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Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease

Orlando Gutierrez^*, Tamara Isakova^*, Eugene Rhee^*, Anand Shah, Julie Holmes, Gina Collerone, Harald Jüppner and Myles Wolf^*,

^* Department of Medicine Internal Medicine Residency Training Program, Renal Unit and Endocrine and Pediatric Nephrology Units, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence to: Dr. Myles Wolf, Bartlett 911, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. Phone: 617-726-7595; Fax: 617-726-7491; E-mail: mswolf{at}partners.org

Received for publication January 13, 2005. Accepted for publication April 10, 2005.

Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D₃, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe_PO4) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe_PO4 was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe_PO4. Increased FGF-23 and decreased 25(OH)D₃ were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe_PO4, and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.

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