575 The Need for More Frequent Dialysis Although mostly anecdotal in nature, an increas ing body of pediatric literature supports using intensified hemodialysis programs to improve patient outcome [30[.]
30 The Cardiovascular Status of Pediatric Dialysis Patients he Need for More Frequent T Dialysis Although mostly anecdotal in nature, an increasing body of pediatric literature supports using intensified hemodialysis programs to improve patient outcome [30, 146–148] Intensified hemodialysis includes different forms of frequent dialysis (such as short daily dialysis) or longer hours on dialysis (such as nocturnal dialysis at home or in center) in different combinations, as well as hemodiafiltration (HDF) The adult literature also supports the potential for improved outcomes with more frequent and intensified dialysis [149, 150] These outcomes include improvements in the following metrics: patient quality of life, phosphate balance, blood pressure, anemia, nutrition and growth, and cardiac indices as measured by echocardiography More frequent dialysis has the potential to result in decreased hospital admissions, increased patient adherence, and a decrease in vascular access complications Patients receiving more frequent home dialysis also have lower health-care costs [151, 152], but not all patients are willing or able to perform home-based therapy [153] HDF is a newer technique of dialysis that utilizes a combination of diffusive and convective solute transport through a highly permeable membrane [154–156], thereby achieving clearance of middle and large molecular weight solutes unlike conventional HD. In recent years, randomized trials in adults have shown that HDF is associated with improved cardiovascular and all-cause mortality compared to HD. A pooled analysis of four randomized trials in adult patients comparing HDF with conventional HD demonstrated a reduction in all-cause and cardiovascular mortality risk [157–159] In children, a short daily dialysis program combining in-center high- efficiency online hemodiafiltration (HDF) with growth hormone therapy has reported impressive catch up growth [30] Small observational studies also suggest that HDF improves cardiovascular function and inflammatory status [160, 161] In a substudy of the ongoing Hemodiafiltration, Heart and Height (3H) study [162], a switch from conventional HD to HDF resulted in significant 575 improvement in inflammation, antioxidant capacity, and endothelial risk profile within just 3 months [163], and keeping all other dialysis- related parameters constant The 3H study has shown that on fully adjusted analyses, the annualized changes in both cIMT-SDS and MAP-SDS were significantly lower in HDF compared to HD patients, largely due to improved fluid removal as well as clearance of middle molecular weight uremic toxins by HDF Patients on longer or more frequent HD programs have less stringent fluid or dietary restrictions, and a reduced medication burden [164], with some patients even requiring phosphate supplementation [165] BP control improves and EPO doses are often reduced [164] A nocturnal home hemodialysis program has been shown to improve the child’s quality of life, school attendance [153], and growth [166] In a crossover study of in-center nocturnal HD and HDF, further improvement of dialysis efficacy with HDF compared to HD was reported [167] Despite the many advantages of frequent / nocturnal HD, its use is limited to few pediatric patients and centers A recent online survey among pediatric nephrologists identified lack of adequate funding, shortage of staff, and to a lesser degree, lack of expertise and motivation as barriers [168] anagement of Key Modifiable Risk M Factors That Contribute to the Development and Progression of CVD in CKD Fluid overload with associated hypertension (see also Chap 31) and chronic mineral dysregulation are likely the key drivers of CVD in childhood CKD. The management of these and other important modifiable risk factors is discussed below Prevention and Treatment of Hypertension and LVH In the child on dialysis, the presence of hypertension, as discussed above, is primarily related to fluid overload Attainment of dry weight will 576 result in lowering (but not necessarily normalization) of blood pressure in the majority of patients Dry weight and dialysis prescription need to be frequently adapted to avoid fluid overload induced hypertension Bioelectrical impedance analysis [169] or assessment of the inferior vena cava diameter [170] may be helpful tools for the assessment of dry weight in combination with standard clinical measures Supportive measures aiming for a low extracellular volume, such as dietary salt restriction, low dialysate sodium content, restriction of fluid intake, and prolonged dialysis time have been shown to maintain normotension in 98% of adult patients [171] More frequent [30] or nocturnal dialysis [167, 172, 173] might also be helpful to maintain dry weight and normal blood pressure An appropriate target for clinical use may