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Risk Factors for Cardiovascular Disease in Children on Maintenance Dialysis
Risk Factors for Cardiovascular Disease in Children on Maintenance Dialysis Blanche Chavers and H. William Schnaper Cardiovascular disease mortality is high in children on maintenance dialysis, accounting for about 25% of patient deaths. Cardiovascular-related mortality rates for children on dialysis are higher than for children with successful kidney transplants. Data on the long-term consequences of risk factors for cardiovascular disease are lacking for pediatric end-stage renal disease patients. This article reviews pediatric data pertaining to the following risk factors: anemia, hypertension, hyperlipidemia, left ventricular hypertrophy, abnormal calcium-phosphorus metabolism, and hyperhomocysteinemia. The potential relationship of end-stage renal disease to the etiology of several functional disorders of the cardiovascular system is discussed. Clinical studies are needed to assess the prevalence of cardiovascular disease and of cardiovascular disease risk factors in the pediatric end-stage renal disease population. Possible preventive and therapeutic guidelines need to be developed for at-risk children on maintenance dialysis. © 2001 by the National Kidney Foundation, Inc. Key words: pediatric, cardiovascular disease, dialysis, risk factors, end-stage renal disease.
ata generated from the United States ReD nal Data System (USRDS) database from through reveal higher death rates in
1996 1998 adults and children on maintenance dialysis, when compared with those with kidney transplants, irrespective of the cause for death. About 25% of the deaths in children on chronic dialysis are caused by cardiovascular causes and include such problems as cardiac arrest, cardiomyopathy, cardiac arrhythmia, acute myocardial infarction, and valvular heart disease.! Cardiovascular death rates were 9 times more common in children on peritoneal dialysis (9.1/1000 patient years at risk) and 7 times more common in children on hemodialysis (7.4/1000 patient years at risk), compared with pediatric kidney transplant recipients (1.0/1000 patient years at risk).! The cardiac morbidity and mortality of pediatric end-stage renal disease (ESRD) patients is a From the Division of Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN; and the Division of Nephrology, Department of Pediatrics, Northwestern University Medical School and Children's Memorial Center, Chicago,IL. Supported in part by grants HL53918 from the National Heart, Lung and Blood Institute and DK49362 from the National Institute of Diabetes, Digestive and Kidney Diseases. Address correspondence to Blanche Chavers, MD, University of Minnesota, Department of Pediatrics, Division of Pediatric Nephrology, 420 Delaware Street SE, MMC 491, Minneapolis, MN 55455. © 2001 by the National Kidney Foundation, Inc. 1073-4449/01/0803-0005$35.00/0 doi:10.1053/jarr.2001.26355
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relatively unexplored area. Multicenter, prospective, clinical studies have not systematically investigated the burden of cardiovascular disease (CVD) in pediatric chronic dialysis patients. Even less clear is the optimal therapeutic approach for pediatric patients with manifest CVD. Table 1 lists cardiovascular abnormalities reported in children on chronic dialysis. 2 - 9 The cardiovascular abnormalities in dialysis patients reflect loss of compliance of the myocardium and the peripheral vessels and fibrotic and atherosclerotic changes in the vascular tree. Problems that are commonly observed in dialysis patients include anemia, chronic volume overload, hypertension, hyperlipidemia, left ventricular hypertrophy (LVH), hyperparathyroidism with vascular calcification, and hyperhomocysteinemia.!o A hallmark of CVD in dialysis patients is the rapid progression of atherosclerotic CVD (ASCVD), disproportionate to patient age. Numerous factors contribute to atheroscleroSiS,1l-13 including all of the risk factors mentioned previously. A critical component is the interaction of macrophages and oxidized lipids, suggesting to some that ASCVD is ultimately a manifestation of inflammation.!4 Lipid peroxidation occurs in the circulation or the subendothelial space, leading to the recruitment and activation of monocytes that phagocytose the oxidized lipid, creating foam cells. The local production of cytokines and the dysregulation of clotting lead to fibrosis and thrombosis, causing narrowing and stiff-
Advances in Renal Replacement Therapy, Vol 8, No 3 (July), 2001: pp 180-190
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Table 1. Cardiovascular Abnormalities in Pediatric Maintenance Dialysis Patients
Author (n)
Dialysis Type
Abnormality
% Abnormal
Morris2 (13)
12 PD/1 HD
Ulmer3 (11)
HD
Germain4 (13) Bosch5 (21) Johnston6 (10)
4PD/9HD 10PD/11 HD PD
Mitsnefes 7 (64) Goodman8 (39)
38 PD/26HD 21 PD/18 HD
Heart murmur Cardiomegaly on CXR Abnormal ECG Increase in cardiac index Interventricular septal hypertrophy Left ventricular hypertrophy Ventricular diastolic dysfunction Heart murmur Abnormal ECG Left ventricular hypertrophy Left ventricular dysfunction Arrhythmia Arrhythmia Interventricular septal hypertrophy Aortic root dilatation Left ventricular hypertrophy Left ventricular hypertrophy Abnormal ECG Coronary-artery calcification
82% 69% 100% 77% 92% 54% 55% 82% 45% 9% 73% 23% 57% 40% 40% 30% 75% 15% 36%
Abbreviations: PD, peritoneal dialysis; HD, hemodialysis; CXR, chest radiograph; ECG, electrocardiogram.
ening of the vasculature. Scarred tissue becomes less responsive to va so dilatory stimuli, exacerbating hypertension and increasing shear stress on the vessel wall. Thus, the triad of inflammation, reactive oxygen species, and fibrosis mediate end-organ damage in the dialysis patient.
Risk Factors in Maintenance Dialysis Anemia Anemia is a major complication of ESRD. Reported mechanisms include erythropoietin deficiency, uremic toxins, decreased erythrocyte life span, blood loss from the gastrointestinal tract and dialyzer, and iron and folate deficiency.1 S-16 Severe anemia leads to increased cardiac demand and an elevated cardiac index caused by decreased oxygen delivery to the tissues and decreased blood viscosity.17-19 A high cardiac output leads to LVH, left ventricular dilatation, and heart failure. 2,3,20-22 Recombinant human erythropoietin (rHuEPO) became available in the United States in 1989 for the clinical treatment of the anemia of chronic renal failure. 23 It has been shown to be safe and effective for the treatment of anemia in children on chronic dialysis.24-28 The recommended target hemoglobin level is 11 to 12 g/ dL in pediatric and adult
dialysis patients. 29,3o Recent data are not available on the percentage of chronic pediatric dialysis patients who have hemoglobin levels below the recommended target. Studies in small numbers of pediatric dialysis patients have shown improvement in cardiac function and a decrease in left ventricular size after partial correction of anemia with rHuEPO.21,31,32 Morris et aF1 showed a reduction in left ventricular end diastolic diameter and cardiac index in 7 children after 6 months of treatment with rHuEPO. After 12 months of treatment, a significant reduction was seen in the cardiothoracic ratio. 21 These results are similar to those published for adult dialysis patients after partial correction of anemia with rHuEPO.22,33-38 However, established concentric LVH in adults might not improve with the correction of anemia39; data on this issue are not yet available in children.
