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Salusky Abbreviations Introduction 1,25D ADHR Children with chronic kidney disease (CKD), especially those on dialysis, have a tenfold increase of cardiovascular (CV) morbidity and mortality, due to a unique combination of traditional and uremia-related risk factors, especially disturbances of mineral and bone metabolism parameters [1] Pediatric CKD patients usually not present with the traditional risk factors for cardiovascular disease (CVD); however, despite our current therapies, CVD remains the leading cause of morbidity and mortality in this patient population [1] The “tip of the iceberg” of these complications is multifactorial, and multiple factors have been identified such as abnormalities in bone and mineral metabolism, resistance to growth hormone (GH), modifications of the GH-insulin-like growth factor type (IGF1) axis, hypogonadism, malnutrition, and drug toxicity (corticosteroids) [2] Not only these complications impact overall quality of life through their effects on both physical and mental well-being in children with CKD, but alterations in mineral metabolism and bone disease also contribute to a significant decrease in life expectancy Therefore, due to the complex interplay between bone disease, mineral metabolism, and cardiovascular disease in patients with CKD, a new definition of renal osteodystrophy (ROD) was proposed: indeed ROD is defined now as a systemic disorder of chronic kidney disease mineral and bone disorder (CKD-MBD) characterized by 1,25-Dihydroxyvitamin D Autosomal dominant hypophosphatemic rickets ALP Alkaline phosphatase CKD Chronic kidney disease CKD-MBD Chronic kidney disease/mineral and bone disorders CV Cardiovascular CVD Cardiovascular disease DXA Dual X-ray absorptiometry ESRD End-stage renal disease FGF23 Fibroblast growth factor 23 GFR Glomerular filtration rate HR-pQCT High-resolution peripheral quantitative computed tomography PTH Parathyroid hormone ROD Renal osteodystrophy J Bacchetta (*) Pediatric Nephrology, Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases and Rare Diseases of Calcium and Phosphate Metabolism, Hôpital Femme Mère Enfant, Bron, France e-mail: justine.bacchetta@chu-lyon.fr I B Salusky Division of Pediatrics Nephrology, Department of Pediatrics, UCLA Mattel Children’s Hospital, Los Angeles, CA, USA © Springer Nature Switzerland AG 2021 B A Warady et al (eds.), Pediatric Dialysis, https://doi.org/10.1007/978-3-030-66861-7_29 541 J Bacchetta and I B Salusky 542 Table 29.1 The spectrum of renal osteodystrophy according to the TMV classification, adapted from [3] Osteomalacia (OM) Adynamic bone (AD) Mild hyperparathyroid-related bone disease (HPT) Mixed uremic osteodystrophy (MUO) Osteitis fibrosa (OF) Turnover Low Low Mild High High one or a combination of the following abnormalities [3, 4]: (1) abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; (2) abnormalities in bone histology, linear growth, or strength; and (3) vascular or other soft tissue calcification The term ROD refers only to the specific abnormalities of bone diagnosed by bone histomorphometry using three main criteria, turnover, mineralization, and volume (TMV classification), as illustrated in Table 29.1 The impact of CKDMBD in children may occur early in the course of CKD and is characterized by hormonal (PTH, 1,25D, and fibroblast growth factor 23, FGF23) and biochemical (serum calcium and phosphorus levels) abnormalities, while delayed complications (e.g., growth retardation, bone deformities, fractures, vascular calcifications, increased morbidity and mortality) may also occur [3].The bone and growth long-term consequences of CKD have been highlighted in a cohort of 249 young Dutch adults with onset of end-stage renal failure before the age of 14 years: in this cohort, 61% of patients had severe growth retardation, 37% severe bone disease (as defined by at least one of the following conditions: deforming bone abnormalities, chronic pain related to the skeletal system, disabling bone abnormalities, aseptic bone necrosis, and low- trauma fractures), and 18% disabilities resulting from bone impairment [5] More recently, a significantly increased risk of fractures was demonstrated in the pediatric North American CKiD cohort, evaluating 537 children with CKD at a median age at inclusion of 11 years At baseline, 16% of them had a history of fractures, and after a median follow-up of 3.9 years, 43 boys and 24 girls experienced fractures, corresponding to a fracture risk two- to threefold higher than in general populations [6] Moreover, risk factors were Tanner stage IV/V, decreased height Z-score, Mineralization Abnormal Normal Normal Abnormal Normal Volume Low to normal Low to normal Normal to high Normal High walking difficulty, and increased PTH levels In contrast, the only protective factor was the use of phosphate binders, mainly calcium-based binders [6] Evidence of vascular calcifications has been demonstrated in children and young adult dialysis patients with ESRD therapy initiated in childhood [7, 8] Our understanding of the relationship between bone and vessels in CKD remains scarce Associations between arterial lesions (atherosclerosis and arterial calcifications) and bone impairment (osteoporosis and abnormal bone activity) are described, usually following the rule “The better the bone, the better the vessels,” at least in adults [9, 10]; however, things are not that clear in pediatric CKD, and using absorptiometry (DXA) and even high-resolution peripheral quantitative computed tomography (HR-pQCT), opposite results were reported [11, 12].The aim of this review is therefore to provide an overview of our current understanding of the abnormalities of bone and mineral metabolism associated with CKD in children undergoing maintenance dialysis, notably in terms of diagnosis and management hanges in Mineral Metabolism C with Progressive CKD CKD-MBD pathogenesis involves a complex interplay among the kidney, bone, and parathyroid glands As functional