be an interdialytic blood pressure below the 90th percentile Long-term data on the effects of strict blood pressure control (e.g., ESCAPE trial target of 24-hour MAP 95 g/ BSA for girls [178] Chinali at al recently developed a simplified method to identify the presence of LVH in pediatric populations: a value of 45 g/ m2.16 was defined as the upper normal limit for LVM index [179] A utility of this index in children with CKD still needs to be determined a–P–PTH and Vitamin D C Management While most physicians now accept that high P levels have deleterious cardiovascular effects, there is much controversy over what “optimal” PTH levels should be “Optimal” PTH levels may be defined as levels that maintain normal bone turnover without increasing the risk of ectopic calcification Guidelines on the optimal levels of Ca, PO4, and PTH levels and all aspects of their control have been proposed by the K/DOQI and the European Paediatric Dialysis Working Group [180, 181] The European recommendations are more conservative and advise keeping PTH levels in the normal range until CKD stage 5, when two to three times the upper limit of normal is 30 The Cardiovascular Status of Pediatric Dialysis Patients recommended K/DOQI has set higher allowable targets of up to twice the upper limit of normal in CKD stage and three to five times the upper limit of normal in patients on dialysis The recently published KDIGO (Kidney Disease Improving Global Outcome) guidelines that are more rigorously evidence-based, suggest maintaining PTH levels at two to nine times the upper limit of normal, reflecting the lack of good clinical studies to inform an evidence base [145] Although dietary management may be adequate to control plasma phosphate in its early stages, most patients develop hyperphosphatasemia by CKD stages 3–4 and require the addition of a phosphate binder One interesting study has demonstrated that the use of any type of phosphate binder, even with phosphate levels in the normal range and therefore below levels currently recommended for phosphate binder use, is associated with decreased mortality in patients on HD [182] A normal diet contains around 800–1500 mg of phosphate, of which 50–70% is absorbed, depending on serum phosphate and vitamin D levels In the first instance in early CKD, dietary restriction may be sufficient to control plasma phosphate levels Dietary phosphate is principally found in protein-containing foods, dairy products in particular However, foods high in phosphate are also usually high in calcium and vitamin D, so that nutritional 25-hydroxyvitamin D [25(OH)D] and calcium deficiency are common in patients with CKD who maintain a phosphorus-restricted diet Phosphate control is a particular problem for patients on conventional thrice weekly HD because it is poorly removed by the dialysis process: most is removed in the first hour, and as the rate of movement out of cells is slow, little is removed when the normal range for phosphate is reached By 12 h post HD, levels are 80% of pre- dialysis values PD is equally inadequate at phosphate removal: ∼800 mg of phosphate is removed in a standard adult HD session (i.e., 2400 mg per week) and 300 mg per day in adults on PD (i.e., 2100 mg/week) In a diet containing ∼1000 mg of phosphate each day, ∼600 mg would be absorbed (and 400 mg would be excreted in the stool), requiring this amount to be bound or 577 cleared by dialysis Therefore, the absorption of around 300 mg of phosphate per day needs to be managed [183] Patients on dialysis are the group in whom calcium-containing phosphate binders can cause the most problems with hypercalcemia, because of the reduced ability to excrete calcium in the urine Use of calcium neutral dialysate (1.25 mmol/L) allows for prescription of larger doses of calcium Short daily or slow nocturnal HD is most effective for removing phosphate, to the point that some patients need phosphate supplementation [153] Phosphate binders are usually divided into calcium containing and non-calcium containing [183, 184] Calcium-containing preparations have been used the longest, but they have fallen out of favor because of their theoretical link with soft-tissue calcification [185] The fear of ectopic calcification with excess calcium intake has led to a switch to newer non-calcium-containing drugs Phosphate binders must be given with food and must not be given at the same time as iron preparations as they form insoluble compounds in the gut Dissociation of calcium carbonate is maximal below a pH of 5, and is therefore not as effective when given with H2-blockers or proton pump inhibitors Calcium acetate, however, has better solubility over a wider range of pH and has a greater binding capacity for the same elemental calcium content so that less calcium is absorbed Calcium absorption will also vary with plasma 1,25(OH)2D levels, being as low as 3% in deficiency to presumably higher than the expected normal range in patients who are prescribed activated vitamin D, when hypercalcemia may occur [183] Several