Hypertension Hypertension in childhood is defined as a repeated blood pressure gretaer than ninetyfifth percentile for age, sex, and height4° and is reportedly more common in children on hemodialysis (HD) than in those on peritoneal dialysis (PD).41-4S Baum et al42 reported that 56% of 16 children on HD were on antihypertensive agents, compared with 39% of 20 chil-
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dren on PD. Potter et a143 reported that 64% of 25 children on HD were on antihypertensive agents, comp.ared with 41 % of 51 children on PD. In contrast, Lingens et al,45 using ambulatory blood pressure monitoring, found that 70% of 17 children on PD were hypertensive, compared with 33% of 18 children on HD. Hypertension is a major cause of morbidity in pediatric dialysis patients and is associated with frequent hospitalizations. 46 The multiple mechanisms for the development of hypertension in dialysis patients include volume expansion, activation of the renin-angiotensin system, high cardiac output attributable to arteriovenous fistula, increased total peripheral resistance, endothelin-associated vasoconstriction, increased sympathetic nervous system activity, disordered nitric oxide metabolism, elevated calcium levels, and erythropoietin administration. 25,47-51 Chronic hypertension has been associated with the development of LVH, left ventricular dysfunction, cardiac failure, and ischemic heart disease. 2,3,6,7,22,52-55 In children, inter dialytic weight gain has been shown to correlate positively with elevated systolic blood pressure. 51 Prolonged or more frequent dialysis treatments might be required to manage hypervolemia in pediatric HD patients. Techniques that allow for continuous monitoring of intravascular volume during hemodialysis have been advocated for use in children. 56-58 A reduction in blood pressure to below the ninetieth to ninety-fifth percentile for age and gender is considered successful treatment of childhood hypertension. Antihypertensive medications, often in combination, are needed to control blood pressure in patients who remain hypertensive despite adequate control of volume overload. Classes of antihypertensive agents used in adults and children on maintenance dialysis are similar and consist of calcium channel blockers, angiotensin-converting enzyme inhibitors, beta blockers, and peripheral vasodilators. 59-62 Studies on the safety and efficacy of angiotensin II receptor blockers in children have not yet been published. Hyperlipidemia Hyperlipidemia is a risk factor for atherosclerotic CVD (ASCVD) in the general adult, di-
alysis, and transplant populations. 63-66 Abnormalities might include hypertriglyceridemia, hypercholesterolemia, elevated low-density lipoprotein (LDL), decreased high-density lipoprotein, or elevated lipoprotein (a). The prevalence of hyperlipidemia in pediatric dialysis patients is high and has been shown to persist over 2 years of follow-up.67-71 Broyer et a167 found elevated triglyceride and cholesterol levels to persist during a 24-month study of 15 PD patients; levels were higher in the younger patients, although the difference attributable to age did not achieve statistical significance. Similar findings were reported in larger studies by Scolnik68 and Querfeld. 69 Querfeld et a169 found that 90% of 68 pediatric PD patients had high triglyceride levels and 69% had high cholesterol levels at the initiation of dialysis. Levels remained elevated over the 2-year follow-up period in that study. Hyperlipidemia has been implicated in the pathogenesis of atherosclerosis. The earliest lesion of atherosclerosis is seen as a nonelevated yellow patch on the intimal surface of the vessel wall called a fatty streak.72 This phenomenon has been observed in pediatric HD and transplant patients. Pennisi et aF3 examined autopsy samples of material from the left coronary arteries of 12 children who died while on chronic HD or after a renal transplant. Of the 12 patients, 10 (83%) had increased collagenization of the intima when compared with age-matched controls. This finding was considered to represent fatty streaks, an early indication of coronary artery disease. Specific guidelines for managing hyperlipidemia in pediatric chronic dialysis patients have not been published, whereas general guidelines for managing hyperlipidemia in children recommend screening based on a family history of hyperlipidemia and CVD.74,75 Dietary modification is recommended as the first approach to treatment of hyperlipidemia in children over 2 years old. A multicenter, randomized, controlled trial of hyperlipidemia in 663 children (8 to 10 years old) showed that dietary fat intake could be safely lowered. Children with cholesterol levels between the eightieth and ninety-eighth percentiles for age and gender were assigned ran-
Maintenance Dialysis Risk Factors
domly to either a low-fat or a usual diet. Serum LDL-cholesterol levels were lower in the low-fat group at 3 years, compared with the control group?6 Supplementation with fish oil rich in omega-3-polyunsaturated fatty acids has been shown to reduce serum triglyceride levels in 7- to 8-year-old patients on chronic dialysis. 77 Fish oil reportedly works by reducing hepatic triglyceride production. Bile acid sequestrants (resins), which are effective cholesterol-lowering agents, are the only drugs approved for use in children with hyperlipidemia. Adequate dosing might be difficult because of gastrointestinal side effects such as constipation and bloating. Pill formulations might be more palatable to children than powder formulations. Agents such as niacin, probucol, gemfibrozil, and 3-hydroxy-3 methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors have not been approved by the Food and Drug Administration (FDA) for use in children76; however, the use of HMG-CoA reductase inhibitors has been reported in children.78 LVH LVH is an independent risk factor for cardiovascular morbidity and mortality in the general adult79,80 and adult dialysis populations.1O,81-83 Prevalence rates in adult dialysis patients range from 60% to 80%. LVH develops primarily as a consequence of chronic hemodynamic overload and stiffening of the arterial tree. 81 ,84 It can lead to ischemic heart disease, heart failure, left ventricular diastolic dysfunction, dialysis-associated hypotension, arrhythmias, or sudden death.1o,81,84 The incidence of LVH varies by diagnostic technique; echo cardiography is more sensitive than electrocardiography.79,85 However, echocardiography reportedly overestimates the incidence of LVH in dialysis patients, compared with magnetic resonance imaging. 86 Risk factors for LVH in adult dialysis patients include more advanced age, systolic hypertension, anemia, and interdialytic weight gain.10,20,22,34,53,54,81-84,87 Most studies of LVH in pediatric dialysis patients have involved small numbers of patients with prevalence rates ranging from 9% to 92%.3,6,7,21 In a large European study, LVH was present in 51% of 198 children on HD by echocardiography and in 38% of 188 children
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by electrocardiography.85 In children on PD, the values were 29% by echocardiography (n = 85) and 18% by electrocardiography (n = 74). However, the authors noted that in their study, 25% of children on HD and 34% of children on PD did not undergo echocardiography.85 Mitsnefes et aF also found a slightly higher incidence of LVH in children on HD (85% of 26), compared with PD (68% of 38). Risk factors for LVH in pediatric dialysis patients include anemia and hypertension. 3,7,21 The contribution of LVH to cardiac-associated mortality in pediatric ESRD is not known. Vascular Calcification Abnormal calcium-phosphorus metabolism is a risk factor for myocardial and vascular calcification in dialysis patients.8,88-94 Myocardial and vascular calcification might result in cardiac dysfunction, arrhythmia, and death. Goodman et al,8 using electron beam tomography, screened 39 chronic dialysis patients with a mean age 19 years. Of 16 patients 20 to 30 years old, 14 (87.5%) had coronary artery calcification. In contrast, none of the patients younger than 20 years old had detectable abnormalities. Coronary artery calcification correlated with more advanced age, longer duration of dialysis, high serum phosphorus levels, elevated calcium X phosphorus product, and a high daily intake of calcium salts. An elevated calcium X phosphorus product, with or without hyperphosphatemia, has been found in patients with calcification of the aortic and mitral valves,89,9o myocardial tissue,91,93 coronary arteries,8,93,94 and aorta. 94,95 The primary factors associated with calcification appear to be altered calcium-phosphorus metabolism in dialysis patients and secondary hyperparathyroidism with inadequate control of hyperphosphatemia. 88 However, the process of cardiac valve calcification does not represent simply the result of precipitation from an excessively high calcium X phosphorus product. Instead, it represents the net outcome of multiple, highly regulated cellular and biochemical events. Virchow96 first reported that histologic analysis of atherosclerotic plaques in nonuremic patients shows the presence of trabecular bone formation. Further, in an apparently reciprocal relationship, the same stimuli that can deplete bone cal-
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cium in chronic renal failure appear to enhance calcium deposition and bone formation in atherosclerotic plaques.97 Although the basis for this phenomenon is less well understood in uremia, it is known that excess vitamin D stimulates metastatic calcification, whereas parathyroidectomy is associated with delayed progression of vascular calcification. Thus, newer treatments for hyperparathyroidism and early identification of vascular calcification might prevent the development or progression of cardiovascular disease. Homocysteine Levels Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis in dialysis patients. 98-lOO Hyperhomocysteinemia results from alterations in methionine metabolism because of hereditary enzyme deficiencies, vitamin deficiencies (folate, B6 , Bd or kidney failure. Proposed pathogenic mechanisms include increased oxidant stress, endothelial cell damage, smooth muscle cell proliferation, and thrombosis formation. Elevated plasma homocysteine levels are present in as many as 97% of adult dialysis patients and correlate negatively with serum folate levels. 98-102 Elevated levels obtained after fasting or after a methionine-loading test are used for diagnosis and are defined as from greater than 13.5 to greater than 16 ILmol/L. Supplemental folate, even in the absence of folate deficiency, in doses ranging from 1 to 15 mg/ day, has reduced, but not normalized homocysteine levels in adult chronic dialysis patients.1 02-104 A reduction in homocysteine levels also has been reported in adult hemodialysis patients using superflux dialyzers.1 os Reference homocysteine levels have been published for children.106-108 In a United States study of 3,524 schoolchildren ages 13 and 14 years, nonfasting total serum homocysteine levels ranged from 0.1 to 25.7 ILmol/L (median, 4.9 ILmol/L).1 06 Levels were higher in boys, blacks, nonusers of multiple vitamins, and smokers. Also, levels were correlated inversely with serum levels of folic acid. Schroder et al102 reported hyperhomocysteinemia in 9 of 12 pediatric PD patients and 8 of 9 pediatric HD patients. All patients showed a reduction in homocysteine levels after folic acid
(2.5 mg/ d for 4 weeks). Similarly, Lilien et aP08 reported hyperhomocysteinemia in 92% of 12 children on HD. Large, randomized, controlled trials of vitamin (folate) use for treating hyperhomocysteinemia and modifying or preventing CVD have not been conducted in dialysis patients.
