545 cineurin/NFAT pathway Faul et al demonstrated that high FGF23 levels were associated with left ventricular hypertrophy (LVH) in cohorts of adult patients with chronic kidney disease (CKD), and the[.]
29 The Management of CKD-MBD in Pediatric Dialysis Patients cineurin/NFAT pathway Faul et al demonstrated that high FGF23 levels were associated with left ventricular hypertrophy (LVH) in cohorts of adult patients with chronic kidney disease (CKD), and they highlighted hypertrophic and pro-fibrotic effects of FGF23 in rat cardiomyocytes [23] Since then, it has been demonstrated that the two MAPK and calcineurin/NFTA pathways may co-exist, for example, in the parathyroid glands: the MAPK pathway nevertheless remains the dominant pathway in this case [24] FGF23 is also an inhibitor of monocytic 1α hydroxylase, with a concomitant suppression of the antibacterial cathelicidin [25]; in line with this, clinical studies in patients on hemodialysis have confirmed a higher risk of infection with increasing FGF23 levels [26] In the renal tubule, FGF23 stimulates sodium reabsorption, thus increasing blood pressure [27] In hippocampal cells, FGF23 enhances the number of primary neurites and the synaptic density in a FGFR-dependent manner, but it also decreases arborization, thus leading to a less complex morphology of neuron, possibly explaining, at least partly, the learning and memory deficits often observed in CKD patients [28] FGF23 may also have a role in the growth hormone axis, since therapy with recombinant human growth hormone increases FGF23 levels in the long term, even after adjusting for age and phosphate levels [29] Recently, novel endocrine loops have also been described, notably between FGF23 and adiponectin, with suppression of renal α-Klotho, decreased bone FGF23 release, and calcium renal loss by adiponectin both in mice and in CKD patients [30] A link between iron metabolism and FGF23 has also been highlighted; systemic inflammation may have an impact on FGF23 levels; FGF23 levels are higher in patients with glomerular diseases when compared to CAKUT [31] FGF23 directly targets hepatocytes to promote inflammation and C-reactive protein synthesis [32] In a cohort of 700 patients with stable renal transplants, it was shown that C-terminal FGF23 levels were higher in iron-deficient patients [33] The effects of iron infusions on FGF23/phosphate metabolism differ depending of the iron preparation Specifically, ferric carboxymaltose, the currently preferred iv iron formulation, specifically induces transient 545 hypophosphatemia via its carbohydrate moiety and not as a direct consequence of the iron infusion [34] Older formulations such as iron sucrose avoid this specific effect That being said, even though all these experimental findings demonstrate the role of FGF23 as a systemic (deleterious) hormone, their clinical relevance is not yet clear and will not change clinical management as long as prospective randomized trials are performed to assess the “off-target” effects of FGF23 Subsequently, with CKD progression, abnormalities in other parameters of mineral metabolism appear During mild CKD (stages and 3), calcitriol levels decline in response to increased FGF23 concentrations Since calcitriol suppresses PTH secretion, declining 1,25(OH)2vitamin D levels are followed, in moderate (stages and 4) CKD, by increasing PTH concentrations and by loss of pulsatility in PTH secretion Ultimately, in late stage CKD, h ypocalcemia and hyperphosphatemia develop in approximately 50–60% of patients in response to decreased intestinal calcium absorption (from critically low calcitriol concentrations) and decreased phosphate excretion (from critically low renal mass), respectively Finally, 25(OH)vitamin D deficiency, which is prevalent worldwide, likely also contributes to the development of secondary hyperparathyroidism Patients with CKD are particularly prone to 25(OH)vitamin D deficiency (defined by values below 30 ng/mL or 75 nmol/L), due to several combined factors including decreased sunlight exposure, relative scarcity of vitamin D in occidental diets, lack of supplementation in vitamin D due to the current underestimation for recommended daily intake, and increased body fat mass in populations [35] In addition to providing a substrate for the formation of calcitriol, thus indirectly suppressing PTH levels, Ritter et al identified that 25(OH)vitamin D continues to directly suppress PTH synthesis even when parathyroid gland 1α-hydroxylase is inhibited, thus demonstrating a direct effect of 25(OH)vitamin D on PTH synthesis, independent of 1,25(OH)2vitamin D [36] Moreover, a placebo-controlled randomized trial demonstrated that ergocalciferol was able to delay the onset of secondary hyperparathyroidism in pediatric patients with pre-dialysis 546 CKD [37] 25(OH)vitamin D likely also has a direct effect on bone biology, independent of its effects on mineral metabolism; indeed, in a cohort of 675 deceased adults, mineralization defects were found when serum 25(OH)vitamin D level was below 30 ng/mL [38] However, the skeletal mineralization defect observed across the spectrum of CKD was not associated with vitamin D deficiency New roles of vitamin D in global health have also been highlighted: vitamin D may represent a protective factor against infections, auto-immune diseases, cardiovascular diseases, and cancer [39, 40] ffects of Non-mineral Factors E on CKD-MBD Non-mineral metabolism factors such as iron status, erythropoietin, and