- Email: [email protected]
Cardiovascular complications in chronic kidney disease
Cardiovascular Complications in Chronic Kidney Disease Mark J. Sarnak, MD ● The risk for cardiovascular disease (CVD) morbidity and mortality remains alarmingly high in all stages of chronic kidney disease (CKD). CVD often begins before end-stage renal disease (ESRD), and patients with reduced kidney function are more likely to die of CVD than to develop ESRD. Three pathological forms of CVD should be considered in patients with CKD: alterations in cardiac geometry, including left ventricular hypertrophy, atherosclerosis, and arteriosclerosis. All are highly prevalent in patients with CKD. Although patients with CKD share many of the same risk factors for CVD as the general population, there are a number of uremia-related risk factors, such as anemia and alterations in calcium/phosphorus metabolism, that also play a role in promoting CVD. Treatment of both traditional and uremia-related risk factors should be initiated in the earlier stages of CKD. Additional clinical trials with a goal to reduce CVD are urgently needed in CKD. Am J Kidney Dis 41(S5):S11-S17. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Cardiovascular disease (CVD); chronic kidney disease (CKD); anemia; calcium; phosphorus.
CARDIOVASCULAR DISEASE MORBIDITY AND MORTALITY IN CHRONIC KIDNEY DISEASE
P
ATIENTS WITH chronic kidney disease (CKD) are at significantly increased risk for both morbidity and mortality from cardiovascular disease (CVD). Cardiac disease is the single most important cause of death among patients receiving long-term dialysis, accounting for 44% of overall mortality.1 As part of the National Kidney Foundation Task Force on CVD, CVD mortality rates in the general population (⬃2 million deaths) were compared with CVD mortality rates in dialysis patients (⬃50,000 deaths). These results showed that annual CVD mortality rates are much greater in dialysis patients despite stratification for sex, race, or age group. Younger dialysis patients have an approximately 500-fold increased CVD mortality rate compared with their counterparts in the general population, and rates remain approximately five times higher, even among the oldest patients (Fig 1).2 There are two potential reasons for the dramatically increased risk for CVD mortality in the dialysis population. The first is the high prevalence of CVD, and the second is the high case fatality rate in those who already have CVD. Numerous data have shown that dialysis patients have a greater prevalence of both clinical ischemic heart disease and congestive heart failure compared with the general population (Table 1).2 In addition, the percentage of patients with left ventricular (LV) hypertrophy (LVH) is as high as 75% in dialysis patients.2 Dialysis patients with CVD also have a high case fatality rate. Herzog et al1 examined outcomes of 34,189 long-term dialysis patients from
the US Renal Data System who were hospitalized between 1977 and 1995 with acute myocardial infarction. The prognosis for these patients was poor: at 2 years postinfarction, 73% of patients had died. By year 5, the mortality rate was nearly 90%. Cardiac-related mortality rates were 51.8% at 2 years and 70.2% at 5 years.1 It is important to emphasize that the prevalence of CVD is increased among all patients with CKD, not only those with end-stage renal disease (ESRD). That is, the prevalence of LVH increases as glomerular filtration declines, and as many as 30% of patients reaching ESRD already have clinical evidence of ischemic heart disease or heart failure. Furthermore, it is important to note that patients with a reduced glomerular filtration rate (GFR) are more likely to die of CVD than they are to develop ESRD.3 These data reinforce the need to intervene in the earlier stages of CKD, before ESRD, to both prevent and treat CVD. Unfortunately, there have been few studies of CVD in the earlier stages of CKD. However, the limited data available suggest that although such treatments as -blockers and aspirin are not used as frequently in patients with CVD and reduced From the Division of Nephrology, Tufts New England Medical Center, Boston, MA. Supported by an unrestricted educational grant from Watson Pharma, Inc. Address reprint requests to Mark J. Sarnak, MD, TuftsNew England Medical Center, Box 391, Division of Nephrology, New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4106-0503$30.00/0 doi:10.1016/S0272-6386(03)00372-X
American Journal of Kidney Diseases, Vol 41, No 6, Suppl 5 (June), 2003: pp S11-S17
S11
S12
MARK J. SARNAK
Fig 1. CVD mortality (death from arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema) in the general population (GP) compared with patients with ESRD treated by dialysis. Reprinted with permission.2
GFR, they are of benefit in this subset of the population.4,5 SPECTRUM OF CVD IN PATIENTS WITH CKD
It is reasonable to consider three pathological forms of CVD that are highly prevalent in patients with CKD. The first is an alteration in cardiac geometry and includes eccentric LVH, concentric LVH, and LV remodeling. In the case of concentric LVH, thickness of the wall increases to a greater extent than LV diameter, whereas in eccentric LVH, the increase in wall thickness is in proportion to the increase in LV diameter. Risk factors for concentric LVH include pressure overload secondary to hypertension, arteriosclerosis, or aortic stenosis, and risk factors for eccentric LVH include volume overload secondary to fluid retention, anemia, or arteriovenous fistulae.6 The second pathological form of CVD is atherosclerosis. Atherosclerosis is the primary cause of ischemic heart disease in dialysis patients; however, it should be recognized that one study, Table 1.