Modification of Vascular Function Data are lacking on the associations between inflammation, increased oxidative stress, and CVD for pediatric dialysis patients, although studies have been conducted in the adult dialysis populationl09-112 and in animal models. Inflammation As proposed by Ross,14 the macrophage might playa critical role in the pathogenesis of atherosclerosis. Thus, activation of the immune system could accelerate atherogenesis. Patients undergoing treatment for ESRD show increases in cytokine production and, as a marker for immune activation, elevated C-reactive protein, a predictor of atherosclerosis.1 13 Dialysis patients manifest increased advanced glycosylation end products (AGEs), increased acute phase reactants such as fibrinogen, and elevated serum amyloid. lI4 Hemodialysis could activate the immune system in 3 ways: increased complement activation, exposure to endotoxin, and the effects of direct contact of blood components with nonnative materials. lIS Another aspect of inflammation is abnormal coagulation. End-stage renal disease is associated with increased Factor VII, fibrinogen, plasmin-antiplasmin complexes, plasminogen activator inhibitor-I, and D-dimer.1 16 In addition, hyperhomocysteinemia is associated with increased atherothrombotic phenomena.1 17 Oxidation Although some studies have disagreed,118 most investigators report that reactive oxygen metabolites, the generation of which is critical for lipid peroxidation, are elevated in dialysis patients. The elevation is most clear in hemodialysis, with intermediate elevations in peritoneal dialysis. Reactive oxygen species are not significantly above normal in patients
Maintenance Dialysis Risk Factors
with chronic renal failure before starting dialysis. Although this association could reflect disease severity, it .likely represents an effect of treatment modality.1 19 Conversely, antioxidant levels, including those of lycopene, delta tocopherol, gamma tocopherol and retinol are decreased in hemodialysis patients relative to controls.120 Increased AGEs also suggest an oxidative environment. 121 Thus, dialysis (particularly hemodialysis) could contribute significantly to accelerated atherosclerosis in uremic patients. Vascular Reactivity and Fibrosis Several groups have reported that patients with ESRD manifest endothelial dysfunction, with impaired nitric oxide synthase regulation.122 Poor vascular reactivity also might be reflected in decreased cardiac f3-adrenergic receptor function, found in humans and rats with chronic uremia.1 23 One group has suggested that abnormal serotonin release from activated platelets also impairs vasodilatation124; however, consistent with fibrotic atherogenesis, uremic patients have an increased ratio of intimal to medial vessel wall thickness. 125 This observation suggests that decreased compliance is another cause of a decreased response to vasodilators.122,126 Thus, fibrous thickening of the vascular wall might play an important role. An interesting consideration is the potential role of hyperparathyroidism in this process.127 Hyperparathyroidism and excess vitamin D are associated with progressive aortic stenosis in adult patients. 128 Experimental studies support a role for parathyroid hormone in vascular fibrogenesis. Rats with subtotal nephrectomy in whom eucalcemia was maintained received exogenous PTH. Elevated levels of the hormone were re-
quired for cardiac wall thickening to occur.1 29 In contrast, hypertension alone was insufficient to cause cardiac wall fibrosis. 130 Therapeutic Implications Some of these changes are potentially amenable to therapy, although most such approaches should be considered experimental or theoretical. Hyperhomocysteinemia may be treated with pyridoxine and folic acid.1 31 No antiinflammatory agents have been identified as having salient effects on atherogenesis, whether from uremia or other causes. Recent work suggests that vitamin E supplementation or use of vitamin E-modified dialyzers might decrease oxidant stress and thereby reduce the incidence of CVD in adult dialysis patients. In a multicenter, randomized, placebocontrolled trial of adult HD patients with known CVD, Boaz et aP32 found that daily oral supplementation with 800 IU of vitamin E reduced the incidence of myocardial infarction and other CVD endpoints. Galli et aP33 found that vitamin E-modified dialyzers also could be an effective form of vitamin E supplementation and antioxidant defense. Similar studies have not been reported for pediatric dialysis patients. Several treatments might be suggested for fibrogenesis. Data after vasoconstrictive cardiomyopathy in rats 134 or chronic congestive heart failure in humans 135 suggest that angiotensin-converting enzyme inhibitors might be effective in reversing or slowing the progression of cardiac or vascular fibrosis. Similar studies are not available in uremic children. Endothelin receptor antagonists have been found to be effective in preventing cardiac fibrosis in uremic rats,136 even in normoten-
Table 2. Risk Factors and Possible Interventions for Cardiovascular Disease in Pediatric Maintenance Dialysis Patients
Risk Factor Anemia Hypertension Hyperlipidemia Abnormal calcium-phosphorus metabolism Hyperhomocysteinemia Left ventricular hypertrophy
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Possible Intervention Erythropoietin, iron supplementation Volume control, salt restriction, antihypertensive agents to reduce blood pressure to <90th percentile Dietary modification, ? lipid-lowering agents Phosphorus restriction, Ca X P product < 60, phosphatebinding agents Folate supplementation, ?B 6 , ?B12 Antihypertensive agents, erythropoietin
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sive animals; an effect on blood pressure was not needed.137
7.
Vision for the Future Although the adverse impact of CVD risk factors is more commonly seen in adulthood, many risk factors might appear first in childhood. Some of these risk factors are potentially reversible (Table 2). The alarming increase in CVD in children on dialysis clearly requires attention; however, a successful strategy for addressing CVD in pediatric dialysis patients requires additional information, including (1) epidemiologic studies of CVD prevalence and risk factors, (2) development of guidelines for screening and treatment of at-risk children, (3) studies on effective treatment of modifiable risk factors, and (4) studies on the pharmacokinetics, safety, and efficacy of statin use in children. A CVD checklist should be incorporated into the routine monitoring of pediatric dialysis patients to enhance the likelihood that all of us will begin to focus on the prevention, early detection, and treatment of CVD in children who require renal replacement therapy.