new non-calcium-containing phosphate binders: magnesium carbonate, sevelamer hydrochloride, and lanthanum carbonate are now available [183, 184] Sevelamer, the most widely used in children, is a nonabsorbable polymer of allyamine hydrochloride that acts like an exchange resin [139] In addition to phosphate, sevelamer also binds bile salts, thereby exerting a beneficial effect on plasma total and low-density cholesterol, while at the same time binding fat- soluble vitamins The first report of the use of sevelamer in children appeared in 2003 [186] 578 Only two randomized controlled trials have examined phosphate-lowering therapy in children with CKD or on dialysis The first RCT examined biochemical end-points only and showed equivalent phosphate control with calcium acetate and sevelamer hydrochloride in an 8-week cross-over trial; phosphate control was similar but with fewer episodes of hypercalcemia in the sevelamer group, although acidosis was more common [187] In the second, 29 children were randomized to different combinations of phosphate binders and vitamin D analogs: bone biopsies suggested that the sevelamer group had reduced bone formation at 8-month follow-up, but patient numbers were too small for comparison Biochemical and histological abnormalities improved in both groups, but serum calcium levels were at the lower limit of the normal range in the sevelamer group Sevelamer may, in turn, increase the safety of treatment with activated vitamin D in patients with secondary hyperparathyroidism [188, 189] On the other hand, 20% of the sevelamer treated group needed calcium supplements [188], and the development of hypocalcaemia is as high as 24% in adult studies [190] Sevelamer carbonate (as opposed to sevelamer hydrochloride) does not cause metabolic acidosis; safety and efficacy were recently confirmed in a first multicenter study of hyperphosphatemic pediatric patients with CKD [191] Since hypercalcemia is frequent with calcium-containing binders, more studies in pediatric patients are needed to evaluate calcium-free preparations A recent study from CKiD in 537 children with pre- dialysis CKD reported that phosphate binder treatment (calcium based in 82%) was associated with decreased risk of incident fractures (HR 0.37, 95% CI 0.15–0.941), independent of age, sex, eGFR, and PTH levels [192] It has also been suggested that sevelamer can attenuate the progress of coronary and aortic calcification when compared to calcium-based phosphate binders [46] A recent review of 23 randomized trials in adults patients comparing sevelamer with calcium-based binders concluded that sevelamer attenuated the progression of coronary and aortic calcification, but was not associated with a significant difference in all-cause or R Shroff and M M Mitsnefes cardiovascular mortality [193] Several other calcium-free phosphate binders have been used in adult patients; however, a recent meta-analysis evaluating all currently available phosphate binders found no evidence that phosphate binder treatment reduces all-cause mortality compared to placebo in adults with CKD [194] However, a study of progression of CAC in 48 children over 2 years with CKD stage was not able to demonstrate an association between the type of phosphate binder and CAC [195] Likewise, the Dialysis Clinical Outcomes Revisited trial found no difference in the mortality rate at 2 years in just over 2000 adult HD patients randomized to either sevelamer or calcium-based binders, being 26% and 27%, respectively, despite the additional lipid-lowering benefits of sevelamer [196] Sevelamer is of potential benefit in patients who have a high dietary calcium intake However, children on a low-phosphate diet who are not receiving a calcium-containing phosphate binder probably not have a positive calcium balance when they are on maintenance dialysis Indeed, KDOQI recommends that in children exclusively on sevelamer, a higher dialysate calcium concentration and/or calcium supplementation with a calcium-containing phosphate binder should be considered [180] An interesting new approach to phosphorus management is the use of chewing gum to remove salivary phosphate between meals: Chitosan is a natural polymer that binds phosphate [197] Salivary phosphate levels may be as much as five times higher than plasma levels, and, in adults, there is between 350 and 400 mg of phosphate in saliva available to be bound [197] Treatment of CKD-MBD is especially difficult in the pediatric population due to the demands of a growing skeleton Undertreatment with vitamin D preparations carries the risk of rickets, diminished growth, uncontrolled hyperparathyroidism and high-turnover bone disease, while oversuppression of PTH may result in adynamic bone disease and – especially in combination with calcium-containing phosphate binders – vascular calcification, stiffening, and premature aging of arteries [198] Recent guidelines from KDIGO [52, 199], the National 30 The Cardiovascular Status of Pediatric Dialysis Patients Institute for