General population Reduced GFR Hemodialysis Peritoneal dialysis
admittedly in the pre-erythropoietin era, has shown that as many as 50% of nondiabetic dialysis patients with angina may not have significant large-vessel coronary artery disease (CAD; defined by a luminal narrowing ⬎ 50% on angiography).7 Rather, the ischemia in the latter case is believed to result from small-vessel disease in combination with severe LVH. In comparison to the general population, coronary artery plaques in dialysis patients tend to be more advanced, with greater degrees of media thickening and calcification.8 The effect of this pathological difference on clinical outcomes has not been defined. The third type of vascular disease that is more prevalent in patients with CKD is arteriosclerosis or disease of the large vessels, such as the carotid or aorta. This process involves vessel remodeling, loss of elasticity, and development of noncompliant vessels.9 The latter results in increased pulse pressure, which in turn has been recognized as a factor for CVD outcomes in dialysis patients.10
Prevalence of CVD by Target Population
CAD (clinical)
LVH (echocardiography)
CHF (clinical)
5–12 (depending on age) NA 40 40
20 25–50 75 75
5 (age 60 y) NA 40 40
Abbreviation: NA, not available. Reprinted with permission.2
CARDIOVASCULAR COMPLICATIONS IN CHRONIC KIDNEY DISEASE Table 2.
Traditional Versus Uremia-Related Risk Factors for CVD
Traditional Risk Factors
Older age Male sex Hypertension Higher LDL cholesterol Lower HDL cholesterol Diabetes Smoking Physical inactivity Menopause Family history of CVD LVH
Uremia-Related Risk Factors
Albuminuria Hyperhomocysteinemia Anemia Abnormal calcium/phosphate metabolism Extracellular fluid volume overload and electrolyte imbalance Oxidative stress Inflammation Malnutrition Thrombogenic factors Sleep disturbances Altered nitric oxide/endothelin balance
Abbreviations: LDL, low-density lipoprotein; HDL, highdensity lipoprotein. Data from Sarnak et al.11
CVD RISK FACTORS IN THE CKD POPULATION
Two types of risk factors have been defined in patients with CKD.11 Traditional risk factors, described primarily in the Framingham population, include, among others, hypertension, smoking, diabetes, hyperlipidemia, LVH, and male sex. Although patients with CKD have a high prevalence of many of these traditional risk factors, such as diabetes, hypertension, and LVH, they also are exposed to nontraditional, or uremiarelated, risk factors that increase in prevalence as kidney function declines (Table 2).11 For example, a high percentage of hemodialysis patients have high levels of homocysteine, oxidative stress, lipoprotein(a), and lipoprotein remnants. Levels of thrombogenic factors, such as fibrinogen, and inflammatory markers, such as C-reactive protein, also are high. In addition, recent studies have suggested that dialysis patients have a greater prevalence of sleep apnea and other sleep disorders that may contribute to the increased risk for CVD.12 The following paragraphs focus on two uremiarelated risk factors, anemia and altered calcium/ phosphorus metabolism, not because they are necessarily more important than other risk factors, but because there has been recent controlled clinical trial data on each of them.
S13
Anemia The first risk factor, anemia, results in decreased erythrocyte count, plasma viscosity, and peripheral resistance and increased venous return. Anemia also results in decreased hemoglobin (Hgb) level and oxygen delivery and increased sympathetic activity, which in turn increases heart rate and venous tone. Increased venous return, increased heart rate, and increased venous tone all increase cardiac output. Increased cardiac output has two effects. First, it increases arterial volume and LV wall tension, causing initially adaptive LVH and, subsequently, if the anemia is not corrected, maladaptive hypertrophy. Second, it increases arterial tension, causing maladaptive arterial hypertrophy and arteriosclerosis.13 Observational studies have shown that anemia is a risk factor for adverse CVD outcomes in dialysis patients. In a 1996 study, Foley et al14 showed that a low Hgb level (⬍8.8 g/dL [88 g/L]) was a risk factor for all-cause mortality in univariate analysis (Fig 2).14 The same study showed that anemia was independently associated with a greater risk for LV dilatation, cardiac failure, and death. Anemia also appears to be associated with CVD in the earlier stages of CKD. In a 12-month prospective study by Levin et al15 involving 246 patients with creatinine clearances of 25 to 75 mL/min (0.42 to 1.25 mL/s) at baseline, each 0.5-g/dL (5-g/L) decrease in Hgb level was associated with a 32% increased odds of LV growth. It remains unclear whether efforts to correct anemia can prevent CVD-related morbidity and mortality in patients with ESRD. Two random-
Fig 2. Kaplan-Meier curve showing mortality in patients with ESRD by Hgb level. Reprinted with permission.14
S14