Acknowledgment The authors thank Mary Knatterud for editorial assistance.
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anaemia and erythropoietin therapy. Nephrol Dial Transplant 14:1317-1323, 1999 39. Foley RN, Parfrey PS, Morgan J, et al: Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 58:13251335, 2000 40. National Heart, Lung, and Blood Institute: Update on the 1987 Task Force on High Blood Pressure in Children and Adolescents: A Working Group from the National High Blood Pressure Education Program. Pediatrics 98:649-658, 1996 41. Drukker A: Hypertension in children and adolescents with chronic renal failure and end-stage renal disease. Child Nephrol Urol11:152-158, 1991 42. Baum M, Powell D, Calvin S, et al: Continuous ambulatory peritoneal dialysis in children. Comparison with hemodialysis. N Engl J Med 307:1537-1542, 1982 43. Potter DE, San Luis E, Wipfler JE, et al: Comparison of continuous ambulatory peritoneal dialysis and hemodialysis in children. Kidney Int 30:S11-S14, 1986 44. Sorof JM: Ambulatory blood pressure monitoring in pediatric end-stage renal disease: chronic dialysis and transplantation. Blood Press Monit 4:171-174,1999 45. Lingens N, Soergel M, Loirat C, et al: Ambulatory blood pressure monitoring in paediatric patients treated by regular haemodialysis and peritoneal dialysis. Pediatr Nephrol 9:167-172, 1995 46. Verrina E, Edefonti A, Perfumo F, et al: A multicenter study on the hospitalization of pediatric patients on chronic peritoneal dialysis. Adv Perit Dial 10:315-317, 1994 47. Zucchelli P, Santoro A, Zuccala A: Genesis and control of hypertension in hemodialysis patients. Semin Nephrol 8:163-167, 1988 48. Converse RL, Jacobsen TN, Toto RD, et al: Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 327:1912-1918,1992 49. Mailloux LU, Haley WE: Hypertension in the ESRD patient: pathophysiology, therapy, outcomes, and future directions. Am J Kidney Dis 32:705-719, 1998 50. Nissenson AR: Erythropoietin overview 1993. Blood Purif 12:6-13, 1994 51. Sorof JM, Brewer ED, Portman RJ: Ambulatory blood pressure monitoring and interdialytic weight gain in children receiving chronic hemodialysis. Am J Kidney Dis 33:667-674,1999 52. Daniels SR: Hypertension-induced cardiac damage in children and adolescents. Blood Press Monit 4:165-170, 1999 53. Lopez-Gomez JM, Verde E, Perez-Garcia R: Blood pressure, left ventricular hypertrophy and long-term prognosis in hemodialysis patients. Kidney Int 68: S92-S98, 1998 54. Foley RN, Parfrey PS, Harnett JD, et al: Impact of hypertension on cardiomyopathy, morbidity and mortality in end-stage renal disease. Kidney Int 49: 1379-1385,1996 55. Drukker A, Urbach J, Glaser J: Hypertrophic cardiomyopathy in children with end-stage renal disease and hypertension. Proc Eur Dial Transplant Assoc 18:542-547, 1981
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56. Steuer RR, Germain MI, Leypoldt JK, et al: Enhanced fluid removal guided by blood volume monitoring during chronic hemodialysis Artif Organs 22:627632, 1998 . 57. Sanjeev RI, Smith L, Brewer ED, et al: Non-invasive intravascular monitoring in the pediatric hemodialysis population. Pediatr NephroI16:15-18, 2001 58. Miltenyi G, Tory K, Stubnya G, et al: Monitoring cardiovascular changes during hemodialysis in children. Pediatr Nephrol 16:19-24, 2001 59. Bartosh SM, Aronson AJ: Childhood hypertension: An update on etiology, diagnosis, and treatment. Pediatr Clin North Am 46:235-252, 1999 60. Temple ME, Nahata MC: Treatment of pediatric hypertension. Pharmacotherapy 20:140-150, 2000 61. Tallian KB, Nahata MC, Turman MA, et al: Efficacy of amlodipine in pediatric patients with hypertension. Pediatr Nephrol13:304-310, 1999 62. Sica DA, Marino MR, Hammett JL, et al: The pharmacokinetics of irbesartan in renal failure and maintenance hemodialysis. Clin Pharmacol Ther 62:610618,1997 63. National cholesterol education program: Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). J Am Med Assoc 269:3015-3023, 1993 64. Grundy SM: Lipid abnormalities and coronary heart disease. Clin Symp 49:1-32, 1997 65. Parsy D, Dracon M, Cachera C, et al: Lipoprotein abnormalities in chronic hemodialysis patients. Nephrol Dial Transplant 3:51-56,1988 66. Atkins RC, Wood C: Hyperlipidemia in CAPD. Perit Dial Int 13:5415-5417, 1993 67. Broyer M, Niaudet P, Champion G, et al: Nutritional and metabolic studies in children on continuous ambulatory peritoneal dialysis. Kidney Int 24:S106S110, 1983 68. Scolnik D, Balfe JW: Initial hypoalbuminemia and hyperlipidemia persist during chronic peritoneal dialysis in children. Perit Dial Int 13:136-139, 1993 69. Querfeld U, Salusky IE, Nelson P, et al: Hyperlipidemia in pediatric patients undergoing peritoneal dialysis. Pediatr Nephrol 2:447-452, 1988 70. Berger M, James GP, Davis ER, et al: Hyperlipidemia in uremic children: Response to peritoneal dialysis and hemodialysis. Clin Nephrol 9:19-24, 1978 71. VanGool S, Van Damme-Lombaerts R, Cobbaert C, et al: Lipid and lipoprotein abnormalities in children on hemodialysis and after transplantation. Transplant Proc 23:1375-1377,1991 72. Robertson WB, Geer Jc, Strong JP, et al: The fate of the fatty streak. Exp Mol Pathol 1:28-39, 1963 73. Pennisi AI, Heuser ET, Mickey MR, et al: Hyperlipidemia in pediatric hemodialysis and renal transplant patients. Associated with coronary artery disease. Am J Dis Child 130:957-961, 1976 74. National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 89:525-584, 1992 75. Stare TJ: Management of hyperlipidemia in children. Prog Pediatr Cardiol 12:205-213, 2001
76. Lauer RM, Obarzanek E, Hunsberger SA, et al: Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: The dietary intervention study in children. Am J Clin Nutr 72:S1332-S1342, 2000 77. Goren A, Stankiewicz H, Goldstein R, et al: Fish oil treatment of hyperlipidemia in children and adolescents receiving renal replacement therapy. Pediatrics 88:265-268, 1991 78. Duplaga BA: Treatment of childhood hypercholesterolemia with HMG-CoA reductase inhibitors. Ann Pharmacother 33:1224-1227, 1999 79. Vakili BA, Okin PM, Devereux RB: Prognostic implications of left ventricular hypertrophy. Am Heart J 141:334-341, 2001 80. Benjamin EI, Levy D: Why is left ventricular hypertrophy so predictive of morbidity and mortality? Am J Med Sci 31:168-175, 1999 81. London GM, Parfrey PS: Cardiac disease in chronic uremia: Pathogenesis. Adv Ren Replace Ther 4:194211,1997 82. Silberberg JS, Barre PE, Prichard SS, et a1: Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 36:286-290, 1989 83. Foley RN, Parfrey PS: Cardiovascular disease and mortality in ESRD. J Nephrol 11:239-245, 1998 84. Meeus F, Kourilsky 0, Guerin AP, et al: Pathophysiology of cardiovascular disease in hemodialysis patients. Kidney Int 58:S140-S147, 2000 85. Loirat C, Ehrich JHH, Geerlings W, et al: Report on management of renal failure in children in Europe, XXIII, 1992. Nephrol Dial Transplant 1:S26-S40, 1994 86. Stewart GA, Foster I, Cowan M, et al: Echocardiography overestimates left ventricular mass in hemodialysis patients relative to magnetic resonance imaging. Kidney Int 56:2248-2253, 1999 87. Harnett JD, Kent GM, Barre PE, et al: Risk factors for the development of left ventricular hypertrophy in a prospectively followed cohort of dialysis patients. J Am Soc NephroI4:1486-1490, 1994 88. Block GA, Port FK: Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. Am J Kidney Dis 35:1226-1237, 2000 89. Huting J: Predictive value of mitral and aortic valve sclerosis for survival in end-stage renal disease on continuous ambulatory peritoneal dialysis. Nephron 64:63-68, 1993 90. Ribeiro S, Ramos A, Brandao A, et al: Cardiac valve calcification in haemodialysis patients: role of calcium-phosphate metabolism. Nephrol Dial Transplant 13:2037-2040, 1998 91. Rostand SG, Sanders Pc, Rutsky EA: Cardiac calcification in uremia. Contrib Nephrol 106:26-29, 1994 92. Morales MA, Ferdeghini EM, Pizzarelli F, et al: Characterization of myocardial tissue in patients undergoing maintenance hemodialysis by quantitative echocardiography. J Am Soc Echocardiogr 9:480-487, 1996 93. Milliner DS, Zinsmeister AR, Lieberman E, et al: Soft tissue calcification in pediatric patients with endstage renal disease. Kidney Int 38:931-936,1990
