Bone Mineral Density and Vascular Calcification in Children and Young Adults with Chronic Kidney Disease

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. It is not known if mineral accrual by the growing skeleton protects young people with CKD from extraosseous calcification. My hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: Multicentre longitudinal study in children and young people (5-30 years) with CKD stages 4-5 or on dialysis. Cortical (Cort) and trabecular (Trab) BMD were assessed by peripheral quantitative Computed Tomography and lumbar spine BMD by DXA (Dual Energy X-ray Absorptiometry). Vascular calcification was assessed by cardiac CT for coronary artery calcification (CAC) and ultrasound for carotid intima-media thickness (cIMT). Arterial stiffness was measured by pulse wave velocity (PWV) and carotid distensibility. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed-up after a median of 1.45 years. The cohort had a significant bone and cardiovascular disease burden. 10% suffered at least one previous atraumatic fracture, and 58% reported bone pain affecting activities of daily living. The majority had evidence of vascular calcification and arterial stiffness with increased cIMT and PWV z-scores. 10% had CAC at baseline. Baseline TrabBMD was independently associated with cIMT (R2=0.10, β=0.34, p=0.001). An annualised increase in TrabBMD was an independent predictor of cIMT increase (R2=0.48, β=0.40, p=0.03), with 6-fold greater odds of an increase in ΔcIMT in those with an increase in ΔTrabBMD [(95%CI 1.88 to 18.35), p=0.003]. Young people that demonstrated statural growth (n=33) had attenuated vascular changes compared to those with static growth. Conclusion: These hypothesis generating studies suggest that children and young adults with CKD or on dialysis may develop vascular calcification even as BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraskeletal calcification

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged &gt;3 years, its efficacy and safety for children aged &lt;3 years is unknown. Methods: We identified 26 children aged &lt;3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11–27) months, serum parathyroid hormone (PTH) was 792 (411–1397) pg/ml, corresponding to 11.6 (5.9–19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43–2.75) mmol/l, and serum phosphate 1.47 (1.16–1.71) mmol/l. Serum 25-OH vitamin D (25–OHD) was 70 (60–89) nmol/l, 3 children were vitamin D deficient (&lt;50 nmol/l). The initial cinacalcet dose was 0.4 (0.2–0.8) mg/kg/d and the maximum dose was 1.1 (0.6–1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7–2.0) years. PTH decreased to 4.3 (2.2–7.8) times the ULN after 6 months, to 2.0 (1.0–5.3) times ULN after 12 months, and to 1.6 (0.5–3.4) times thereafter (P = 0.017/0.003/&lt;0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes &lt;2.10 mmol/l. Oral calcium intake was 84% (66%–117%) of recommended nutrient intake at start, 100% (64%–142%) at 3 months and declined to 78% (65%–102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty.Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged &lt;3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.</p

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged &gt;3 years, its efficacy and safety for children aged &lt;3 years is unknown. Methods: We identified 26 children aged &lt;3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11–27) months, serum parathyroid hormone (PTH) was 792 (411–1397) pg/ml, corresponding to 11.6 (5.9–19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43–2.75) mmol/l, and serum phosphate 1.47 (1.16–1.71) mmol/l. Serum 25-OH vitamin D (25–OHD) was 70 (60–89) nmol/l, 3 children were vitamin D deficient (&lt;50 nmol/l). The initial cinacalcet dose was 0.4 (0.2–0.8) mg/kg/d and the maximum dose was 1.1 (0.6–1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7–2.0) years. PTH decreased to 4.3 (2.2–7.8) times the ULN after 6 months, to 2.0 (1.0–5.3) times ULN after 12 months, and to 1.6 (0.5–3.4) times thereafter (P = 0.017/0.003/&lt;0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes &lt;2.10 mmol/l. Oral calcium intake was 84% (66%–117%) of recommended nutrient intake at start, 100% (64%–142%) at 3 months and declined to 78% (65%–102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty.Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged &lt;3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.</p

The burden of subclinical cardiovascular disease in children and young adults with chronic kidney disease and on dialysis.

Background Cardiovascular disease (CVD) is a common cause of morbidity and mortality even in young people with chronic kidney disease (CKD). We examined structural and functional CV changes in patients ˂30 years of age with CKD Stages 4 and 5 and on dialysis. Methods A total of 79 children and 21 young adults underwent cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima-media thickness (cIMT), carotid-femoral pulse wave velocity (cfPWV) and echocardiography. Differences in structural (CAC, cIMT -score, left ventricular mass index) and functional (carotid distensibility -score and cfPWV -score) measures were examined between CKD Stages 4 and 5 and dialysis patients. Results Overall, the cIMT -score was elevated [median 2.17 (interquartile range 1.14-2.86)] and 10 (10%) had CAC. A total of 16/23 (69.5%) patients with CKD Stages 4 and 5 and 68/77 (88.3%) on dialysis had at least one structural or functional CV abnormality. There was no difference in the prevalence of structural abnormalities in CKD or dialysis cohorts, but functional abnormalities were more prevalent in patients on dialysis (P 2 standard deviation (SD) or distensibility <-2 SD) had less carotid dilatation (lumen:wall cross-sectional area ratio) compared with those with normal cIMT and distensibility. Conclusions There is a high burden of subclinical CVD in young CKD patients, with a greater prevalence of functional abnormalities in dialysis compared with CKD patients. Longitudinal studies are required to test these hypothesis-generating data and define the trajectory of CV changes in CKD

Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The 44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease

Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease.

BACKGROUND Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk. METHODS This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis. RESULTS Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = -0.44, P < 0.0001) and alkaline phosphatase (ALP; r = -0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below -2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (β = -0.43 , P < 0.0001), ALP (β = -0.36, P < 0.0001) and Ca (β = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model. CONCLUSIONS Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4-5D