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MONITORING CARDIOVASCULAR RISK FACTORS IN CHILDREN ON DIALYSIS

Great Ormond Street Hospital for Children NHS Trust, London, U.K.

Correspondence to: R. Shroff, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH U.K. ShrofR{at}gosh.nhs.uk

	ABSTRACT

TOP ABSTRACT MEASURING CARDIAC AND VASCULAR... RISK FACTORS FOR THE... SENSITIVITY OF CURRENTLY... IS THERE A NEED... REFERENCES

 

Cardiovascular disease (CVD) is the most common cause of death in patients with chronic kidney disease (CKD). Structural and functional vascular abnormalities and arterial calcification begin early in the course of renal decline and can be found even in children, contributing to their high mortality risk. Here, I discuss the burden of CVD in children with CKD; currently available methods of monitoring cardiac and vascular damage; the sensitivity of monitoring methods; and whether there is a need for regular monitoring in children with CKD.

KEY WORDS: Children; cardiovascular disease; monitoring.

A seminal paper by Foley et al. drew the attention of the medical community to the very high rate of cardiovascular (CV) deaths in patients on dialysis (1). The authors showed that the mortality of young adults on dialysis was approximately 700 times the age-related mortality in a general population and equivalent to that of an 80-year-old adult. Subsequently, several large national registries published similar findings (2–4). Data from the U.S. Renal Data System (4) show that 23% of all deaths among patients who received renal replacement therapy as children are from CV causes, and that deaths on hemodialysis (HD) are approximately twice as common as deaths on peritoneal dialysis (PD): 49% as compared with 22%. Arrhythmia was the most common (20%) cardiac event, followed by valvular heart disease (12%), cardiomyopathy (9%), and cardiac arrest (3%) (5). Thus, children with chronic kidney disease (CKD), particularly those on dialysis, have a significant burden of CV disease (CVD), although that disease is often clinically silent. Also, an independent and graded association between renal function and CV events and death has been shown (6), emphasizing the importance of recognizing and controlling modifiable risk factors from the earliest stages of CKD.

	MEASURING CARDIAC AND VASCULAR CHANGES IN CKD PATIENTS

TOP ABSTRACT MEASURING CARDIAC AND VASCULAR... RISK FACTORS FOR THE... SENSITIVITY OF CURRENTLY... IS THERE A NEED... REFERENCES

 
A number of surrogate measures of CV events are available:

• Echocardiography to measure the presence, type, and degree of left ventricular hypertrophy (LVH)
  
• High-resolution ultrasound to measure carotid artery intima media thickness (cIMT), indicating structural changes in the arterial tree
  
• Carotid distensibility and aortic and brachioradial pulse wave velocity (PWV) to measure stiffness or loss of compliance
  
• Endothelium-dependent and endothelium-independent flow-mediated dilatation multislice computed tomography to demonstrate direct evidence of calcification in the coronary arteries, cardiac valves, and aortic root
  

Importantly, none of these methods has been validated as a surrogate measure of CVD in children, and also, none can distinguish intimal from medial calcification.

Left ventricular hypertrophy develops early in the course of renal decline and is widely prevalent in children on dialysis, with 85% of HD and 65% of PD patients having eccentric LVH (7). Progression of LVH has been associated with anemia, systolic hypertension, and hyperparathyroidism (7).

In the extensive studies of cIMT in children with CKD, all studies have consistently shown that children on dialysis have a higher cIMT than do pre-dialysis CKD or transplant patients (8,9). These vascular changes begin as early as the first decade of life in children on dialysis (8,10–12) and are also present in pre-dialysis CKD stages 2 – 4 (8,11). Post-transplantation removal, or at least reduction, of uremic toxins can lead to a lower cIMT in transplanted patients as compared with those on dialysis (8,9). Interestingly, an increase in vessel wall thickness is coupled with a remodeling of the vessel so that an increase in the carotid artery lumen occurs, possibly to counter the stiffness or loss of compliance of the vessel (8).

Vascular stiffness as demonstrated by carotid distensibility (8) or PWV (12,13) is also increased in children on dialysis. In adult dialysis patients, aortic PWV is one of the strongest predictors of CV mortality, and although pediatric studies have no data to support the poor prognostic effects of increased vascular stiffness, an association between PWV and increased cIMT and greater left ventricular mass index has been shown (13).