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94. Guerin AP, London GM, Marchais SJ, et al: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15:1014-1021, 2000 95. Bommer J, Strohbeck E, Georich J, et al: Arteriosclerosis in dialysis patients. Int J Artif Organs 19:638644,1996 96. Virchow R: Cellular Pathology: As based upon physiological and pathological histology [trans. Frank Chance, 1971; an unabridged and unaltered republication of the English translation originally published by Dover]. New York, NY, Dover, 1863, pp 404-408 97. Parhami F, Morrow AD, Balucan J, et al: Lipid oxidation products have opposite effects of calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Art Thromb Vasc Bioi 17: 680-687, 1997 98. Chauveau P, Chadefaux B, Coude M, et al: Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int 41:S72-S77, 1993 99. Bostom AG, Shemin D, Verhoef P, et al: Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients: A prospective study. Arterioscler Thromb Vasc Bioi 17:2554-2558, 1997 100. Shemin D, Lapane KL, Bausserman L, et al: Plasma total homocysteine and hemodialysis access thrombosis: a prospective study. J Am Soc Nephrol 10: 1095-1099, 1999 101. DeVecchi AF, Bamonti-Catena F, Finazzi S, et al: Homocysteine, vitamin B12, and serum and erythrocyte folate in peritoneal dialysis and hemodialysis patients. Perit Dial Int 20:168-173, 2000 102. Schroder CH, deBoer AW, Giesen AM, et al: Treatment of hyperhomocysteinemia in children on dialysis by folic acid. Pediatr Nephrol 13:583-585, 1999 103. Dierkes J, Domrose U, Ambrosch A, et al: Response of hyperhomocysteinemia to folic acid supplementation in patients with end-stage renal disease. Clin Nephrol 51:108-115, 1999 104. Bostom AG, Shemin D, Gohh RY, et al: Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant reCipients. Kidney Int 59:S246S252, 2001 105. VanTellingen A, Grooteman MP, Bartels PC, et al: Long-term reduction of plasma homocysteine levels by super-flux dialyzers in hemodialysis patients. Kidney Int 59:342-347, 2001 106. Osganian SK, Stampfer MJ, Speigelman D, et al: Distribution of and factors associated with serum homocysteine levels in children. Child and adolescent trial for cardiovascular health. JAMA 281:11891196,1999 107. Vilaseca MA, Moyano 0, Artuch R, et al: Total homocysteine in pediatric patients. Clin Chern 43: 690-692, 1997 108. Lilien M, Duran M, Van Hoeck K, et al: Hyperhomocyst(e)inaemia in children with chronic renal failure. Nephrol Dial Transplant 14:366-368, 1999 109. Fiorillo C, Oliviero C, Rizzuti G, et al: Oxidative
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stress and antioxidant defenses in renal patients receiving regular haemodialysis. Clin Chern Lab Med 36:149-153,1998 110. Becker BN, Himmelfarb J, Henrich WL, et al: Reassessing the cardiac risk profile in chronic hemodialysis patients: A hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Neph 8:475-486, 1997 111. Zimmermann J, Herrlinger S, Pruy A, et al: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55:648-658, 1999 112. Stenvinkel P, Heimburgr 0 , Lindholm B, et al: Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA syndrome). Nephrol Dial Transplant 15:953-960, 2000 113. Arici M and Walls J: End-stage renal disease, atherosclerosis, and cardiovascular mortality: Is C-reactive protein the missing link? Kidney Int 59:407-414,2001 114. Schwedler S, Schinzel R, Vaith P, et a1: Inflammation and advanced glycation end products in uremia: Simple coexistence, potentiation or causal relationship? Kidney Int 59:S32-S36, 2001 (suppl) 115. Deppisch RM, Beck W, Goehl H, et al: Complement components as uremic toxins and their potential role as mediators of microinflammation. Kidney Int 59: S271-S277, 2001 (suppl) 116. Oda H, Ohno M, Ohashi H: Coagulation and fibrinolysis factors in dialysis patients with and without ischemic heart disease. Adv Perit Dial 16:152-155, 2000 117. van Guldener C, Starn F, Stehouwer CD: Homocysteine metabolism in renal failure. Kidney Int 59:S234S237, 2001 (suppl) 118. Bergesio F, Monzani G, Ciuti R, et al: Autoantibodies against oxidized LDL in chronic renal failure: Role of renal function, diet, and lipids. Nephron 87:127-133, 2001 119. Nourooz-Zadeh J: Effect of dialysis on oxidative stress in uraemia. Redox Rept 4: 17-22, 1999 120. Lim PS, Chan EC, Lu TC, et al: Lipophilic antioxidants and iron status in ESRD patients on hemodialysis. Nephron 86:428-435, 2000 121. Zoccali C, Mallamaci F, Tripepi G: AGEs and carbonyl stress: Potential pathogenetic factors of longterm uraemic complications. Nephrol Dial Transplant 15 : 7-11, 2000 (suppl) 122. Passauer J, Bussemaker E, Range U, et al: Evidence in vivo showing increase of baseline nitric oxide generation and impairment of endothelium-dependent vasodilation in normotensive patients on chronic hemodialysis. J Am Soc Nephrol 11:17261734,2000 123. Dhein S, Rohnert P, Markau S, et al: Cardiac betaadrenoceptors in chronic uremia: Studies in humans and rats. J Am Coli Cardiol 32:608-617, 2000 124. Pawlak D, Malyszko J, Malyszko JS, et al: Peripheral serotonergic system in uremia. Thromb Res 83:189194, 1996 125. Kennedy R, Case C, Fathi R, et al: Does renal failure cause an atherosclerotic milieu in patients with endstage renal disease? Am J Med 110:198-204,2001
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126. Cupisti A, Rossi M, Placidi 5, et al: Responses of the skin microcirculation to acetylcholine and to sodium nitroprusside in chronic uremic patients. Int J Clin Lab Res 30~157-162, 2000 127. Rostand SG, Drueke TB: Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 56:383-392, 1999 128. Urena P, Malergue Me, Goldfarb B, et al: Evolutive aortic stenosis in hemodialysis patients: Analysis of risk factors. Nephrologie 20:217-225, 1999 129. Amann K, Tornig J, Flechtenmacher C, et al: Bloodpressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: Evidence for a permissive action of PTH. Nephrol Dial Transplant 10:2043-2048, 1995 130. Fabris B, Carretta R, Fischetti F, et al: Contribution of systemic blood pressure to myocardial remodeling in uremic rats. Hypertension 26:321-326, 1995 131. Arnadottir M, Brattstrom L, Simonsen 0, et al: The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients. Clin Nephrol 40: 236-240, 1993
