Renal Elimination of Sclerostin Increases With Declining Kidney Function

Context: Sclerostin serum levels are increased in patients with chronic kidney disease (CKD). Osteoporosis and CKD often occur simultaneously. Currently antisclerostin antibodies are in clinical development for the treatment of osteoporosis. Objective: The objective of this study was to study the renal handling of sclerostin. Design: This was a cross-sectional study. Setting: The study was conducted at a university hospital and outpatient renal clinic. Patients: One hundred twenty men and women with CKD stage 1-5 participated in the study. Intervention: Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, alpha 1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry. Main Outcome Measure: Urinary excretion of sclerostin was measured. Results: Urinary sclerostin excretion increased with declining eGFR (R = -0.75, P < .001), from 10.4 (+/- 12.7) pmol/L in patients with eGFR greater than 90 mL/min per 1.73 m(2) (CKD stage 1) to 117.9 (+/- 65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m(2) (CKD stage 5, P < .001). Fractional excretion of sclerostin increased with declining eGFR (R = -0.83, P < .001) from 0.45% (+/- 0.6%) in CKD 1 to 26.3% (+/- 17.6%) in CKD 5 (P < .001). Fractional excretion of sclerostin correlated with fractional excretion of alpha 1-microglobulin (R = 0.82, P < .001). No association between serum sclerostin and fractional excretion of phosphorus was found in a multivariate analysis. Sclerostin was detected in proximal tubular cells, showing a diffuse cytoplasmic staining pattern. Conclusion: Increased sclerostin serum levels in CKD patients are not due to decreased renal elimination. On the contrary, renal elimination increases with declining kidney function. Whether this has consequences on antisclerostin antibody dosing, efficacy, or safety in patients with CKD remains to be determined.