ized controlled trials, the Normal Hematocrit Trial and the Canadian Normalization of Hemoglobin Trial, have addressed this issue. The Normal Hematocrit Trial involved approximately 1,200 patients with ischemic heart disease or congestive heart failure who were randomly assigned to a hematocrit goal of either 30% or 42%.16 The primary outcome measure was time to first myocardial infarction or death. Patients assigned to the low-hematocrit group did slightly (although not significantly) better than those randomly assigned to the high-hematocrit group. The Canadian Normalization of Hemoglobin Trial evaluated 146 patients who had either asymptomatic concentric LVH or LV dilatation.16 These patients were randomly assigned to receive doses of recombinant human erythropoietin designed to achieve a target Hgb level of either 10 or 13 g/dL (100 or 130 g/L). Results showed that in the concentric LVH group, changes in LV mass index were similar in the randomized groups. Similarly, in the LV dilatation group, changes in volume index were similar in the randomized groups. However, patients with concentric LVH were less likely to develop progressive LV dilatation if they were assigned to the high Hgb target group.17 These trials suggest that although there may be some benefit to treatment of anemia in hemodialysis patients before the development of clinical CVD, additional trials should be conducted in earlier stages of CKD. Calcium and Phosphorus Metabolism The second risk factor, altered calcium/phosphorus metabolism, is related directly to the decline in kidney function. As the level of kidney function declines, phosphorus levels increase, calcium levels decrease, and parathyroid hormone levels increase. Calcium-containing phosphate binders have been used to decrease phosphorus absorption, and 1,25-dihydroxy vitamin D (or vitamin D analogues) has been used to inhibit parathyroid hormone. The result may be a positive calcium balance and high calcium/ phosphorus product, both of which may lead to metastatic calcification of coronary vessels and valves, as well as other large vessels of the body. A 1998 trial by Block et al18 showed that an elevated serum phosphorus level or calcium phos-
MARK J. SARNAK
Fig 3. Relative mortality risk by serum phosphorus quintiles in 6,407 patients with renal disease who had been on hemodialysis therapy for at least 1 year. Reprinted with permission.18
phorus product is an independent risk factor for all-cause mortality. In this retrospective study of approximately 6,500 hemodialysis patients from the US Renal Data System, a significant increase in relative risk for all-cause mortality was seen with serum phosphorus levels greater than 6.5 mg/dL (Fig 3).18 Similar results have been shown for exclusively CVD-related mortality. The positive calcium balance in dialysis patients significantly increases the risk for coronary calcification, a phenomenon shown by a number of studies. Braun et al19 used electron-beam computed tomography (EBCT) to assess calcification in coronary arteries and valves of 49 hemodialysis patients. Results were compared with those of 102 patients without renal disease who had undergone cardiac catheterization for suspected CAD. (The presence of CAD, defined as coronary artery stenosis ⬎ 50%, was confirmed in 80 of 102 patients.) Mean coronary artery calcium scores were stratified by age. Results showed that coronary artery calcification scores were approximately 2.5- to 5-fold higher in hemodialysis patients compared with nonhemodialysis patients regardless of the age group (Fig 4).19 In addition, when hemodialysis patients were restudied a short period later (⬃1 year), progression of coronary artery calcification was frequent. A second study specifically examined the extent of coronary calcification in younger patients being treated by dialysis. The 39 patients in this study, aged 7 to 30 years, were compared using EBCT with 60 healthy controls, aged 20 to 30 years, for extent of calcification.20 In the dialysis
CARDIOVASCULAR COMPLICATIONS IN CHRONIC KIDNEY DISEASE
Fig 4. Coronary calcification in dialysis patients compared with nonrenal disease patients with or without CAD. Reprinted with permission.19
group, age was found to be significantly associated with the presence of calcification. Although none of the 23 patients who were younger than 20 years had evidence of coronary artery calcification, it was present in 14 of 16 patients aged 20 to 30 years. Among those with calcification, mean score was 1,157. Conversely, only 3 of 60 healthy patients showed evidence of calcification. In addition to age, duration of dialysis therapy (mean of 14 years for the calcification group versus 4 years for the noncalcification group; P ⬍ 0.001) and higher calcium intake (6,456 versus 3,325 mg/d; P ⫽ 0.02) were significantly associated with calcification. The association between calcium intake and coronary artery calcification has raised concern regarding the potential detrimental effects of excess administration of calcium to bind phosphorus in these patients. Raggi et al21 assessed the presence of atherosclerotic vascular disease in a population of 205 patients on maintenance hemodialysis therapy. Using EBCT, the researchers compared patients with and without clinical evidence of atherosclerotic CVD and correlated these findings with calcification scores.21 More than 80% of patients with calcification scores greater than 1,000 had atherosclerotic vascular disease, and coronary artery calcium scores were significantly related to the prevalence of myocardial infarction (P ⬍ 0.0001) and angina (P ⬍ 0.0001). Calcification was significantly associated with older age, white race, male sex, presence of diabetes, and higher serum calcium or phosphorus levels. Although it remains to be determined whether calcification itself is a cause of CVD or a marker
S15
