Prevention and Treatment of Cardiovascular Complications in Children Undergoing Dialysis

Cardiovascular Mortality in Children on Maintenance Dialysis

Reports from international registries since 2000 have confirmed, that like in adults, cardiovascular disease (CVD) is the leading cause of death in children with end-stage renal disease (ESRD) and young adults with childhood onset of CKD. There has been some improvement in mortality rates; however, it still remains about 30 times higher than in the general pediatric population. Not surprisingly, recently updated American Heart Association guidelines for cardiovascular (CV) risk reduction in high-risk pediatric patients continue to stratify pediatric patients with ESRD in the “highest risk” category for the development of CVD.

Of the specific causes of CV deaths, cardiac arrest is the most common. These causes are different from those of adults. In adults, coronary artery disease and congestive heart failure due to cardiomyopathy are two leading causes of mortality from CVD. The mortality from these causes is extremely low in children and adults younger than 30 years of age. The high rate of sudden death in children, especially in infants with ESRD, is poorly understood and warrants further investigation. The risk factors and pathogenic mechanisms leading to CVD in adults who had the onset of chronic kidney disease (CKD) in childhood are better understood than are those producing cardiac morbidity and mortality in children. The recent study by Modi et al. confirmed that diabetes, coronary artery disease, and heart failure were notable risk factors for CV-related mortality in young adults with childhood onset of ESRD. This chapter will focus on the prevention of the “classic” form of CVD as seen in adults who developed CKD in childhood.

Development of Cardiovascular Disease in Children with Chronic Kidney Disease

There are two groups of risk factors responsible for accelerated CVD in adults with ESRD. First, compared to the nonuremic population, there is an overrepresentation of classical risk factors, e.g., diabetes, hypertension, and hyperlipidemia. A majority of the adults who develop ESRD do so as a complication of diabetes or generalized atherosclerosis. Often, cardiac disease antedates the onset of CKD in these patients. Second, there are numerous uremia-related risk factors, such as dyslipidemia, anemia, inflammation, infection, abnormal calcium-phosphorus metabolism, and oxidative stress, that may singly or in concert, trigger the development of CVD. Many of the same risk factors are present in high frequency in children on dialysis, making them extremely susceptible to CVD.

There are two parallel processes involved in the development of CVD in children with ESRD. The first is uremic cardiomyopathy. It is initially manifest by disorders of the left ventricle (LV), which lead to adoptive LV remodeling. Two types of LV remodeling are recognized. Concentric LV hypertrophy (LVH) results primarily from pressure overload, as occurs with hypertension. Eccentric LVH has been related primarily to volume overload as frequently seen in patients on dialysis or with severe anemia. It is likely that the effects of hemodynamic overload on the LV are augmented by other nonhemodynamic causes such as high levels of fibroblast growth factor 23 (FGF23), sympathetic hyperactivity, systemic inflammation, and local production of angiotensin II. With time, a maladaptive phase of LVH develops, characterized by decreased capillary density, decreased coronary reserve and subendocardial perfusion, a tendency to arrhythmia, and the development of myocardial fibrosis. All this leads to myocyte death and, finally, to diastolic and systolic dysfunction. Symptomatic cardiomyopathy is very rare in children, but early abnormalities of cardiac structure and function can be seen frequently. LVH develops when CKD is mild or moderate in children and progresses as renal function deteriorates. LVH is very common (52%–75%) during long-term dialysis. Both concentric and eccentric geometric patterns of LVH are present in these patients, suggesting that, as in adults with ESRD, the mechanism of LVH in advanced CKD in children is volume and pressure overload. LVH is prevalent in both children on hemodialysis and peritoneal dialysis. Small retrospective studies suggest that with good blood pressure (BP) and anemia control, LVH will regress in young patients on dialysis. In contrast to adults, with whom systolic dysfunction is frequently associated with early cardiac failure and decreased survival, in children, systolic LV function is usually preserved. On the other hand, these children may develop LV diastolic dysfunction, often the initial manifestation of abnormal cardiac function. Small studies also indicate that, like in adults, myocardial stunning can be present in children indicating decreased perfusion during a dialysis session.

The second process involves accelerated vascular injury, which manifests by arterial hypertrophy and stiffness. This leads to arterio- and atherosclerosis. Children on dialysis have a high prevalence of asymptomatic vascular disease, as demonstrated by abnormal carotid intima-medial thickness (IMT), diminished arterial wall compliance, and coronary artery calcification. This eventually leads to symptomatic (ischemic) coronary artery disease in young adults with childhood onset of ESRD. In ESRD patients, a variety of factors have been associated with the development of atherosclerosis. Many of these factors are similar to those involved in the development of cardiac hypertrophy and include hypertension, dyslipidemia, abnormal calcium-phosphorus metabolism, chronic inflammation, and others.

Evaluation and Treatment Recommendations

The overall strategy in prevention of CV complications in children with ESRD is avoidance of long-term dialysis. The goal is to prevent development and delay the progression of cardiomyopathy and atherosclerosis. Even though kidney transplantation poses continuous CV risk (hypertension, hyperlipidemia, allograft dysfunction), it eliminates many uremia-related risks, reduces risk of cardiac death by approximately 80%, and prolongs life span by 20–30 years. A recent study showed that graft failure after the first kidney transplant was associated with almost five times higher mortality rate as compared to children with a functioning graft. Having maintenance dialysis even for a few months before a transplant was also associated with worse survival in this study. Thus, preemptive kidney transplantation should be the ultimate goal to minimize CV morbidity and mortality. Recent pediatric studies, like in adults, indicate that initiation of dialysis at a relatively high (> 10–12 mL/min/1.73 m ² ) estimated glomerular filtration rate (eGFR) was associated with worse survival when compared to initiation at lower eGFR. Delayed initiation of dialysis, if this can be safely achieved, may be beneficial by postponing exposure to the psychological and physical burdens that are associated with chronic dialysis therapy, and especially important in this regard is the progression of CVD in children on dialysis. While CV risk factors and subclinical cardiac and vascular abnormalities are present in children prior to dialysis, CVD quickly accelerates after dialysis initiation. Thus, delaying initiation of dialysis for a few months might prevent the development or progression of CVD. For those patients who must have long-term dialysis, the strategy is directly linked to the achievement of adequate dialysis outcomes, which include aggressive monitoring and management of hypertension, dyslipidemia, calcium-phosphorus metabolism, anemia, nutrition, systemic inflammation, and other dialysis complications.