An initial paper by Goodman et al. (14) suggested that calcification is not present before the age of 20 years, but subsequent studies (12,15) reported a 10% – 20% prevalence of coronary artery calcification (CAC) that was demonstrated in children as young as 5.6 years of age (12). Interestingly, the presence of CAC correlated with all of the parameters originally described by Goodman: dialysis vintage, dysregulated mineral metabolism, higher Ca intake from binders, and dose of activated vitamin D compounds (12,15). In young adult survivors of pediatric dialysis programs, CAC was present in 92% (3), suggesting that in the pro-calcific and proinflammatory uremic milieu "calcium begets calcium" (14).

	RISK FACTORS FOR THE DEVELOPMENT OF CV DISEASE

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Patients with CKD have a higher prevalence of both the "traditional" Framingham risk factors (such as dyslipidemia, hypertension, diabetes, smoking, and physical inactivity) and nontraditional risk factors that are both disease-related (for example, dysregulated mineral metabolism, anemia, hypertension, fluid overload, inflammation, and oxidative stress) and potentially treatment-related (for example, calcium overload from dialysate, calcium-based phosphate binders, and vitamin D therapy). Hypertension is possibly the single most important risk factor, accounting for LVH, vascular damage, and vascular remodeling (9); however, dysregulated mineral metabolism is largely responsible for the medial calcification typical of CKD.

Studies consistently report worsening cIMT and a higher prevalence of CAC with longer dialysis vintage, higher mean serum PO₄ and CaxPO₄ levels, and higher doses of Ca intake from PO₄ binders and vitamin D compounds (8,10–12,16), suggesting that dysregulated mineral metabolism is central to the vasculopathy of CKD. Our group found a strong linear correlation between mean serum PO₄ and cIMT in pediatric dialysis patients: every 1 mmol/L difference in serum PO₄ was associated with a 0.15-mm increase in cIMT (12). Also, children on dialysis with mean levels of parathyroid hormone (PTH) more than twice the upper limit of normal (>2ULN) were more likely to have thicker cIMT (p < 0.0001), stiffer vessels (p = 0.03), and increased calcification (p = 0.004) than were those with PTH levels below 2ULN (12). In the same study, we showed a significant positive correlation between cIMT, aortic stiffness, and the presence of cardiac calcification, suggesting that the arteriopathy of CKD is widespread and that carotid artery ultrasound—a cheap, easily available, highly reproducible, and noninvasive test to measure cIMT—may reliably substitute for other methods in the detection, monitoring, and prognostication of vascular damage in dialysis patients (12). In a subsequent study, we found that both low and high 1,25-dihydroxyvitamin D levels are associated with adverse morphology changes in large arteries, and that these changes may be mediated by the effects of 1,25(OH)₂D on Ca–PO₄ homeostasis and inflammation (17). Finally, a subset of patients with CKD do not develop calcification despite exposure to the same pro-calcific uremic milieu, and physiologic inhibitors of calcification, fetuin-A, osteoprotegerin, and matrix -carboxyglutamic acid protein have been associated with vascular stiffness and calcification (18).

	SENSITIVITY OF CURRENTLY AVAILABLE METHODS IN DETECTING EARLY CALCIFICATION

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Using vessels that are routinely removed at surgery from pre-dialysis and dialysis patients, our group quantified the vessel Ca load and correlated that load with clinical, biochemical, and vascular measures in the patients. We showed that calcification begins in the predialysis stage and rapidly accelerates on dialysis. However, the currently available clinical measures (cIMT, PWV, and CAC) were not sensitive enough to detect early Ca loading, implying that a normal or negative result from vascular measures must be interpreted with caution (19).

	IS THERE A NEED FOR REGULAR MONITORING OF CV RISK FACTORS?

TOP ABSTRACT MEASURING CARDIAC AND VASCULAR... RISK FACTORS FOR THE... SENSITIVITY OF CURRENTLY... IS THERE A NEED... REFERENCES

 
A number of surrogate markers of CVD are monitored in the course of routine clinical practice. These include Ca, PO₄, and PTH levels, hemoglobin, cholesterol, lipid parameters, and blood pressure. Serum creatinine may itself be considered a marker of CV risk, given the increasing risk of CVD with advancing CKD. Emerging data suggest a role for regular monitoring of vitamin D levels. The role of regular vascular measures such as cIMT in all CKD patients remains unclear, and until further longitudinal studies are available to inform this practice, I would recommend serial cIMT monitoring only for research purposes or in CKD patients at a high risk of CVD.

	REFERENCES

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16. Briese S, Wiesner S, Will JC, Lembcke A, Opgen–Rhein B, Nissel R, et al. Arterial and cardiac disease in young adults with childhood-onset end-stage renal disease—impact of calcium and vitamin D therapy. Nephrol Dial Transplant 2006;21 : 1906-14.[Abstract/Free Full Text]
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19. Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A, et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.2008; 118:1748 -57.

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