of underlying CVD, recent studies have suggested that excess calcification may play a pathological role in promoting CVD. Calcification has been shown to be an independent determinant of increasing arterial stiffness,22 which in turn may result in higher systolic blood pressure, lower diastolic pressure, higher pulse pressure, LVH, decreased coronary perfusion, and increased CVD outcomes. Using aortic pulse wave velocity as a measure of vessel stiffness, Blacher et al23 showed that dialysis patients with increased stiffness of the aorta have a lower probability of survival compared with patients with more elastic vessels (Fig 5). In this study involving 241 dialysis patients, each 1-millisecond increase in pulse wave velocity resulted in a 39% increase in the odds for all-cause mortality. The role of arterial stiffening was independent of age, overall duration of ESRD, preexisting CVD, blood pressure, and Hgb levels. Additional observational studies have also shown that higher aortic calcification scores increase the probability of all-cause mortality.24 There are randomized trials that have evaluated whether a decrease in the use of calciumbased phosphorus binders results in an improvement in CVD outcomes. Chertow et al25 compared the use of sevelamer, a nonabsorbed non-calcium– containing polymer, with calcium-based phosphate binders to determine whether use of the
Fig 5. Probability of overall survival in patients with ESRD with aortic stiffening, divided into tertiles. Patients in the highest tertile (pulse wave velocity [PWV] >12 milliseconds) were 5.4 times as likely to die of any cause than those in the lowest tertile (PWV < 9.4 milliseconds) and 5.9 times as likely to die of cardiovascular causes. Reprinted with permission.23
S16
MARK J. SARNAK
uremia-related risk factors. Finally, additional clinical trials with a goal to reduce CVD are urgently needed in CKD. REFERENCES
Fig 6. Median percentage of change at 52 weeks in (A) coronary calcification and (B) aortic calcification compared with baseline in patients randomly assigned to sevelamer (■) or a calcium-containing phosphate binder (䊐). Reprinted with permission.25
non-calcium–containing product would reduce the likelihood of progressive cardiovascular calcification. The 200 hemodialysis patients in this study were randomly assigned to treatment with sevelamer or calcium-based phosphate binders for 52 weeks and were assessed by EBCT. At week 52, the percentage increase in coronary and aortic calcium was less in the sevelamer group compared with patients administered calciumcontaining phosphate binders (P ⬍ 0.001; Fig 6).25 Although questions have been raised regarding the interpretation of the results,26 the results are important, and additional research using clinical outcome end points must be conducted to determine whether the reduction in calcification translates into a lower risk for CVD events or mortality. CONCLUSIONS
Patients with CKD have a high burden of cardiomyopathy, atherosclerosis, and arteriosclerosis. Although patients with CKD share many of the same cardiovascular risk factors with the general population, there are additional risk factors, such as anemia and abnormal calcium/ phosphorus metabolism, that place these patients at even greater risk for CVD mortality. Because CVD begins during the early stages of CKD, before ESRD, it is important to identify patients at risk long before the need for renal replacement therapy and to address both the traditional and
1. Herzog CA, Ma JZ, Collins AJ: Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339:799-805, 1998 2. Foley RN, Parfrey PS, Sarnak MJ: Cardiovascular disease in chronic renal disease: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112-S119, 1998 (suppl 3) 3. Shulman NB, Ford CE, Hall WD, et al, on behalf of the Hypertension Detection and Follow-Up Program Cooperative Group: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: Results from the Hypertension Detection and Follow-up Program. Hypertension 13:SI80-SI93, 1989 (suppl I) 4. Wright RS, Reeder GS, Herzog CA, et al: Acute myocardial infarction and renal dysfunction: A high-risk combination. Ann Intern Med 137:563-570, 2002 5. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB: Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 137:555-562, 2002 6. Schunkert H, Hense HW: A heart price to pay for anaemia. Nephrol Dial Transplant 16:445-448, 2001 7. Rostand SG, Kirk KA, Rutsky EA: Dialysis-associated ischemic heart disease: Insights from coronary angiography. Kidney Int 25:653-659, 1984 8. Schwarz U, Buzello M, Ritz E, et al: Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 15:218-223, 2000 9. London GM, Marchais SJ, Guerin AP, et al: Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 17:1713-1724, 2002 10. Klassen PS, Lowrie EG, Reddan DN, et al: Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA 287:1548-1555, 2002 11. Sarnak MJ, Levey AS: Cardiovascular disease and chronic renal disease: A new paradigm. Am J Kidney Dis 35:S117-S131, 2000 (suppl 1) 12. De Santo NG, Cirillo M, Perna A, et al: The heart in uremia: Role of hypertension, hypotension, and sleep apnea. Am J Kidney Dis 38:S38-S46, 2001 (suppl 1) 13. Metivier F, Marchais SJ, Guerin AP, et al: Pathophysiology of anaemia: Focus on the heart and blood vessels. Nephrol Dial Transplant 15:S14-S18, 2000 (suppl 3) 14. Foley RN, Parfrey PS, Harnett JD, et al: The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 28:53-61, 1996 15. Levin A, Thompson CR, Ethier J, et al: Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin. Am J Kidney Dis 34:125-134, 1999 16. Besarab A, Bolton WK, Nissenson AR, et al: The Normal Haematocrit Trial in dialysis patients with cardiac disease. Nephrol Dial Transplant 14:2043-2044, 1999 17. Foley RN, Parfrey PS, Morgan J, et al: Effect of
CARDIOVASCULAR COMPLICATIONS IN CHRONIC KIDNEY DISEASE
hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 58:1325-1335, 2000 18. Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 31:607-617, 1998 19. Braun J, Oldendorf M, Moshage W, et al: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394-401, 1996 20. Goodman WG, Goldin J, Kuizon BD, et al: Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478-1483, 2000 21. Raggi P, Boulay A, Chasan-Taber S, et al: Cardiac calcification in adult hemodialysis patients: A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 39:695-701, 2002
S17
22. Guerin AP, London GM, Marchais SJ, Metivier F: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15:1014-1021, 2000 23. Blacher J, Guerin AP, Pannier B, et al: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99:2434-2439, 1999 24. Blacher J, Guerin AP, Pannier B, et al: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938-942, 2001 25. Chertow GM, Burke SK, Raggi P, for the Treat to Goal Working Group: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 26. Canavese C, Bergamo D, Dib H, Bermond F, Burdese M: Calcium on trial: Beyond a reasonable doubt? Kidney Int 63:381-382, 2003 (letter)
CARDIOVASCULAR DISEASE MORBIDITY AND MORTALITY IN CHRONIC KIDNEY DISEASE
P
ATIENTS WITH chronic kidney disease (CKD) are at significantly increased risk for both morbidity and mortality from cardiovascular disease (CVD). Cardiac disease is the single most important cause of death among patients receiving long-term dialysis, accounting for 44% of overall mortality.1 As part of the National Kidney Foundation Task Force on CVD, CVD mortality rates in the general population (⬃2 million deaths) were compared with CVD mortality rates in dialysis patients (⬃50,000 deaths). These results showed that annual CVD mortality rates are much greater in dialysis patients despite stratification for sex, race, or age group. Younger dialysis patients have an approximately 500-fold increased CVD mortality rate compared with their counterparts in the general population, and rates remain approximately five times higher, even among the oldest patients (Fig 1).2 There are two potential reasons for the dramatically increased risk for CVD mortality in the dialysis population. The first is the high prevalence of CVD, and the second is the high case fatality rate in those who already have CVD. Numerous data have shown that dialysis patients have a greater prevalence of both clinical ischemic heart disease and congestive heart failure compared with the general population (Table 1).2 In addition, the percentage of patients with left ventricular (LV) hypertrophy (LVH) is as high as 75% in dialysis patients.2 Dialysis patients with CVD also have a high case fatality rate. Herzog et al1 examined outcomes of 34,189 long-term dialysis patients from
the US Renal Data System who were hospitalized between 1977 and 1995 with acute myocardial infarction. The prognosis for these patients was poor: at 2 years postinfarction, 73% of patients had died. By year 5, the mortality rate was nearly 90%. Cardiac-related mortality rates were 51.8% at 2 years and 70.2% at 5 years.1 It is important to emphasize that the prevalence of CVD is increased among all patients with CKD, not only those with end-stage renal disease (ESRD). That is, the prevalence of LVH increases as glomerular filtration declines, and as many as 30% of patients reaching ESRD already have clinical evidence of ischemic heart disease or heart failure. Furthermore, it is important to note that patients with a reduced glomerular filtration rate (GFR) are more likely to die of CVD than they are to develop ESRD.3 These data reinforce the need to intervene in the earlier stages of CKD, before ESRD, to both prevent and treat CVD. Unfortunately, there have been few studies of CVD in the earlier stages of CKD. However, the limited data available suggest that although such treatments as -blockers and aspirin are not used as frequently in patients with CVD and reduced From the Division of Nephrology, Tufts New England Medical Center, Boston, MA. Supported by an unrestricted educational grant from Watson Pharma, Inc. Address reprint requests to Mark J. Sarnak, MD, TuftsNew England Medical Center, Box 391, Division of Nephrology, New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4106-0503$30.00/0 doi:10.1016/S0272-6386(03)00372-X
American Journal of Kidney Diseases, Vol 41, No 6, Suppl 5 (June), 2003: pp S11-S17
S11
S12
MARK J. SARNAK
Fig 1. CVD mortality (death from arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema) in the general population (GP) compared with patients with ESRD treated by dialysis. Reprinted with permission.2
GFR, they are of benefit in this subset of the population.4,5 SPECTRUM OF CVD IN PATIENTS WITH CKD
It is reasonable to consider three pathological forms of CVD that are highly prevalent in patients with CKD. The first is an alteration in cardiac geometry and includes eccentric LVH, concentric LVH, and LV remodeling. In the case of concentric LVH, thickness of the wall increases to a greater extent than LV diameter, whereas in eccentric LVH, the increase in wall thickness is in proportion to the increase in LV diameter. Risk factors for concentric LVH include pressure overload secondary to hypertension, arteriosclerosis, or aortic stenosis, and risk factors for eccentric LVH include volume overload secondary to fluid retention, anemia, or arteriovenous fistulae.6 The second pathological form of CVD is atherosclerosis. Atherosclerosis is the primary cause of ischemic heart disease in dialysis patients; however, it should be recognized that one study, Table 1.