Health and Care Excellence (NICE) [200], and the European Society for Pediatric Nephrology [132, 133] have therefore argued for the use of vitamin D preparations and calcium- based phosphate binders as first-line treatment in children, reserving non-calcium-based binders only for those with hypercalcemia Given the association of high PTH levels with reduced bone mineralization and vascular calcification, children are likely to need calcitriol or other active vitamin D analog therapy A recent Cochrane review has examined vitamin D therapy for bone disease in children with CKD stages 2–5 and on dialysis Bone disease, as assessed by changes in PTH levels, was improved by all vitamin D preparations regardless of preparation or route or frequency of administration [201] High PTH levels were independently associated with reduced tibial cortical BMD Z-scores [202] and are associated with coronary artery calcification in children on dialysis [52] The use of calcimimetics presents a paradigm shift in our management of mineral dysregulation in CKD [203–205] They allow for higher vitamin D usage and are overall thought to be safe in children [205]; however, there are few studies on long-term effects, particularly on the growing skeleton Parathyroidectomy may be required as a “last ditch” attempt in controlling the hypercalcemia of tertiary hyperparathyroidism when dietary and pharmacological interventions have failed [206] revention and Treatment of Lipid P Abnormalities General measures to prevent dyslipidemia in CKD patients include prevention or treatment of malnutrition, correction of metabolic acidosis, hyperparathyroidism, and anemia, all of which may contribute to dyslipidemia [37, 207, 208] In addition, referring to evidence from the general population, therapeutic life-style modification (diet, exercise, weight reduction) is recommended for adults and children with CKD-related dyslipidemia [209] However, the lipid-lowering effect of lifestyle modifications in CKD patients 579 is not very impressive Nonetheless, diet and physical exercise may exert beneficial effects on cardiovascular health independent of those on dyslipidemia In a study more than 25 years ago, dietary supplementation of fish oil effectively improved lipid profiles in a small cohort of children receiving renal replacement therapy [210] Statins effectively lower cholesterol and triglyceride levels in CKD patients by up to 30% [209] The 2013 K/DIGO guidelines recommend using statins in pre-dialysis CKD and after kidney transplantation in adults However, results from large randomized prospective trials in hemodialyzed adults (4D [211], AURORA [212], and SHARP [213]) [155] and subsequent metaanalyses [214, 215] showed no effect of statin therapy on overall patient mortality despite significant reduction of lipid levels Thus, K/DIGO guidelines not recommend statin use in adults on dialysis In children, statins are used reluctantly as the impact of HMG-CoA reductase inhibitors on nutrition, growth, and pubertal maturation has not been fully elucidated Thus, due to the very limited available data for children, including those with pre-dialysis CKD, dialysis, and after transplantation, K/DIGO guidelines not recommend the use of statins in children with CKD aged 10 years and postmenarchal girls) with severely elevated LDL-C or with multiple additional CV risk factors such as family history of premature coronary disease, diabetes, hypertension, smoking, and ESRD might be candidates for earlier statin use (lowest dose possible) [209] Although bile acid resins are safe to use in CKD children of all ages without dose adjustment, adherence to therapy is often poor due to a high incidence of adverse gastrointestinal side effects Supportive Treatment Several supportive measures for the optimal care of dialysis patients will also contribute to an improved cardiovascular outcome [216] This includes optimal nutrition (with tube feeding as necessary), prevention or correction of hypoalbu- 580 minemia, anemia, and metabolic acidosis A healthy lifestyle with adequate physical activity and avoidance of smoking should be encouraged The use of statins, folic acid, and antioxidants remains controversial as discussed above Conclusion As the management of children with CKD continues to improve, children and young adults with CKD no longer die from renal failure, but so from CVD. 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Guidelines for Cardiovascular Disease in Dialysis Patients [174] recommend screening echocardiography within 3 months of beginning maintenance dialysis, with follow-up examinations every 6 months for... populations: a value of 45 g/ m2.16 was defined as the upper normal limit for LVM index [179] A utility of this index in children with CKD still needs to be determined a–P–PTH and Vitamin D C Management... phosphate each day, ∼600 mg would be absorbed (and 400 mg would be excreted in the stool), requiring this amount to be bound or 577 cleared by dialysis Therefore, the absorption of around 300 mg of