title: Renal elimination of sclerostin increases with declining kidney function.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a cross-sectional study.
  
  
  METHODS
  The study was conducted at a university hospital and outpatient renal clinic.
  
  
  METHODS
  One hundred twenty men and women with CKD stage 1-5 participated in the study.
  
  
  METHODS
  Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, α1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry.
  
  
  METHODS
  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 m2 (CKD stage 1) to 117.9 (±65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m2 (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 α1-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine III (D.C., M.P., T.R., M.H.), Division of Nephrology and Dialysis, Department of Laboratory Medicine (R.M.), Clinical Institute of Pathology (N.K.), and Department of Medicine III (A.G.), Division of Endocrinology and Metabolism, Medical University Vienna (D.C., R.M., N.K., M.P., T.R., A.G., M.H.), 1090 Vienna, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cejka
authors.forename: Rodrig
authors.initials: R
authors.lastname: Marculescu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kozakowski
authors.forename: Max
authors.initials: M
authors.lastname: Plischke
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiter
authors.forename: Alois
authors.initials: A
authors.lastname: Gessl
authors.forename: Martin
authors.initials: M
authors.lastname: Haas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000652:urine*; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005819:Genetic Markers; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000503:physiopathology / Q000652:urine*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human