General population Reduced GFR Hemodialysis Peritoneal dialysis
admittedly in the pre-erythropoietin era, has shown that as many as 50% of nondiabetic dialysis patients with angina may not have significant large-vessel coronary artery disease (CAD; defined by a luminal narrowing ⬎ 50% on angiography).7 Rather, the ischemia in the latter case is believed to result from small-vessel disease in combination with severe LVH. In comparison to the general population, coronary artery plaques in dialysis patients tend to be more advanced, with greater degrees of media thickening and calcification.8 The effect of this pathological difference on clinical outcomes has not been defined. The third type of vascular disease that is more prevalent in patients with CKD is arteriosclerosis or disease of the large vessels, such as the carotid or aorta. This process involves vessel remodeling, loss of elasticity, and development of noncompliant vessels.9 The latter results in increased pulse pressure, which in turn has been recognized as a factor for CVD outcomes in dialysis patients.10
Prevalence of CVD by Target Population
CAD (clinical)
LVH (echocardiography)
CHF (clinical)
5–12 (depending on age) NA 40 40
20 25–50 75 75
5 (age 60 y) NA 40 40
Abbreviation: NA, not available. Reprinted with permission.2
CARDIOVASCULAR COMPLICATIONS IN CHRONIC KIDNEY DISEASE Table 2.
Traditional Versus Uremia-Related Risk Factors for CVD
Traditional Risk Factors
Older age Male sex Hypertension Higher LDL cholesterol Lower HDL cholesterol Diabetes Smoking Physical inactivity Menopause Family history of CVD LVH
Uremia-Related Risk Factors
Albuminuria Hyperhomocysteinemia Anemia Abnormal calcium/phosphate metabolism Extracellular fluid volume overload and electrolyte imbalance Oxidative stress Inflammation Malnutrition Thrombogenic factors Sleep disturbances Altered nitric oxide/endothelin balance
Abbreviations: LDL, low-density lipoprotein; HDL, highdensity lipoprotein. Data from Sarnak et al.11
CVD RISK FACTORS IN THE CKD POPULATION
Two types of risk factors have been defined in patients with CKD.11 Traditional risk factors, described primarily in the Framingham population, include, among others, hypertension, smoking, diabetes, hyperlipidemia, LVH, and male sex. Although patients with CKD have a high prevalence of many of these traditional risk factors, such as diabetes, hypertension, and LVH, they also are exposed to nontraditional, or uremiarelated, risk factors that increase in prevalence as kidney function declines (Table 2).11 For example, a high percentage of hemodialysis patients have high levels of homocysteine, oxidative stress, lipoprotein(a), and lipoprotein remnants. Levels of thrombogenic factors, such as fibrinogen, and inflammatory markers, such as C-reactive protein, also are high. In addition, recent studies have suggested that dialysis patients have a greater prevalence of sleep apnea and other sleep disorders that may contribute to the increased risk for CVD.12 The following paragraphs focus on two uremiarelated risk factors, anemia and altered calcium/ phosphorus metabolism, not because they are necessarily more important than other risk factors, but because there has been recent controlled clinical trial data on each of them.
S13
Anemia The first risk factor, anemia, results in decreased erythrocyte count, plasma viscosity, and peripheral resistance and increased venous return. Anemia also results in decreased hemoglobin (Hgb) level and oxygen delivery and increased sympathetic activity, which in turn increases heart rate and venous tone. Increased venous return, increased heart rate, and increased venous tone all increase cardiac output. Increased cardiac output has two effects. First, it increases arterial volume and LV wall tension, causing initially adaptive LVH and, subsequently, if the anemia is not corrected, maladaptive hypertrophy. Second, it increases arterial tension, causing maladaptive arterial hypertrophy and arteriosclerosis.13 Observational studies have shown that anemia is a risk factor for adverse CVD outcomes in dialysis patients. In a 1996 study, Foley et al14 showed that a low Hgb level (⬍8.8 g/dL [88 g/L]) was a risk factor for all-cause mortality in univariate analysis (Fig 2).14 The same study showed that anemia was independently associated with a greater risk for LV dilatation, cardiac failure, and death. Anemia also appears to be associated with CVD in the earlier stages of CKD. In a 12-month prospective study by Levin et al15 involving 246 patients with creatinine clearances of 25 to 75 mL/min (0.42 to 1.25 mL/s) at baseline, each 0.5-g/dL (5-g/L) decrease in Hgb level was associated with a 32% increased odds of LV growth. It remains unclear whether efforts to correct anemia can prevent CVD-related morbidity and mortality in patients with ESRD. Two random-
Fig 2. Kaplan-Meier curve showing mortality in patients with ESRD by Hgb level. Reprinted with permission.14
S14
ized controlled trials, the Normal Hematocrit Trial and the Canadian Normalization of Hemoglobin Trial, have addressed this issue. The Normal Hematocrit Trial involved approximately 1,200 patients with ischemic heart disease or congestive heart failure who were randomly assigned to a hematocrit goal of either 30% or 42%.16 The primary outcome measure was time to first myocardial infarction or death. Patients assigned to the low-hematocrit group did slightly (although not significantly) better than those randomly assigned to the high-hematocrit group. The Canadian Normalization of Hemoglobin Trial evaluated 146 patients who had either asymptomatic concentric LVH or LV dilatation.16 These patients were randomly assigned to receive doses of recombinant human erythropoietin designed to achieve a target Hgb level of either 10 or 13 g/dL (100 or 130 g/L). Results showed that in the concentric LVH group, changes in LV mass index were similar in the randomized groups. Similarly, in the LV dilatation