nephrons are lost and GFR declines, a cascade of maladaptive events develops that result in bone disease, extra-skeletal calcification, and adverse cardiovascular outcomes Different factors have been implicated in the pathogenesis of this maladaptive response, but the primary trigger remains to be defined In the 29 The Management of CKD-MBD in Pediatric Dialysis Patients early stages of CKD, FGF23 levels increase, while phosphate, calcium, and PTH levels remain within normal ranges [13] With CKD progression, there are increase in phosphate levels, increased levels of FGF23 and PTH, progressive decline in 1,25D levels in order to lessen enteral phosphate absorption, and decreased ionized calcium levels via increased binding Elevated FGF23 levels further decrease 1,25D levels via renal 1α-hydroxylase suppression and 24-hydroxylase induction Decreased 1,25D levels reduce intestinal calcium absorption, and low 1,25D and low ionized calcium both further increase PTH levels, resulting in secondary hyperparathyroidism, as summarized in Fig. 29.1 [14] Since bone consists primarily of calcium and phosphorus, in the form of hydroxyapatite, it is not surprising that alterations in mineral metabolism, as occur with progressive CKD, lead to bone disease However, all these biochemical alterations not completely explain CKD- 543 MBD. In 2000, a novel hormone negatively regulating phosphate, 1,25D, and PTH has been identified, FGF23, completely modifying our view of CKD-MBD [15–17] Indeed, the earliest biochemical abnormality in CKD is an increase in circulating FGF23 levels [13, 16] FGF23, in conjunction with its co- receptor, Klotho, activates FGF receptor (FGFR1) and acts on the kidney to induce renal phosphate wasting and to suppress renal 1α-hydroxylase activity [18–20] FGF23 also acts on the parathyroid gland and may play a role in suppressing parathyroid hormone (PTH) levels [21] FGF23 is stimulated by phosphate and 1,25(OH)2vitamin D, and, in both adults and children, FGF23 increases as GFR decreases, with elevations in circulating and bone levels occurring in very early stages of CKD, prior to any apparent alterations in circulating mineral content [22] This increase could be explained by different factors, including a decreased renal 1-25 vitamin D Phosphate Calcium FGF23 / Klotho PTH Stimulating effect / Inhibiting effect Fig 29.1 Overview of normal phosphate/calcium metabolism Phosphate and calcium are mainly stored in bone, but the gut and the kidneys have a key role in their homeostasis Three hormones are crucial to maintain calcium and phosphate within the normal range: 1,25-dihydroxyvitamin D (1,25D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) Green lines correspond to a stimulating effect Red lines correspond to an inhibitory effect J Bacchetta and I B Salusky 544 clearance of FGF23, a compensatory mechanism to excrete an increased phosphate load, a response to treatment with active vitamin D analogs, and/ or a compensatory mechanism to the loss of the kidney-secreted Klotho protein However, the initial factor that triggers FGF23 production remains to be defined Data from CKiD nevertheless argue against the first hypothesis, since at the very early stages of pediatric CKD, circulation and bone FGF23 levels are already increased, whereas phosphate SDS are significantly decreased [13] Although these increased circulating levels of FGF23 in CKD patients consist almost exclusively of the intact, active form of the molecule, it is not clear whether the biological effects of FGF23 are increased or decreased in the context of decreased kidney function Indeed, decreased expression of FGFR1 and Klotho in parathyroid cells from dialysis patients and a resistance to the suppressive effects of FGF23 on PTH in uremic rats suggest that FGF23 signaling to the parathyroid glands is downregulated in CKD and may explain, at least in part, the refractory secondary hyperparathyroidism observed in CKD patients Over the last decade, the extra-skeletal and systemic effects of FGF23 have been well characterized in adults and children, highlighting a global “negative” role of FGF23 in global health [14], notably on the cardiovascular, immune, and central nervous systems, as illustrated in Fig. 29.2 The first “off-target” effect of FGF23 to be described was demonstrated on cardiomyocytes [23] This seminal paper was a milestone in the understanding of FGF23 physiology since it was the first time that a Klotho-independent effect of FGF23 was demonstrated, with different downstream phosphorylation pathways, mainly the cal- Heart & Cardiomyocytes Kidney Saito, J Biol Chem 2003 Andrukhova, EMBO 2014 Faul, JCI 2011; Leifheit-Nestler NDT 2018 Hippocampal cells and CNS Parathyroid Hensel, J Neurochem 2016 Silver, PN 2010 Olauson Plos One 2013 Hematopoiesis FGF23 Hanudel AmJPhysiol2016, NDT 2018 Immune system Hepatocytes Bacchetta, JBMR 2012 Chonchol, JASN 2015 & JASN 2016 Singh Kidney Int 2016 Bone Cartilage Kawai, JBC 2013 Wang JBMR 2008, Wesseling Perry JCEM 2009, Allard CTI 2015 Dentoalveolar complex Chu, Anat Rec 2010 Fig 29.2 Systemic effects of FGF23, adapted from [14] Besides its “classical” effects on phosphate, calcium, PTH, and vitamin D metabolism, the knowledge in FGF23 physiology has dramatically improved recently Complex regulations between FGF23 and all these systems have been described; the relevant papers are referenced on the figure, but this list is not exhaustive ... however, despite our current therapies, CVD remains the leading cause of morbidity and mortality in this patient population [1] The “tip of the iceberg” of these complications is multifactorial, and... of 249 young Dutch adults with onset of end-stage renal failure before the age of 14 years: in this cohort, 61% of patients had severe growth retardation, 37% severe bone disease (as defined... following the rule “The better the bone, the better the vessels,” at least in adults [9, 10]; however, things are not that clear in pediatric CKD, and using absorptiometry (DXA) and even high-resolution