inflammation also contribute to increased FGF23 production in CKD, and understanding the impact of each of them in the context of CKD may have potential effects on the pathophysiology and treatment of CKD- MBD. Inflammation increases bone and circulating FGF23 levels [41] Iron deficiency, which is common in CKD, also increases FGF23 expression Iron chelation increases FGF23 expression in vitro [42], and iron-deficient mice with normal and impaired kidney function have increased osteocytic FGF23 expression [43] Hypoxia- inducible factor alpha (HIF1α) protein may mediate the effects of iron deficiency on FGF23 transcription [42] In patients with congenital heart disease and normal kidney function, more severe chronic hypoxemia was associated with plasma FGF23 levels [44] In murine models, both absolute iron deficiency, induced by low- iron diets, and “functional” iron deficiency, induced by inflammation or administration of exogenous hepcidin, increase bone FGF23 expression [41] In a small study of iron-deficient dialysis patients, iron supplementation decreased circulating FGF23 levels [45] In non-dialysis CKD patients, the use of ferric citrate both lowered serum phosphate levels and improved iron parameters, contributing to production in FGF23 concentrations [46] J Bacchetta and I B Salusky Erythropoietin can also stimulate FGF23 production Conversely FGF23 itself may have effects on erythropoiesis Indeed, FGF23 knockout mice have increased serum EPO levels and erythropoiesis and increased measures of erythropoiesis [47] These data suggest that FGF23 may have negative regulatory effects on erythropoiesis Consistent with these murine studies, in a large cohort of human CKD patients, elevated total FGF23 levels were independently associated with both prevalent and incident anemia [48] These associations underscore the complex interrelationships among aspects of CKD-related anemia, CKD-MBD, and their respective treatment modalities that will have to be elucidated in order to define better strategic therapeutic approaches ssessment of CKD-MBD A in Children Undergoing Maintenance Dialysis When taking care of a child with ESRD, it is important to evaluate mineral metabolism, by assessing in parallel bone quality, growth, and cardiovascular status In order to emphasize the complexity and interdependency of all CKD- MBD, the 2017 KDIGO CKD-MBD recommendations highlighted that treatments of CKD-MBD should be based on serial assessment of phosphate, calcium, and PTH levels and considered together for clinical decision-making [4] The first step will consist of clinical evaluation with height, growth velocity, blood pressure, and a “bone-focused” examination, searching for bone pain, deformations, and/or fractures [49] The second step will consist on the biological evaluation of CKD-MBD, mainly by assessing calcium, phosphate, PTH, and 25-D levels and alkaline phosphatase (ALP) However, the additional biomarkers such as FGF23, Klotho, 1,25D, DKK1, sclerostin, bone ALP, and sclerostin among others are currently utilized only for research purposes; neither are bone imaging techniques, such as DXA or pQCT/HR-pQCT, nor cardiovascular evaluation such as coronary calcification scores by computed tomography, carotid intima/media thickness, or pulse wave 29 The Management of CKD-MBD in Pediatric Dialysis Patients 547 Table 29.2 Reference values for phosphate and calcium metabolism in children, adapted from [53] Age range Birth–5 months 6–12 months 1–5 years 6–12 years Normal range for Normal range for ionized calcium calcium (mmol/L) (mmol/L) 2.18–2.83 1.22–1.40 2.18–2.75 1.20–1.40 2.35–2.70 1.22–1.32 2.35–2.58 1.15–1.32 Daily recommended intake for calcium (mg) 210 270 500 800 13–20 years 2.20–2.55 1300 1.12–1.30 Normal range for phosphate (mmol/L) 1.50–2.40 1.50–2.10 1.20–1.90 0.70–1.50 Daily recommended intake for phosphate (mg) 100 275 460 500 until 8 years, 1250 after 1250 For calcium, the conversion factor from mmol/L to mg/dL is to multiply by 4.0 The calculation formula for corrected calcium (CaC, mmol/L) using measured calcium (mmol/L) and albuminemia (g/L) is the following: CaC = Ca – 0.25 × (albuminemia − 40) If albuminemia is not available, CaC may be calculated with protidemia (g/L) with the following formula: CaC = Ca/(0.55 + P/160) For phosphate, the conversion factor from mmol/L to mg/dL is to multiply by 3.1 velocity However, these latter techniques are crucial for research in the field [50, 51] The 2017 KDIGO guidelines indicate to perform bone biopsies in patients with CKD3a-5D if knowledge of the type of renal osteodystrophy will impact treatment decisions Normal serum phosphate and calcium levels in children are age-dependent, and physicians must be aware of such values in order to adapt therapies accordingly [52, 53], as summarized in Table 29.2 The extracellular calcium fraction is tightly regulated and can be measured in serum, where approximately half is bound to negatively charged molecules such as albumin, serum proteins, and serum anions such as phosphate and citrate; the remainder corresponds to “free” or ionized calcium, this latter form being biologically active and responsible for most of its physiological functions notably muscular contraction, protein kinase activation, and enzyme phosphorylation [54, 55] Indeed, only the ionized calcium is available to move into cells and activate cellular processes It is not influenced by alterations in albumin, circulating levels of anions, and acid-base status