Serum phosphate modifies the vascular response to vitamin D receptor activation in chronic kidney disease (CKD) patients.
Vitamin D receptor activation (VDRA) ameliorates endothelial dysfunction in CKD patients but also increases phosphate and FGF-23, which may attenuate the beneficial effect of VDRA on endothelial function.



This is a pre-specified secondary analysis of the PENNY trial (NCT01680198) testing the effect of phosphate and FGF-23 on the flow mediated vasodilatory (FMD) response to paricalcitol (PCT, 2 μg/day) and placebo over a 12-weeks treatment period. Eighty-eight stage G3-4 CKD patients were randomized to PCT (n = 44) and Placebo (n = 44). Endothelial function was assessed by measuring endothelium dependent forearm blood flow (FBF) response to ischemia. The FMD response was by the 61% higher in PCT treated patients than in those on placebo (P = 0.01). Phosphate (+11%, P = 0.039), calcium (+3%, P = 0.01) and, particularly so, FGF23 (+164%, P < 0.001) increased in PCT treated patients. Changes in FMD by PCT associated inversely with phosphate (r = -0.37, P = 0.01) but were independent of FGF-23, calcium and PTH changes. The response to PCT was maximal in patients with no changes in phosphate (1st tertile), attenuated in those with mild-to-moderate rise in phosphate (2nd tertile) and abolished in those with the most pronounced phosphate increase (3rd tertile) (effect modification P = 0.009). No effect modification by FGF-23 and other variables was observed.



The beneficial effect of PCT on endothelial function in CKD is maximal in patients with no or minimal changes in phosphate and it is abolished in patients with a pronounced phosphate rise. These findings generate the hypothesis that the endothelium protective effect by VDRA may be potentiated by phosphate lowering interventions.
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy. Electronic address: carmine.zoccali@tin.it.
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Zoccali
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Torino
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Curatola
Nephrology, Hypertension and Renal Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy.
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Panuccio
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Tripepi
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Pizzini
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Versace
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Bolignano
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Cutrupi
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
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Ghiadoni
Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA.
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Thadhani
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy.
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Tripepi
CNR-IBIM/IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Reggio Calabria, Italy; Nephrology, Hypertension and Renal Transplantation Unit, Ospedali Riuniti, Reggio Calabria, Italy.
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Mallamaci
D000368:Aged; D015415:Biomarkers / Q000097:blood; D001916:Brachial Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004872:Ergocalciferols / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000097:blood*; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism; D012039:Regional Blood Flow; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000009:adverse effects / Q000627:therapeutic use*
D015415:Biomarkers; D004872:Ergocalciferols; C000717427:FGF23 protein, human; D010710:Phosphates; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014665:Vasodilator Agents; D005346:Fibroblast Growth Factors; C084656:paricalcitol; D000089703:Fibroblast Growth Factor-23
CKD; Effect modification; Flow mediated vasodilation; Paricalcitol; Phosphate