132. Boaz M, Smetana 5, Weinstein T, et al: Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): Randomised placebo-controlled trial. Lancet 356:1213-1218, 2000 133. Galli F, Varga Z, Balla J, et al: Vitamin E, lipid profile, and peroxidation in hemodialysis patients. Kidney Int 59:5148-5154, 2001 134. Katoh M, Egashira K, Kataoka C, et al: Regression by ACE inhibition of arteriosclerotic changes induced by chronic blockade of NO synthesis in rats. Am J Physiol Heart Circ Physiol 280:H2306-H2312, 2001 135. MacFadyen RJ, Barr CS, Struthers AD: Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 35:30-34, 1997 136. Wolf SC, Gaschler F, Brehm 5, et al: Endothelinreceptor antagonists in uremic cardiomyopathy. J Cardiovasc Pharmacol 36:5348-5350, 2000 (suppl) 137. Nabokov AV, Amalll K, Wessels 5, et al: Endothelin receptor antagonists influence cardiovascular morphology in uremic rats. Kidney lnt 55:512-519, 1999
ata generated from the United States ReD nal Data System (USRDS) database from through reveal higher death rates in
1996 1998 adults and children on maintenance dialysis, when compared with those with kidney transplants, irrespective of the cause for death. About 25% of the deaths in children on chronic dialysis are caused by cardiovascular causes and include such problems as cardiac arrest, cardiomyopathy, cardiac arrhythmia, acute myocardial infarction, and valvular heart disease.! Cardiovascular death rates were 9 times more common in children on peritoneal dialysis (9.1/1000 patient years at risk) and 7 times more common in children on hemodialysis (7.4/1000 patient years at risk), compared with pediatric kidney transplant recipients (1.0/1000 patient years at risk).! The cardiac morbidity and mortality of pediatric end-stage renal disease (ESRD) patients is a From the Division of Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, MN; and the Division of Nephrology, Department of Pediatrics, Northwestern University Medical School and Children's Memorial Center, Chicago,IL. Supported in part by grants HL53918 from the National Heart, Lung and Blood Institute and DK49362 from the National Institute of Diabetes, Digestive and Kidney Diseases. Address correspondence to Blanche Chavers, MD, University of Minnesota, Department of Pediatrics, Division of Pediatric Nephrology, 420 Delaware Street SE, MMC 491, Minneapolis, MN 55455. © 2001 by the National Kidney Foundation, Inc. 1073-4449/01/0803-0005$35.00/0 doi:10.1053/jarr.2001.26355
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relatively unexplored area. Multicenter, prospective, clinical studies have not systematically investigated the burden of cardiovascular disease (CVD) in pediatric chronic dialysis patients. Even less clear is the optimal therapeutic approach for pediatric patients with manifest CVD. Table 1 lists cardiovascular abnormalities reported in children on chronic dialysis. 2 - 9 The cardiovascular abnormalities in dialysis patients reflect loss of compliance of the myocardium and the peripheral vessels and fibrotic and atherosclerotic changes in the vascular tree. Problems that are commonly observed in dialysis patients include anemia, chronic volume overload, hypertension, hyperlipidemia, left ventricular hypertrophy (LVH), hyperparathyroidism with vascular calcification, and hyperhomocysteinemia.!o A hallmark of CVD in dialysis patients is the rapid progression of atherosclerotic CVD (ASCVD), disproportionate to patient age. Numerous factors contribute to atheroscleroSiS,1l-13 including all of the risk factors mentioned previously. A critical component is the interaction of macrophages and oxidized lipids, suggesting to some that ASCVD is ultimately a manifestation of inflammation.!4 Lipid peroxidation occurs in the circulation or the subendothelial space, leading to the recruitment and activation of monocytes that phagocytose the oxidized lipid, creating foam cells. The local production of cytokines and the dysregulation of clotting lead to fibrosis and thrombosis, causing narrowing and stiff-
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Table 1. Cardiovascular Abnormalities in Pediatric Maintenance Dialysis Patients
Author (n)
Dialysis Type
Abnormality
% Abnormal
Morris2 (13)
12 PD/1 HD
Ulmer3 (11)
HD
Germain4 (13) Bosch5 (21) Johnston6 (10)
4PD/9HD 10PD/11 HD PD
Mitsnefes 7 (64) Goodman8 (39)
38 PD/26HD 21 PD/18 HD
Heart murmur Cardiomegaly on CXR Abnormal ECG Increase in cardiac index Interventricular septal hypertrophy Left ventricular hypertrophy Ventricular diastolic dysfunction Heart murmur Abnormal ECG Left ventricular hypertrophy Left ventricular dysfunction Arrhythmia Arrhythmia Interventricular septal hypertrophy Aortic root dilatation Left ventricular hypertrophy Left ventricular hypertrophy Abnormal ECG Coronary-artery calcification
82% 69% 100% 77% 92% 54% 55% 82% 45% 9% 73% 23% 57% 40% 40% 30% 75% 15% 36%
Abbreviations: PD, peritoneal dialysis; HD, hemodialysis; CXR, chest radiograph; ECG, electrocardiogram.
ening of the vasculature. Scarred tissue becomes less responsive to va so dilatory stimuli, exacerbating hypertension and increasing shear stress on the vessel wall. Thus, the triad of inflammation, reactive oxygen species, and fibrosis mediate end-organ damage in the dialysis patient.
Risk Factors in Maintenance Dialysis Anemia Anemia is a major complication of ESRD. Reported mechanisms include erythropoietin deficiency, uremic toxins, decreased erythrocyte life span, blood loss from the gastrointestinal tract and dialyzer, and iron and folate deficiency.1 S-16 Severe anemia leads to increased cardiac demand and an elevated cardiac index caused by decreased oxygen delivery to the tissues and decreased blood viscosity.17-19 A high cardiac output leads to LVH, left ventricular dilatation, and heart failure. 2,3,20-22 Recombinant human erythropoietin (rHuEPO) became available in the United States in 1989 for the clinical treatment of the anemia of chronic renal failure. 23 It has been shown to be safe and effective for the treatment of anemia in children on chronic dialysis.24-28 The recommended target hemoglobin level is 11 to 12 g/ dL in pediatric and adult
dialysis patients. 29,3o Recent data are not available on the percentage of chronic pediatric dialysis patients who have hemoglobin levels below the recommended target. Studies in small numbers of pediatric dialysis patients have shown improvement in cardiac function and a decrease in left ventricular size after partial correction of anemia with rHuEPO.21,31,32 Morris et aF1 showed a reduction in left ventricular end diastolic diameter and cardiac index in 7 children after 6 months of treatment with rHuEPO. After 12 months of treatment, a significant reduction was seen in the cardiothoracic ratio. 21 These results are similar to those published for adult dialysis patients after partial correction of anemia with rHuEPO.22,33-38 However, established concentric LVH in adults might not improve with the correction of anemia39; data on this issue are not yet available in children.
