CARDIOVASCULAR DISEASE is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD) Stage 5.1,2 Although there have been significant improvements in management of CVD in the general population, it is not known if these interventions result in similar benefits for patients with CKD Stage 5. Subtle differences in the types, distribution, mortality and pathophysiology of CVD in patients with CKD Stage 5 suggest that generalization of data from patients without kidney disease should be extrapolated with caution.
Cardiovascular risk factors among patients with CKD Stage 5 may be divided into those that are nonspecific to kidney disease but are more prevalent, and those that are specific to CKD Stage 5. There is increased prevalence of many traditional factors for cardiovascular risk (age, male gender, hypertension, diabetes, dyslipidemia, and physical inactivity). In addition, patients with CKD Stage 5 have disease-related risk factors such as anemia, hyperhomocysteinemia, hyperparathyroidism, oxidative stress, hypoalbuminemia, chronic inflammation, prothrombotic factors, among others. Data suggest that uremic factors, or factors related to renal replacement therapy (RRT)/dialysis may be implicated in the pathogenesis of heart disease in patients treated by dialysis, because cardiovascular survival improves after transplantation even in high-risk patients.3,4 Conversely, aspects of the dialysis treatment itself may contribute to CVD.
Target Population
Cardiovascular Disease Risks in this Population
Definitions
Within years of the first clinical experience with hemodialysis, cardiovascular mortality was found to be very high.5 Current literature substantiates a high mortality from CVD, compared to the general population.1 Cardiovascular disease includes the specific diagnoses: myocardial infarction (MI), pericarditis, atherosclerotic heart disease (AHD), cardiomyopathy, arrhythmia, valvular heart disease (VHD), congestive heart failure (CHF), CBVD, and PVD. In addition, patients with CKD Stage 5 have a unique excess of sudden death from cardiac arrest.1,2 This is somewhat confusing, as the USRDS classification is “cardiac arrest, cause unknown” (47% of cardiac death) and includes a separate category for arrhythmia (13% of cardiac death).
Cardiovascular disease is the leading cause of death in patients with end-stage kidney failure. (strong)
The United States Renal Data System (USRDS) annual data (abstracted from prevalent patients in the years 1998-2000) shows that 75.47 (42.2%) of the 178.92 deaths per 1,000 patient years at risk have cardiovascular causes. Of these deaths 36.51 (46%) were recorded as cardiac arrest.2
Cardiovascular mortality is markedly greater in patients treated by RRT than in the age-matched general population. (strong)
Direct comparisons between patients with CKD Stage 5 and the general population are difficult. However, many studies use Framingham data for reference. Some researchers have developed a Sensitivity Analysis method for contrasting cardiovascular mortality in the general population and in patients with CKD Stage 5-matching for such factors as sex, race, age and the presence of a diagnosis of diabetes.1,6 Their results show that cardiovascular mortality is 5- to 100-fold greater in CKD Stage 5 than in specific reference groups. However, patients with CKD Stage 5 who develop cardiac events have a greatly increased mortality compared to patients with normal renal function.7,8 A limited number of autopsy studies are instructive in their support of the clinical data. There is a widely accepted hypothesis that increased cardiovascular risk is caused by accelerated atherogenesis.5 While atherosclerosis is widespread, anatomically documented MI is only present in approximately 8%-12% of patients at autopsy.9-12 Both coronary artery and valvular calcifications are common; however, there is no direct connection between advanced coronary lesions (as graded by the degree of calcification) and cause of death.11 There is a high incidence of subclinical pericarditis. In addition, the frequent autopsy finding of ventricular hypertrophy emphasizes the importance of primary cardiac muscle dysfunction (e.g., CHF, cardiomyopathy, etc.) in patients with CKD Stage 5 (see Guideline 7). As the number of cardiovascular comorbidities increases, the risk of complications rises. Thus, the severity of comorbid factors may play a role in the morbidity and mortality of CVD in CKD Stage 5. There is good evidence that the current population of patients starting RRT is older and sicker (i.e., more severe comorbidities) than in earlier years. The unique pathophysiology of CKD Stage 5 and its treatment results in differences in the incidence and prevalence of various cardiovascular disease processes noted at the time of death in RRT patients compared to the general population.
Patients who survive more than 7-10 years demonstrate a complex picture. In general the long-term survivors have lower risks (younger, women, lower phosphorus), which can be interpreted as a “survivor effect”. But when adjustments for comorbidity are made, mortality remains about the same as in patients on RRT for shorter periods of time. (Weak)
Comparison of dialysis modalities is a serious research need in this field. The current literature suggests that peritoneal dialysis (PD) is more effective in controlling fluid-volume status than hemodialysis (HD); however, there is higher mortality for cardiovascular events. Selection bias, “informative censoring” of healthier patients receiving transplantation, and the inherent difference in techniques make comparisons very difficult
Much of the confusion in this literature stems from a lack of uniform and standardized approaches to gathering data. In many papers, adequate detail about comorbid conditions is missing. Standard dialysis management has changed with time. It is rare to find clear information about dialysis adequacy or a specific dialysis therapy. Because of selection bias, it is very difficult to compare the effects of HD and PD on CVD, and equally difficult to compare the U.S. experience with that of other countries. This section reviews papers based on clinical, nontechnological diagnosis. Papers using diagnostic testing to define diagnoses or risks were intentionally excluded (see Sections II and IV). Therefore, specific diagnostic modalities (EKG or echocardiography) are likely to provide more accurate measures for determining treatment outcomes.
There is a marked paucity of detail about causes of sudden death in patients with CKD Stage 5. A recent study shows an increased risk of death on Monday and Tuesday compared to other days of the week in patients treated by HD.13 This study focuses attention on the 3-day hiatus between hemodialysis treatments that is part of current standard management. At present, it is unclear if the associated risks of hyperkalemia, the rate of change in potassium with dialysis treatment, and fluid overload are the cause of the increased mortality. Careful studies of dialysis-specific risks and outcomes in CVD are likely to yield important insight into this problem.