compared to 81.4% of the population which is non-diabetic and accounted for only 9.2% of all deaths.


Thus, diabetes is a common and important risk factor for death, and in particular enhances the cardiovascular risk of the patient. Management of this important group of patients will require an aggressive treatment strategy in order to impact on these poor outcomes.

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NUTRITION

As improvements in dialysis therapy have been made and sensitivity to the need for adequacy has increased, the importance of nutrition as a prognostic indicator has emerged. Although a number of parameters of nutrition have been used, albumin has been the most easily measured and reliable predictor of outcome. In virtually every study in which albumin has been assessed as a risk factor, albumins below 35 g/L are associated with higher mortality and morbidity. This is true in the USRDS, Canadian Morbidity Study and CANUSA study, to mention a few21,22,23,24,25,26,27. The questions that remain unanswered about albumin relate to its coexistence with markers of chronic inflammation, such as C-reactive protein and the late start of renal replacement therapy. This raises the question as to whether albumin is a simple marker of nutrition or a marker of a more complex interaction of biologic processes27. If so, future studies on the impact of nutritional management on outcomes may be confounded by underlying associations with hypoalbuminemia. Nonetheless, given the strength of the association between hypoalbuminemia and poor outcomes, treatment strategies are needed to address the problem.

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CONCLUSIONS

Although advances have been in the management of patients with ESRD through appropriate renal replacement therapy, overall mortalities remain far in excess of the general population. The most important predictors of poor outcome in ESRD are increasing age, cardiovascular disease, diabetes, and poor nutrition as reflected by hypoalbuminemia. Future prospective studies need to be initiated which will assess the impact of interventions which modify directly these comorbidities. Furthermore, strenuous attempts need to be made to manage patients in the pre-ESRD phase of their illness so that they will enter renal replacement therapy with fewer of the comorbidities that are associated with a poor prognosis.

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