Hypertension Hypertension in childhood is defined as a repeated blood pressure gretaer than ninetyfifth percentile for age, sex, and height4° and is reportedly more common in children on hemodialysis (HD) than in those on peritoneal dialysis (PD).41-4S Baum et al42 reported that 56% of 16 children on HD were on antihypertensive agents, compared with 39% of 20 chil-
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dren on PD. Potter et a143 reported that 64% of 25 children on HD were on antihypertensive agents, comp.ared with 41 % of 51 children on PD. In contrast, Lingens et al,45 using ambulatory blood pressure monitoring, found that 70% of 17 children on PD were hypertensive, compared with 33% of 18 children on HD. Hypertension is a major cause of morbidity in pediatric dialysis patients and is associated with frequent hospitalizations. 46 The multiple mechanisms for the development of hypertension in dialysis patients include volume expansion, activation of the renin-angiotensin system, high cardiac output attributable to arteriovenous fistula, increased total peripheral resistance, endothelin-associated vasoconstriction, increased sympathetic nervous system activity, disordered nitric oxide metabolism, elevated calcium levels, and erythropoietin administration. 25,47-51 Chronic hypertension has been associated with the development of LVH, left ventricular dysfunction, cardiac failure, and ischemic heart disease. 2,3,6,7,22,52-55 In children, inter dialytic weight gain has been shown to correlate positively with elevated systolic blood pressure. 51 Prolonged or more frequent dialysis treatments might be required to manage hypervolemia in pediatric HD patients. Techniques that allow for continuous monitoring of intravascular volume during hemodialysis have been advocated for use in children. 56-58 A reduction in blood pressure to below the ninetieth to ninety-fifth percentile for age and gender is considered successful treatment of childhood hypertension. Antihypertensive medications, often in combination, are needed to control blood pressure in patients who remain hypertensive despite adequate control of volume overload. Classes of antihypertensive agents used in adults and children on maintenance dialysis are similar and consist of calcium channel blockers, angiotensin-converting enzyme inhibitors, beta blockers, and peripheral vasodilators. 59-62 Studies on the safety and efficacy of angiotensin II receptor blockers in children have not yet been published. Hyperlipidemia Hyperlipidemia is a risk factor for atherosclerotic CVD (ASCVD) in the general adult, di-
alysis, and transplant populations. 63-66 Abnormalities might include hypertriglyceridemia, hypercholesterolemia, elevated low-density lipoprotein (LDL), decreased high-density lipoprotein, or elevated lipoprotein (a). The prevalence of hyperlipidemia in pediatric dialysis patients is high and has been shown to persist over 2 years of follow-up.67-71 Broyer et a167 found elevated triglyceride and cholesterol levels to persist during a 24-month study of 15 PD patients; levels were higher in the younger patients, although the difference attributable to age did not achieve statistical significance. Similar findings were reported in larger studies by Scolnik68 and Querfeld. 69 Querfeld et a169 found that 90% of 68 pediatric PD patients had high triglyceride levels and 69% had high cholesterol levels at the initiation of dialysis. Levels remained elevated over the 2-year follow-up period in that study. Hyperlipidemia has been implicated in the pathogenesis of atherosclerosis. The earliest lesion of atherosclerosis is seen as a nonelevated yellow patch on the intimal surface of the vessel wall called a fatty streak.72 This phenomenon has been observed in pediatric HD and transplant patients. Pennisi et aF3 examined autopsy samples of material from the left coronary arteries of 12 children who died while on chronic HD or after a renal transplant. Of the 12 patients, 10 (83%) had increased collagenization of the intima when compared with age-matched controls. This finding was considered to represent fatty streaks, an early indication of coronary artery disease. Specific guidelines for managing hyperlipidemia in pediatric chronic dialysis patients have not been published, whereas general guidelines for managing hyperlipidemia in children recommend screening based on a family history of hyperlipidemia and CVD.74,75 Dietary modification is recommended as the first approach to treatment of hyperlipidemia in children over 2 years old. A multicenter, randomized, controlled trial of hyperlipidemia in 663 children (8 to 10 years old) showed that dietary fat intake could be safely lowered. Children with cholesterol levels between the eightieth and ninety-eighth percentiles for age and gender were assigned ran-
Maintenance Dialysis Risk Factors
domly to either a low-fat or a usual diet. Serum LDL-cholesterol levels were lower in the low-fat group at 3 years, compared with the control group?6 Supplementation with fish oil rich in omega-3-polyunsaturated fatty acids has been shown to reduce serum triglyceride levels in 7- to 8-year-old patients on chronic dialysis. 77 Fish oil reportedly works by reducing hepatic triglyceride production. Bile acid sequestrants (resins), which are effective cholesterol-lowering agents, are the only drugs approved for use in children with hyperlipidemia. Adequate dosing might be difficult because of gastrointestinal side effects such as constipation and bloating. Pill formulations might be more palatable to children than powder formulations. Agents such as niacin, probucol, gemfibrozil, and 3-hydroxy-3 methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors have not been approved by the Food and Drug Administration (FDA) for use in children76; however, the use of HMG-CoA reductase inhibitors has been reported in children.78 LVH LVH is an independent risk factor for cardiovascular morbidity and mortality in the general adult79,80 and adult dialysis populations.1O,81-83 Prevalence rates in adult dialysis patients range from 60% to 80%. LVH develops primarily as a consequence of chronic hemodynamic overload and stiffening of the arterial tree. 81 ,84 It can lead to ischemic heart disease, heart failure, left ventricular diastolic dysfunction, dialysis-associated hypotension, arrhythmias, or sudden death.1o,81,84 The incidence of LVH varies by diagnostic technique; echo cardiography is more sensitive than electrocardiography.79,85 However, echocardiography reportedly overestimates the incidence of LVH in dialysis patients, compared with magnetic resonance imaging. 86 Risk factors for LVH in adult dialysis patients include more advanced age, systolic hypertension, anemia, and interdialytic weight gain.10,20,22,34,53,54,81-84,87 Most studies of LVH in pediatric dialysis patients have involved small numbers of patients with prevalence rates ranging from 9% to 92%.3,6,7,21 In a large European study, LVH was present in 51% of 198 children on HD by echocardiography and in 38% of 188 children
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by electrocardiography.85 In children on PD, the values were 29% by echocardiography (n = 85) and 18% by electrocardiography (n = 74). However, the authors noted that in their study, 25% of children on HD and 34% of children on PD did not undergo echocardiography.85 Mitsnefes et aF also found a slightly higher incidence of LVH in children on HD (85% of 26), compared with PD (68% of 38). Risk factors for LVH in pediatric dialysis patients include anemia and hypertension. 3,7,21 The contribution of LVH to cardiac-associated mortality in pediatric ESRD is not known. Vascular Calcification Abnormal calcium-phosphorus metabolism is a risk factor for myocardial and vascular calcification in dialysis patients.8,88-94 Myocardial and vascular calcification might result in cardiac dysfunction, arrhythmia, and death. Goodman et al,8 using electron beam tomography, screened 39 chronic dialysis patients with a mean age 19 years. Of 16 patients 20 to 30 years old, 14 (87.5%) had coronary artery calcification. In contrast, none of the patients younger than 20 years old had detectable abnormalities. Coronary artery calcification correlated with more advanced age, longer duration of dialysis, high serum phosphorus levels, elevated calcium X phosphorus product, and a high daily intake of calcium salts. An elevated calcium X phosphorus product, with or without hyperphosphatemia, has been found in patients with calcification of the aortic and mitral valves,89,9o myocardial tissue,91,93 coronary arteries,8,93,94 and aorta. 94,95 The primary factors associated with calcification appear to be altered calcium-phosphorus metabolism in dialysis patients and secondary hyperparathyroidism with inadequate control of hyperphosphatemia. 88 However, the process of cardiac valve calcification does not represent simply the result of precipitation from an excessively high calcium X phosphorus product. Instead, it represents the net outcome of multiple, highly regulated cellular and biochemical events. Virchow96 first reported that histologic analysis of atherosclerotic plaques in nonuremic patients shows the presence of trabecular bone formation. Further, in an apparently reciprocal relationship, the same stimuli that can deplete bone cal-
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cium in chronic renal failure appear to enhance calcium deposition and bone formation in atherosclerotic plaques.97 Although the basis for this phenomenon is less well understood in uremia, it is known that excess vitamin D stimulates metastatic calcification, whereas parathyroidectomy is associated with delayed progression of vascular calcification. Thus, newer treatments for hyperparathyroidism and early identification of vascular calcification might prevent the development or progression of cardiovascular disease. Homocysteine Levels Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis in dialysis patients. 98-lOO Hyperhomocysteinemia results from alterations in methionine metabolism because of hereditary enzyme deficiencies, vitamin deficiencies (folate, B6 , Bd or kidney failure. Proposed pathogenic mechanisms include increased oxidant stress, endothelial cell damage, smooth muscle cell proliferation, and thrombosis formation. Elevated plasma homocysteine levels are present in as many as 97% of adult dialysis patients and correlate negatively with serum folate levels. 98-102 Elevated levels obtained after fasting or after a methionine-loading test are used for diagnosis and are defined as from greater than 13.5 to greater than 16 ILmol/L. Supplemental folate, even in the absence of folate deficiency, in doses ranging from 1 to 15 mg/ day, has reduced, but not normalized homocysteine levels in adult chronic dialysis patients.1 02-104 A reduction in homocysteine levels also has been reported in adult hemodialysis patients using superflux dialyzers.1 os Reference homocysteine levels have been published for children.106-108 In a United States study of 3,524 schoolchildren ages 13 and 14 years, nonfasting total serum homocysteine levels ranged from 0.1 to 25.7 ILmol/L (median, 4.9 ILmol/L).1 06 Levels were higher in boys, blacks, nonusers of multiple vitamins, and smokers. Also, levels were correlated inversely with serum levels of folic acid. Schroder et al102 reported hyperhomocysteinemia in 9 of 12 pediatric PD patients and 8 of 9 pediatric HD patients. All patients showed a reduction in homocysteine levels after folic acid
(2.5 mg/ d for 4 weeks). Similarly, Lilien et aP08 reported hyperhomocysteinemia in 92% of 12 children on HD. Large, randomized, controlled trials of vitamin (folate) use for treating hyperhomocysteinemia and modifying or preventing CVD have not been conducted in dialysis patients.
