Learning objectives: To review recent data on the epidemiology of CVD in children with CKD To understand the mechanisms of cardiovascular abnormalities in pediatric CKD To review recent advances in the diagnosis and clinical presentation of cardiovascular complications in children with CKD To outline current understanding in the strategies to prevent progression of CVD in children with CKD. Cardiovascular mortality and morbidity 1 2 3 4 5 6 6 7 8 9 6 6 10 Risk factors for cardiovascular disease 1 Table 1 Cardiovascular risk factors in chronic kidney disease in adults Traditional CKD-related Older age Decreased GFR White race Proteinuria Male gender Peripheral renin-angiotensin-aldosterone activity Hypertension Abnormal calcium and phosphorus ↑ LDL Cholesterol Dyslipidemia ↓ HDL Cholesterol Hypoalbuminemia Diabetes mellitus Hemodynamic overload Tobacco use Anemia Physical inactivity Thrombogenic factors Psychosocial stress Hyperhomocysteinemia Family history of CVD Oxidative stress LVH Chlamydia pneumoniae Obesity Chronic inflammation 11 14 15 18 19 21 22 24 25 26 27 29 30 31 32 33 34 35 36 37 38 39 40 41 42 2 Table 2 Prevalence of risk factors for CVD in children with CKD Risk factors a b c References Hypertension 48 52–75 63–81 a b c Dyslipidemia 25–53 33–87 55–84 a a, b c Anemia 48 40–67 32–64 a b c Hyperparathyroidism 32.6–43.7 58 – 43 Hyperhomocysteinemia  87–92 25–100 c b, c c b ↑ CRP  76 16 b c Hypoalbuminemia – 40–60 – b b b 60 Mechanisms of cardiovascular disease in chronic kidney disease 1 Fig. 1 Cardiovascular disease in chronic kidney disease  61 62 63 64 The second process involves vascular injury. Exposure to CV risk factors results in vascular changes, including atherosclerotic and arteriosclerotic processes and vascular calcification. 65 66 67 69 70 71 72 73 2 3 74 75 Spectrum of cardiovascular abnormalities in children with CKD Over the last decade, abnormalities of the LV such as LVH and LV dysfunction, abnormalities of the large arteries such as stiffness and increased intima-medial thickness (IMT) of the carotids, and calcification of the coronaries have been accepted as early markers of cardiomyopathy and atherosclerosis. They constitute strong independent predictors of cardiac morbidity and mortality both in the general population and in adults with CKD. In children and young adults with CKD, recent studies have proven that these abnormalities are also present and that risk factors for cardiac and vascular injury in children with CKD are similar to those for adults. Left ventricular hypertrophy 76 78 79 80 81 8 76 82 85 86 80 81 9 87 91 92 8 78 79 90 93 96 97 98 99 79 99 100 101 39 8 85 78 79 79 Left ventricular function 76 102 104 103 76 105 106 Arterial structure and compliance 107 108 109 110 3 111 112 113 114 115 116 54 117 Endothelial dysfunction as a marker of early atherosclerosis in children with CKD 118 119 120 122 Evaluation and treatment recommendations The overall strategy in the prevention of cardiovascular complications in children with CKD is avoidance of long-term dialysis. The goal is to prevent the development and delay the progression of cardiomyopathy and atherosclerosis. The identification of modifiable risk factors and markers of CVD and early intervention should be initiated at the time of mild-to-moderate renal insufficiency, prior to the need for dialysis. Even though kidney transplantation poses a continuous CV risk (hypertension, hyperlipidemia and allograft dysfunction), it eliminates many uremia-related risks, reduces the risk of cardiac death by approximately 80 percent and prolongs the life span by 20–30 years. Thus, kidney transplantation should be the ultimate goal to minimize cardiovascular morbidity and mortality in patients with advanced CKD. For those patients who must have long-term dialysis, the strategy is directly linked to achievement of optimal dialysis outcomes, which include aggressive monitoring and management of hypertension, dyslipidemia, calcium-phosphorus metabolism, anemia, nutrition, systemic inflammation and other dialysis complications. 