Bone Hormone Disruption Begins in Children With Mild Kidney Disease

Chronic kidney disease–mineral and bone disorder (CKD-MBD) carries severe consequences for children, whose growing skeletons are especially vulnerable: over 90% of those on dialysis have inadequate bone mineralization, and cardiovascular mortality for children on dialysis runs 100–500 times the general population rate. Despite this, the precise sequence in which CKD-MBD markers become abnormal across CKD stages had never been mapped in pediatric patients using age- and sex-standardized values.

This cross-sectional study enrolled 170 children aged 1–18 years with CKD stages 2 through 5D at Hannover Medical School, Germany. Patients with tubulopathies or other conditions independently affecting mineral metabolism were excluded. The team measured 10 CKD-MBD markers — serum phosphate, calcium, sclerostin, intact FGF23 (iFGF23), total FGF23 (C-terminal assay), soluble Klotho (sKlotho), intact PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, and alkaline phosphatase — and expressed each as a Lambda-Mu-Sigma–derived z-score adjusted for age and sex against healthy pediatric reference populations. This approach controls for the wide physiological variation in growing children.

The most striking finding was how early abnormalities appeared. At CKD stage 2 (eGFR 60–89 ml/min/1.73 m²), children already had significantly elevated sclerostin (z-score +0.97), total FGF23 (+0.72), and alkaline phosphatase (+0.61), combined with reduced serum phosphate (−0.62) and 1,25(OH)₂D₃ (−0.80). Eighty percent of stage 2 patients had vitamin D deficiency or insufficiency — a prevalence higher than recognized. This pattern reflects early skeletal and tubular adaptation before overt GFR loss.

From CKD stage 3A onward, intact FGF23 rose significantly (+0.49 z-score) and PTH began its exponential climb (+1.68 at stage 3A, reaching extreme elevations by stage 5D). Soluble Klotho fell progressively from stage 3A (−0.66 z-score). Hyperphosphatemia and hypocalcemia, classical late features, appeared only in stages 4 and 5D, consistent with FGF23 and PTH maintaining phosphate and calcium homeostasis until GFR drops below roughly 30 ml/min/1.73 m². Sclerostin correlated most strongly with total FGF23 and eGFR. Total FGF23 was associated with serum phosphate, 25(OH)D, transferrin saturation, and iFGF23, suggesting iron status and vitamin D interact with FGF23 regulation even in children.

The clinical implications are significant: sclerostin and total FGF23 elevations, combined with vitamin D insufficiency, are already present in CKD stage 2 and may serve as actionable early targets. These precede the PTH and iFGF23 surge by at least one CKD stage. Limitations include the cross-sectional design, which prevents causal inference or tracking of individual trajectories; the single-center cohort, which may limit generalizability; and the fact that many patients in advanced stages were receiving active treatments (phosphate binders, calcitriol, growth hormone) that could modify observed marker levels.