Modification of Vascular Function Data are lacking on the associations between inflammation, increased oxidative stress, and CVD for pediatric dialysis patients, although studies have been conducted in the adult dialysis populationl09-112 and in animal models. Inflammation As proposed by Ross,14 the macrophage might playa critical role in the pathogenesis of atherosclerosis. Thus, activation of the immune system could accelerate atherogenesis. Patients undergoing treatment for ESRD show increases in cytokine production and, as a marker for immune activation, elevated C-reactive protein, a predictor of atherosclerosis.1 13 Dialysis patients manifest increased advanced glycosylation end products (AGEs), increased acute phase reactants such as fibrinogen, and elevated serum amyloid. lI4 Hemodialysis could activate the immune system in 3 ways: increased complement activation, exposure to endotoxin, and the effects of direct contact of blood components with nonnative materials. lIS Another aspect of inflammation is abnormal coagulation. End-stage renal disease is associated with increased Factor VII, fibrinogen, plasmin-antiplasmin complexes, plasminogen activator inhibitor-I, and D-dimer.1 16 In addition, hyperhomocysteinemia is associated with increased atherothrombotic phenomena.1 17 Oxidation Although some studies have disagreed,118 most investigators report that reactive oxygen metabolites, the generation of which is critical for lipid peroxidation, are elevated in dialysis patients. The elevation is most clear in hemodialysis, with intermediate elevations in peritoneal dialysis. Reactive oxygen species are not significantly above normal in patients
Maintenance Dialysis Risk Factors
with chronic renal failure before starting dialysis. Although this association could reflect disease severity, it .likely represents an effect of treatment modality.1 19 Conversely, antioxidant levels, including those of lycopene, delta tocopherol, gamma tocopherol and retinol are decreased in hemodialysis patients relative to controls.120 Increased AGEs also suggest an oxidative environment. 121 Thus, dialysis (particularly hemodialysis) could contribute significantly to accelerated atherosclerosis in uremic patients. Vascular Reactivity and Fibrosis Several groups have reported that patients with ESRD manifest endothelial dysfunction, with impaired nitric oxide synthase regulation.122 Poor vascular reactivity also might be reflected in decreased cardiac f3-adrenergic receptor function, found in humans and rats with chronic uremia.1 23 One group has suggested that abnormal serotonin release from activated platelets also impairs vasodilatation124; however, consistent with fibrotic atherogenesis, uremic patients have an increased ratio of intimal to medial vessel wall thickness. 125 This observation suggests that decreased compliance is another cause of a decreased response to vasodilators.122,126 Thus, fibrous thickening of the vascular wall might play an important role. An interesting consideration is the potential role of hyperparathyroidism in this process.127 Hyperparathyroidism and excess vitamin D are associated with progressive aortic stenosis in adult patients. 128 Experimental studies support a role for parathyroid hormone in vascular fibrogenesis. Rats with subtotal nephrectomy in whom eucalcemia was maintained received exogenous PTH. Elevated levels of the hormone were re-
quired for cardiac wall thickening to occur.1 29 In contrast, hypertension alone was insufficient to cause cardiac wall fibrosis. 130 Therapeutic Implications Some of these changes are potentially amenable to therapy, although most such approaches should be considered experimental or theoretical. Hyperhomocysteinemia may be treated with pyridoxine and folic acid.1 31 No antiinflammatory agents have been identified as having salient effects on atherogenesis, whether from uremia or other causes. Recent work suggests that vitamin E supplementation or use of vitamin E-modified dialyzers might decrease oxidant stress and thereby reduce the incidence of CVD in adult dialysis patients. In a multicenter, randomized, placebocontrolled trial of adult HD patients with known CVD, Boaz et aP32 found that daily oral supplementation with 800 IU of vitamin E reduced the incidence of myocardial infarction and other CVD endpoints. Galli et aP33 found that vitamin E-modified dialyzers also could be an effective form of vitamin E supplementation and antioxidant defense. Similar studies have not been reported for pediatric dialysis patients. Several treatments might be suggested for fibrogenesis. Data after vasoconstrictive cardiomyopathy in rats 134 or chronic congestive heart failure in humans 135 suggest that angiotensin-converting enzyme inhibitors might be effective in reversing or slowing the progression of cardiac or vascular fibrosis. Similar studies are not available in uremic children. Endothelin receptor antagonists have been found to be effective in preventing cardiac fibrosis in uremic rats,136 even in normoten-
Table 2. Risk Factors and Possible Interventions for Cardiovascular Disease in Pediatric Maintenance Dialysis Patients
Risk Factor Anemia Hypertension Hyperlipidemia Abnormal calcium-phosphorus metabolism Hyperhomocysteinemia Left ventricular hypertrophy
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Possible Intervention Erythropoietin, iron supplementation Volume control, salt restriction, antihypertensive agents to reduce blood pressure to <90th percentile Dietary modification, ? lipid-lowering agents Phosphorus restriction, Ca X P product < 60, phosphatebinding agents Folate supplementation, ?B 6 , ?B12 Antihypertensive agents, erythropoietin
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sive animals; an effect on blood pressure was not needed.137
7.
Vision for the Future Although the adverse impact of CVD risk factors is more commonly seen in adulthood, many risk factors might appear first in childhood. Some of these risk factors are potentially reversible (Table 2). The alarming increase in CVD in children on dialysis clearly requires attention; however, a successful strategy for addressing CVD in pediatric dialysis patients requires additional information, including (1) epidemiologic studies of CVD prevalence and risk factors, (2) development of guidelines for screening and treatment of at-risk children, (3) studies on effective treatment of modifiable risk factors, and (4) studies on the pharmacokinetics, safety, and efficacy of statin use in children. A CVD checklist should be incorporated into the routine monitoring of pediatric dialysis patients to enhance the likelihood that all of us will begin to focus on the prevention, early detection, and treatment of CVD in children who require renal replacement therapy.
Acknowledgment The authors thank Mary Knatterud for editorial assistance.
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