42 123 15 124 2 15 For adolescents with stage 5 CKD and a level of LDL ≥130 mg/dl, K/DOQI recommends treatment to reduce LDL to <130 mg/dl. If LDL is <130 mg/dl, fasting triglycerides ≥200 mg/dl and non-HDL cholesterol (total cholesterol minus HDL) ≥160 mg/dl, treatment should be considered to reduce non-HDL cholesterol to <160 mg/dl. All children with dyslipidemia should follow the recommendations for therapeutic lifestyle changes (TLC), which include diet modification with a reduction in saturated fat intake and increase in fiber intake, and moderate physical activity. Adolescents should be counseled about avoiding smoking. Unfortunately, non-compliance with TLC is one of the major problems in the management of dyslipidemia in adolescents. Pediatric nephrologists must also recognize that appropriate caloric intake, including calories from fat, should be emphasized to avoid malnutrition and ensure normal growth and development, especially in young children. If LDL cholesterol is ≥160 mg/dl and non-HDL cholesterol ≥190 mg/dl, statin therapy is recommended in children older than 10 years. 2 2 42 There are no data available to make evidence-based recommendations on management of hyperhomocysteinemia, chronic inflammation or other potential CVD risk factors. Questions A 14-year-old African-American boy with ESRD secondary to FSGS has been treated with thrice-weekly hemodialysis for 1 year. His pre-dialysis BP is 132/85, hemoglobin is 9.8 g/dl, serum calcium is 10.6 g/dl, serum phosphorus is 8.2 g/dl and iPTH is 412 pg/ml. He is taking a calcium channel blocker to control his hypertension, erythropoietin and iron to control his anemia and calcium carbonate and a vitamin D IV preparation to control his renal bone disease. Which ONE of the following statements would be the BEST therapeutic intervention in this child to minimize the risk of future CV complications? Aggressive treatment of hypertension Maximize dialysis treatment to achieve dry weight Correction of anemia Kidney transplantation Reduction of Ca-P product The patient from the previous question was diagnosed with eccentric LVH. With regard to treatment of his LVH, which ONE of the following actions is MOST LIKELY to lead to reduction of LVH? Adding ACE inhibitor as a second antihypertensive agent Increase the dose of erythropoietin and assure appropriate iron status to treat anemia Achievement of dry weight Switch from hemodialysis to peritoneal dialysis Maximize treatment of secondary hyperparathyroidism The annual evaluation showed that this patient has LDL cholesterol of 170 mg/dl. You would like to start this patient on atorvastatin. With regard to the use of “statin” in this patient, which ONE of the following statements is correct? Statins are not approved by the United States Food and Drug Administration (USFDA) for use in children and adolescents Grapefruit is contraindicated The dose of atorvastatin should be reduced by 50% compared to dosage in adult patients on dialysis to prevent adverse effects on growth and development The target level for LDL cholesterol in children with CKD should be below 100 mg/dl Atorvastatin therapy will reduce mortality risk in this patient Which ONE of the following statements concerning development of cardiovascular complications in a child with CKD is NOT correct? Cardiovascular disease is the cause of mortality in approximately 25% of chronically dialyzed children Cardiac arrest is the most common cardiac cause of death in children with ESRD Cardiac and vascular remodeling might develop in children during early stages of CKD Correction of anemia reduces concentric LVH LVH is the most common cardiac abnormality in children on maintenance dialysis The patient described in the previous questions is at risk for development of vascular calcification. Which ONE of the following choices does NOT correctly describe the mechanisms of vascular calcification in dialyzed patients? Histo-anatomic variants of calcification include classic atherosclerotic (fibrotic) calcification related to disorders of lipid metabolism, medial arterial calcification, vascular calcifilaxis and cardiac valve calcification Increased Ca-P product and hyperphosphatemia are the key drivers of vascular calcification in young patients with CKD Inflammatory mechanisms are involved in mediating all stages of atherosclerosis including calcification Increased serum level of Fetuin-A promotes Ca-P ion product precipitation 2 3 d c b d d