569 tion is common in children with CKD, affecting up to 40% of pediatric HD patients Using mea surements of midwall shortening fraction (mwSF), similar systolic function abnormalities also have been[.]
30 The Cardiovascular Status of Pediatric Dialysis Patients tion is common in children with CKD, affecting up to 40% of pediatric HD patients Using measurements of midwall shortening fraction (mwSF), similar systolic function abnormalities also have been identified in early CKD, albeit at lower frequency [96] The mwSF is thought to be a more accurate marker of systolic function than eSF, particularly in those patients with LVH, as eSF tends to overestimate systolic function in this group One of relatively new markers of subclinical myocardial dysfunction is abnormal LV systolic strain [97] It is considered to be an early predictor of LV dysfunction [98] In the 4C study of children with advanced CKD in Europe, LV strain was assessed by echocardiography [99] While there was no difference in LV ejection fraction (EF) between CKD patients and healthy controls, children with CKD were found to have a higher prevalence of reduced global circumferential strain components [99] Rumman et al using echocardiography, also showed global longitudinal strain (GLS) to be lower in dialysis patients compared to CKD patients [100] These patients were followed longitudinally and found to have improvement of their GLS to their pre- dialysis CKD levels [101] Cardiac MRI has recently been utilized in the assessment of CV structure and function in children with CKD. Malatesta-Muncher et al showed that children on maintenance dialysis had significantly lower circumferential strain than in children after transplantation; strain was inversely correlated with LVMI [102] Hothi et al assessed myocardial stunning in children during hemodialysis treatment [103] In their study, 11 of 12 patients developed myocardial stunning while maintaining LV EF throughout hemodialysis ascular Structure, Function, V and Coronary Artery Calcification (CAC) A number of cross-sectional observational studies in pediatric dialysis patients or young adult survivors of pediatric dialysis programs have described surrogate measures of vascular damage and sought to identify associated risk factors 569 Children provide a good opportunity to study uremic influences on the vasculature as they have fewer confounding pro-atherosclerotic risk factors such as diabetes and dyslipidemia that are major confounders in similar adult studies Since the initial study of CAC in pediatric patients on dialysis published in 2000 by Goodman et al [104], virtually all studies conducted in children on maintenance dialysis consistently have shown increased carotid artery IMT and increased arterial stiffness (e.g., increased PWV) Many of these studies also detected CAC. Key pediatric studies are shown in Table 30.2 Although all of the available pediatric studies are small, often single-center and cross-sectional, they show remarkably similar risk factors associated with cardiovascular damage A key risk factor highlighted by virtually all of the studies is the strong linear association between deteriorating vascular measures and time spent on dialysis [2, 25, 104, 107, 110, 113] Prolonged exposure to the uremic milieu with high, and often worsening Ca–P–PTH control, exposure to pro- inflammatory agents such as advanced glycation end-products and oxidative stress, and reduced levels of the circulating calcification inhibitors all contribute toward deleterious structural and functional changes in the vasculature To support this, vascular measures have consistently and significantly correlated with Ca, P [2, 25, 69, 78, 104, 107–110], and PTH levels [2, 78, 107, 110] The vascular changes have also correlated with medication dosages of calcium-based P binders and vitamin D compounds, suggesting that dysregulated mineral metabolism is central to the vasculopathy of CKD, and that these modifiable risk factors require careful monitoring and strict control from the earliest stages of CKD An increase in cIMT and PWV have been shown to begin even in the first decade of life in children on dialysis [78] and in pre-dialysis CKD stages 2–4 as well [25, 107, 114] The 4C study [17] determined the vascular phenotype in 737 children with advanced CKD: cIMT was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile; PWV was increased in 20.1% The office systolic BP was the single independent factor significantly associ- 570 ated with all surrogate markers of cardiovascular disease Importantly, although structural vascular changes are found in pre-dialysis patients, the vessel retains its normal compliance and distensibility properties as compared to controls [107] However, with progressive duration and severity of uremic damage as found in dialysis patients, a further deterioration in cIMT coupled with increased vascular stiffness occurs Interestingly, an increase in the vessel wall thickness or cIMT is coupled with a remodeling of the vessel such that an increase in the carotid artery lumen occurs, possibly to counter the stiffness or loss of compliance of the vessel [25] It may be this compensatory remodeling in the early stages of CKD and the more plastic vessels of children that protect them against the deleterious consequences of vascular damage Direct evidence of calcification in the coronary vessels has been shown in 15–20% of pediatric chronic dialysis patients [78, 110, 112, 115, 116] and correlates with many of the above listed risk factors However, despite the presence of these risk factors and of CAC, none of the patients in these studies had overt CVD None of the studies in children with CKD have reported the presence of intimal plaques in the cardiac or carotid arteries, and although ultrasound is not an accurate means of assessing intimal versus medial changes in the vessel wall, it appears that uremic vasculopathy, at least in children, is a predominantly medial process R Shroff and M M Mitsnefes Calcification progression on CT scan has also been shown by Civilibal et al., with the time- averaged serum Ca × P product and serum albumin levels predicting the