group, changes in volume index were similar in the randomized groups. However, patients with concentric LVH were less likely to develop progressive LV dilatation if they were assigned to the high Hgb target group.17 These trials suggest that although there may be some benefit to treatment of anemia in hemodialysis patients before the development of clinical CVD, additional trials should be conducted in earlier stages of CKD. Calcium and Phosphorus Metabolism The second risk factor, altered calcium/phosphorus metabolism, is related directly to the decline in kidney function. As the level of kidney function declines, phosphorus levels increase, calcium levels decrease, and parathyroid hormone levels increase. Calcium-containing phosphate binders have been used to decrease phosphorus absorption, and 1,25-dihydroxy vitamin D (or vitamin D analogues) has been used to inhibit parathyroid hormone. The result may be a positive calcium balance and high calcium/ phosphorus product, both of which may lead to metastatic calcification of coronary vessels and valves, as well as other large vessels of the body. A 1998 trial by Block et al18 showed that an elevated serum phosphorus level or calcium phos-
MARK J. SARNAK
Fig 3. Relative mortality risk by serum phosphorus quintiles in 6,407 patients with renal disease who had been on hemodialysis therapy for at least 1 year. Reprinted with permission.18
phorus product is an independent risk factor for all-cause mortality. In this retrospective study of approximately 6,500 hemodialysis patients from the US Renal Data System, a significant increase in relative risk for all-cause mortality was seen with serum phosphorus levels greater than 6.5 mg/dL (Fig 3).18 Similar results have been shown for exclusively CVD-related mortality. The positive calcium balance in dialysis patients significantly increases the risk for coronary calcification, a phenomenon shown by a number of studies. Braun et al19 used electron-beam computed tomography (EBCT) to assess calcification in coronary arteries and valves of 49 hemodialysis patients. Results were compared with those of 102 patients without renal disease who had undergone cardiac catheterization for suspected CAD. (The presence of CAD, defined as coronary artery stenosis ⬎ 50%, was confirmed in 80 of 102 patients.) Mean coronary artery calcium scores were stratified by age. Results showed that coronary artery calcification scores were approximately 2.5- to 5-fold higher in hemodialysis patients compared with nonhemodialysis patients regardless of the age group (Fig 4).19 In addition, when hemodialysis patients were restudied a short period later (⬃1 year), progression of coronary artery calcification was frequent. A second study specifically examined the extent of coronary calcification in younger patients being treated by dialysis. The 39 patients in this study, aged 7 to 30 years, were compared using EBCT with 60 healthy controls, aged 20 to 30 years, for extent of calcification.20 In the dialysis
CARDIOVASCULAR COMPLICATIONS IN CHRONIC KIDNEY DISEASE
Fig 4. Coronary calcification in dialysis patients compared with nonrenal disease patients with or without CAD. Reprinted with permission.19
group, age was found to be significantly associated with the presence of calcification. Although none of the 23 patients who were younger than 20 years had evidence of coronary artery calcification, it was present in 14 of 16 patients aged 20 to 30 years. Among those with calcification, mean score was 1,157. Conversely, only 3 of 60 healthy patients showed evidence of calcification. In addition to age, duration of dialysis therapy (mean of 14 years for the calcification group versus 4 years for the noncalcification group; P ⬍ 0.001) and higher calcium intake (6,456 versus 3,325 mg/d; P ⫽ 0.02) were significantly associated with calcification. The association between calcium intake and coronary artery calcification has raised concern regarding the potential detrimental effects of excess administration of calcium to bind phosphorus in these patients. Raggi et al21 assessed the presence of atherosclerotic vascular disease in a population of 205 patients on maintenance hemodialysis therapy. Using EBCT, the researchers compared patients with and without clinical evidence of atherosclerotic CVD and correlated these findings with calcification scores.21 More than 80% of patients with calcification scores greater than 1,000 had atherosclerotic vascular disease, and coronary artery calcium scores were significantly related to the prevalence of myocardial infarction (P ⬍ 0.0001) and angina (P ⬍ 0.0001). Calcification was significantly associated with older age, white race, male sex, presence of diabetes, and higher serum calcium or phosphorus levels. Although it remains to be determined whether calcification itself is a cause of CVD or a marker
S15
of underlying CVD, recent studies have suggested that excess calcification may play a pathological role in promoting CVD. Calcification has been shown to be an independent determinant of increasing arterial stiffness,22 which in turn may result in higher systolic blood pressure, lower diastolic pressure, higher pulse pressure, LVH, decreased coronary perfusion, and increased CVD outcomes. Using aortic pulse wave velocity as a measure of vessel stiffness, Blacher et al23 showed that dialysis patients with increased stiffness of the aorta have a lower probability of survival compared with patients with more elastic vessels (Fig 5). In this study involving 241 dialysis patients, each 1-millisecond increase in pulse wave velocity resulted in a 39% increase in the odds for all-cause mortality. The role of arterial stiffening was independent of age, overall duration of ESRD, preexisting CVD, blood pressure, and Hgb levels. Additional observational studies have also shown that higher aortic calcification scores increase the probability of all-cause mortality.24 There are randomized trials that have evaluated whether a decrease in the use of calciumbased phosphorus binders results in an improvement in CVD outcomes. Chertow et al25 compared the use of sevelamer, a nonabsorbed non-calcium– containing polymer, with calcium-based phosphate binders to determine whether use of the