that are rather frequent in end-stage renal disease [56] The binding of calcium to albumin occurs in a pHdependent manner, acidosis reducing the binding and thus increasing the ionized part However, even though ionized calcium appears to be a more accurate measure of serum calcium rather than albumin-corrected calcium, in clinical practice, albumin-corrected calcium are usually used It is also important to keep in mind that PTH levels alone are not a good predictor of the underlying osteodystrophy; the combined use of total ALP and PTH levels may improve our ability to detect the underlying type of renal osteodystrophy [57]: in a cohort of 161 pediatric patients undergoing maintenance peritoneal dialysis, PTH levels below 400 pg/ml in combination with total ALP levels below 400 IU/L provided the highest correct prediction rate for patients with both normal bone turnover and normal mineralization Levels of PTH were higher, and serum calcium levels were lower in patients with defective mineralization, irrespective of bone turnover [57] In clinical practice, the treating physician should be aware of the different PTH assays, leading to discrepant results when using assays of different brands for second-generation assessment [58]; moreover, there are important differences between second- and third-generation assays Third-generation PTH assays, also known as “whole PTH assays,” use antibodies that exclusively recognize full-length 1–84 PTH. There is however limited evidence that the differentiation of 1–84 PTH from PTH fragments is of clinical use Values obtained with third- generation assays are about 50–60% lower than those obtained with the second-generation assays with great inter-individual variation, and guidelines have been established with second- generation assays, as discussed below In the future, the assessment of non-oxidized PTH may J Bacchetta and I B Salusky 548 500 cde de e 400 cde bcde cde cde bcde 300 abcd abcd abcd Fig 29.3 PTH levels vary depending on the country of origin, data from the IPPN network, from [61] Variation of intact parathyroid hormone (iPTH) levels by country Only countries with ≥15 registered patients were considered Bars denote medians of patient-specific time- averaged mean PTH levels European countries light gray, Latin American countries dark gray, Turkey horizontally dashed, North America vertically dashed, and Asian coun- Uruguay Chile USA Italy China Turkey India Czech Rep Korea UK abcd abcd Poland ab Germany France a Greace 100 ab abc abc Canada 200 Netherlands Median serum iPTH level (pg/ml) Uncontrolled SHPT in CKD is characterized by a sustained high PTH level in combination with a high or high-normal calcium level SHPT gradually develops into tertiary HPT with important bone, cardiac, and vascular complications, such as osteitis fibrosa and calcium efflux from bone, potentially leading to vascular calcification [60] As illustrated in Fig. 29.3, the management of patients differs considerably between countries [61], and this specific point should be taken into account when analyzing clinical research data in the field Even though of low evidence from a strict methodological point of view, these data obtained in the International Pediatric Peritoneal Argentina hich Targets for PTH in Pediatric W Dialysis? Dialysis Network (IPPN) registry included 890 children and adolescents from 24 countries, therefore providing very interesting “bed-side” data for pediatric nephrologists: an optimal range of PTH between 1.7 and times above the upper normal limit was suggested, namely, a target range between 100 and 200 pg/mL, as shown in Fig. 29.4 Indeed, greater PTH levels were associated with an increased frequency of patients presenting with alterations of bone and mineral metabolism, such as bone pains, limb deformities, extra-osseous calcifications, radiological osteomalacia, or osteopenia [61, 62] However, as discussed above, there may be an important variability between PTH assays, and this is certainly one of the main limitations of these registry studies The optimal PTH levels for children treated with dialysis associated with clinical outcomes such as bone deformities, fractures, and growth retardation remain to be determined There are currently two different recommendations related to target PTH levels in dialyzed children: (1) KDIGO 2017 and (2) European Paediatric Dialysis Working Group Brazil reflect the biological activity of PTH more precisely, but their exact place in the clinical ward remains to be defined [59] In those patients with elevated PTH levels and relatively low alkaline phosphate levels, a bone biopsy may be discussed in order to further define the appropriate therapy tries diagonally dashed bars Letters denote significances (P 1000 PTH (pg/ml) Fig 29.4 PTH as a risk factor of bone and mineral complications in pediatric peritoneal dialysis, data from the IPPN network, from [61] Percentage of patients with alterations of bone and mineral metabolism (bone pain, limb deformities, extra-osseous calcifications, radiological osteomala- cia, and/or osteopenia) stratified by time-averaged mean PTH levels Groups sharing same letters not differ significantly Data were obtained from 890 children and adolescents from 24 countries reported to the International Pediatric Peritoneal Dialysis Network (IPPN) registry The KDIGO guidelines are based on bone histology data that demonstrated in the 1990s the development of more severe growth retardation in those patients with PTH