final CAC score and change in CAC score, respectively [69] This suggests that in the pro-calcific and pro- inflammatory uremic milieu “calcium begets calcium,” so our efforts must be directed at the prevention of calcification starting in the earliest stages CKD. It is fascinating that in all studies, patients who did not have baseline calcification continued to remain free of calcification despite exposure to similar uremic conditions Importantly, the presence of CAC is strongly predictive of myocardial infarction, heart failure and stroke in adult pre-dialysis CKD patients [117], and it is an independent predictor of all-cause mortality, cardiovascular events, and cardiovascular mortality in adult dialysis patients [118] By ameliorating the uremic milieu, renal transplantation might intuitively be thought of as a procedure that might lead to a reversal of some of the cardiovascular damage from dialysis However, there is increasing evidence from adult studies to show that CVD remains a significant problem posttransplantation, a problem that may be driven by hypertension, obesity, and related risk factors and possibly by immunosuppressive agents Krmar et al have shown that there is no increase in cIMT following renal transplantation when there is good blood pressure control [119] As cIMT progressively increases with age, this can be interpreted as a regression in cIMT when hypertension is ameliorated after transplantation Progression of Vascular [120] Litwin et al have shown that cIMT thickCalcification Through Different ening and remodeling of the vessel wall begins Stages of CKD early in CKD and progress rapidly on dialysis, Despite a plethora of observational cross- correlating with the blood pressure and mean sectional studies, there are very few longitudinal serum phosphorus levels Successful transplantastudies that have followed children through pre- tion can improve the cIMT toward pre-dialysis dialysis–dialysis–transplantation phases and values, but cannot normalize it [113] described changes in vascular markers at different stages of uremia Calcification progresses rapidly in patients on dialysis as shown in a sys- Physiological Inhibitors of tematic follow-up study by Goodman et al [78, Calcification 104] When a repeat CT scan was performed after a mean interval of 20 months, the calcification Vascular calcification occurs in the majority of score almost doubled in the 10 patients who had patients with CKD, but as noted above, a subset of evidence of initial calcification [78, 104] patients not develop calcification despite expo- 30 The Cardiovascular Status of Pediatric Dialysis Patients sure to a similar uremic environment [63] There is now a growing body of evidence showing that calcification is a highly regulated cell-mediated process, involving a complex interplay of promoters and inhibitors of calcification Animal knockout models and human single-gene defects have confirmed the role of physiological inhibitors in regulating vascular calcification [121] Fetuin-A (α2-Heremans–Schmid protein) is a key circulating calcification inhibitor that contributes to ∼50% of the calcification inhibitory capacity of human plasma and walls off the nidus of calcification, thereby preventing further crystal growth Fetuin-A is a negative acute phase reactant, and in the pro-inflammatory dialysis milieu its production may be reduced [63] Several studies have reported that adults on dialysis have significantly lower fetuin-A levels than controls Interestingly, whereas a protective upregulation of fetuin-A has been reported in pediatric dialysis patients, with increasing dialysis vintage and in the associated pro-calcific and pro-inflammatory uremic milieu, fetuin-A levels are decreased [84] At the VSMC level, fetuin-A can inhibit apoptosis, enhance phagocytosis, and protect the smooth muscle cell from calcifying [84, 122] Another group has reported lower fetuin-A levels in pediatric transplant recipients, but did not find an association with vascular measures [123] An important local inhibitor of calcification, matrix Gla [γ-carboxyglutamic acid] protein (MGP), is expressed in the media of arteries where it acts as an inhibitor of Ca–P precipitation [97, 124] The γ-carboxylation of MGP is vitamin K dependent, and drugs such as warfarin may inhibit this process, resulting in the accumulation of inactive under-carboxylated MGP and ectopic calcification [84, 124] Osteoprotegerin and pyrophosphate are other potent calcification inhibitors that are shown to be perturbed in children with CKD [84] The importance of circulating calcification inhibitors was recently confirmed by studies using an in vitro test (T50 test) for the determination of calcification propensity in blood The T50 test quantifies the calcification inhibition of serum by treatment with supersaturated calcium and phosphate solutions, which 571 results in the formation of primary calciprotein particles that mainly contain fetuin [125] Calcification propensity was significantly associated with cardiovascular events in pre-dialysis CKD and hemodialysis patients [125, 126] In incident adult dialysis patients, OPG and fetuinA were significantly associated with all-cause and cardiovascular mortality during follow-up [127] While further longitudinal studies are required to fully characterize these circulating biomarkers in children, they may prove to be a useful and convenient measure of an individual patient’s susceptibility to vascular calcification he Role of Vitamin D T in Cardiovascular Health in CKD Virtually all studies in dialysis patients have reported the prevalence of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] deficiency to be on the order of 50–90% [128, 129], and have shown that deficiency begins early in the course of renal decline [129] CKD patients can have low 25(OH)D levels for several reasons: they may have less sunlight exposure, the endogenous synthesis of vitamin D in the skin is reduced in CKD, ingestion of foods that are natural sources of vitamin D may be diminished, and proteinuria may be accompanied by high urinary losses of vitamin D-binding protein [129] In addition, when the GFR falls to