Fig 5. Probability of overall survival in patients with ESRD with aortic stiffening, divided into tertiles. Patients in the highest tertile (pulse wave velocity [PWV] >12 milliseconds) were 5.4 times as likely to die of any cause than those in the lowest tertile (PWV < 9.4 milliseconds) and 5.9 times as likely to die of cardiovascular causes. Reprinted with permission.23
S16
MARK J. SARNAK
uremia-related risk factors. Finally, additional clinical trials with a goal to reduce CVD are urgently needed in CKD. REFERENCES
Fig 6. Median percentage of change at 52 weeks in (A) coronary calcification and (B) aortic calcification compared with baseline in patients randomly assigned to sevelamer (■) or a calcium-containing phosphate binder (䊐). Reprinted with permission.25
non-calcium–containing product would reduce the likelihood of progressive cardiovascular calcification. The 200 hemodialysis patients in this study were randomly assigned to treatment with sevelamer or calcium-based phosphate binders for 52 weeks and were assessed by EBCT. At week 52, the percentage increase in coronary and aortic calcium was less in the sevelamer group compared with patients administered calciumcontaining phosphate binders (P ⬍ 0.001; Fig 6).25 Although questions have been raised regarding the interpretation of the results,26 the results are important, and additional research using clinical outcome end points must be conducted to determine whether the reduction in calcification translates into a lower risk for CVD events or mortality. CONCLUSIONS
Patients with CKD have a high burden of cardiomyopathy, atherosclerosis, and arteriosclerosis. Although patients with CKD share many of the same cardiovascular risk factors with the general population, there are additional risk factors, such as anemia and abnormal calcium/ phosphorus metabolism, that place these patients at even greater risk for CVD mortality. Because CVD begins during the early stages of CKD, before ESRD, it is important to identify patients at risk long before the need for renal replacement therapy and to address both the traditional and
1. Herzog CA, Ma JZ, Collins AJ: Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339:799-805, 1998 2. Foley RN, Parfrey PS, Sarnak MJ: Cardiovascular disease in chronic renal disease: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112-S119, 1998 (suppl 3) 3. Shulman NB, Ford CE, Hall WD, et al, on behalf of the Hypertension Detection and Follow-Up Program Cooperative Group: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: Results from the Hypertension Detection and Follow-up Program. Hypertension 13:SI80-SI93, 1989 (suppl I) 4. Wright RS, Reeder GS, Herzog CA, et al: Acute myocardial infarction and renal dysfunction: A high-risk combination. Ann Intern Med 137:563-570, 2002 5. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB: Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 137:555-562, 2002 6. Schunkert H, Hense HW: A heart price to pay for anaemia. Nephrol Dial Transplant 16:445-448, 2001 7. Rostand SG, Kirk KA, Rutsky EA: Dialysis-associated ischemic heart disease: Insights from coronary angiography. Kidney Int 25:653-659, 1984 8. Schwarz U, Buzello M, Ritz E, et al: Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 15:218-223, 2000 9. London GM, Marchais SJ, Guerin AP, et al: Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 17:1713-1724, 2002 10. Klassen PS, Lowrie EG, Reddan DN, et al: Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA 287:1548-1555, 2002 11. Sarnak MJ, Levey AS: Cardiovascular disease and chronic renal disease: A new paradigm. Am J Kidney Dis 35:S117-S131, 2000 (suppl 1) 12. De Santo NG, Cirillo M, Perna A, et al: The heart in uremia: Role of hypertension, hypotension, and sleep apnea. Am J Kidney Dis 38:S38-S46, 2001 (suppl 1) 13. Metivier F, Marchais SJ, Guerin AP, et al: Pathophysiology of anaemia: Focus on the heart and blood vessels. Nephrol Dial Transplant 15:S14-S18, 2000 (suppl 3) 14. Foley RN, Parfrey PS, Harnett JD, et al: The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 28:53-61, 1996 15. Levin A, Thompson CR, Ethier J, et al: Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin. Am J Kidney Dis 34:125-134, 1999 16. Besarab A, Bolton WK, Nissenson AR, et al: The Normal Haematocrit Trial in dialysis patients with cardiac disease. Nephrol Dial Transplant 14:2043-2044, 1999 17. Foley RN, Parfrey PS, Morgan J, et al: Effect of
CARDIOVASCULAR COMPLICATIONS IN CHRONIC KIDNEY DISEASE
hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 58:1325-1335, 2000 18. Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 31:607-617, 1998 19. Braun J, Oldendorf M, Moshage W, et al: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394-401, 1996 20. Goodman WG, Goldin J, Kuizon BD, et al: Coronaryartery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:1478-1483, 2000 21. Raggi P, Boulay A, Chasan-Taber S, et al: Cardiac calcification in adult hemodialysis patients: A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 39:695-701, 2002
S17
22. Guerin AP, London GM, Marchais SJ, Metivier F: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15:1014-1021, 2000 23. Blacher J, Guerin AP, Pannier B, et al: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99:2434-2439, 1999 24. Blacher J, Guerin AP, Pannier B, et al: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938-942, 2001 25. Chertow GM, Burke SK, Raggi P, for the Treat to Goal Working Group: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 26. Canavese C, Bergamo D, Dib H, Bermond F, Burdese M: Calcium on trial: Beyond a reasonable doubt? Kidney Int 63:381-382, 2003 (letter)