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Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD.

ABSTRACT: INTRODUCTION:Mounting evidence indicates that a disturbed Wnt-?-catenin signaling may be involved in the pathogenesis of chronic kidney disease-mineral and bone and mineral disorder (CKD-MBD). Data on the impact of CKD on circulating levels of the Wnt antagonists sclerostin and Dickkopf related protein 1 (DKK1) and the relationship with laboratory parameters of CKD-MBD are incomplete. METHODS:We analyzed serum sclerostin and DKK1 in 308 patients across the stages of chronic kidney disease (kDOQI stage 1-2 n = 41; CKD stage 3 n = 54; CKD stage 4-5 n = 54; hemodialysis n = 100; peritoneal dialysis n = 59) as well as in 49 healthy controls. We investigated associations with demographics, renal function, parameters of mineral metabolism including 25(OH) vitamin D, 1,25(OH)2 vitamin D, biointact fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), and bone turnover markers. RESULTS:Serum sclerostin, but not DKK1, increases in more advanced stages of CKD and associates with PTH, phosphate, and 1,25(OH)2 vitamin D concentrations. Bone turnover markers are highest in hemodialysis patients presenting the combination of high PTH with low sclerostin level. Serum DKK1 levels are lower in CKD patients than in controls and are not associated with laboratory parameters of mineral metabolism. Interestingly, a direct association between DKK1 and platelet count was observed. CONCLUSION:In CKD, serum levels of the Wnt inhibitors DKK1 and sclerostin are unrelated, indicating different sites of origin and/ or different regulatory mechanisms. Sclerostin, as opposed to DKK1, may qualify as a biomarker of CKD-MBD, particularly in dialysis patients. DKK1 serum levels, remarkably, correlate almost uniquely with blood platelet counts.

SUBMITTER: Behets GJ

PROVIDER: S-EPMC5426702 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD.

Behets Geert J GJ Viaene Liesbeth L Meijers Björn B Blocki Frank F Brandenburg Vincent M VM Verhulst Anja A D'Haese Patrick C PC Evenepoel Pieter P

PloS one 20170511 5

<h4>Introduction</h4>Mounting evidence indicates that a disturbed Wnt-β-catenin signaling may be involved in the pathogenesis of chronic kidney disease-mineral and bone and mineral disorder (CKD-MBD). Data on the impact of CKD on circulating levels of the Wnt antagonists sclerostin and Dickkopf related protein 1 (DKK1) and the relationship with laboratory parameters of CKD-MBD are incomplete.<h4>Methods</h4>We analyzed serum sclerostin and DKK1 in 308 patients across the stages of chronic kidney ...[more]

PMID: 28493902

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Project description:ObjectivesTo define groups of patients according to the changes of biochemical parameters, that is, serum calcium, phosphate and parathyroid hormone (PTH), over a 2-year follow-up period using group-based multi-trajectory modeling (GBMM) among a cohort of dialysis patients with newly diagnosed secondary hyperparathyroidism (SHPT) (ie, PTH≥500 ng/L for the first time) and to compare their patient characteristics and treatments.DesignPharmacoepidemiological study.SettingIn the 12 dialysis units located in the French region of Lorraine.ParticipantsA total of 269 dialysis patients with newly diagnosed SHPT were prospectively included from December 2009 to May 2012 and followed-up for 2 years.ResultsWe identified four distinct trajectory groups: 'rapid PTH drop' experiencing a rapid and sharp decrease (over weeks) in PTH level associated with decreasing phosphate level within normal range (n=34; 12.7%), 'gradual PTH decrease' experiencing a gradual and continuous decrease (over months) in PTH level and maintaining phosphate at a middle level throughout the study (n=98; 36.4%), 'slow PTH decrease with high phosphate' experiencing a slow decrease in PTH level associated with a relatively high phosphate level (n=105; 39.0%) and 'uncontrolled SHPT' with high levels of PTH and phosphate throughout the study (n=32; 11.9%). Patients in the 'uncontrolled SHPT' group were significantly (p<0.00001) younger than patients in other groups. Kidney Disease Improving Global Outcomes (KDIGO) targets for PTH, phosphate and calcium were reached simultaneously for 14.9% of patients at baseline and 16.7% at the end of the study. Patients were given cinacalcet more frequently at months 3 and 6 in the 'rapid PTH drop' and at month 24 in the 'uncontrolled SHPT' groups.ConclusionsOver 2 years following a new SHPT diagnosis, a younger age and a higher rate of alkaline phosphatase were associated to a continuous uncontrolled SHPT. Patients with the lowest PTH at the end of the follow-up tended to receive more often cinacalcet.Trial registration numberClinicalTrials.gov number, NCT02888639, post results.

Project description:In this multicentre double-blind randomized clinical trial, we investigated the effects of oral cholecalciferol supplementation on serum hepcidin and parameters related to anaemia and CKD-MBD among haemodialysis patients. Participants were assigned in a 2:2:1:1 ratio to either (1) thrice-weekly 3,000-IU cholecalciferol, (2) once-monthly cholecalciferol (equivalent to 9,000 IU/week), (3) thrice-weekly placebo, or (4) once-monthly placebo. We also examined the effect modifications by selected single nucleotide polymorphisms in vitamin D-related genes. Out of 96 participants, 94 were available at Month 3, and 88 completed the 6-month study. After adjustment for baseline values, serum hepcidin levels were higher at Day 3 in the combined cholecalciferol (vs. placebo) group, but were lower at Month 6 with increased erythropoietin resistance. Cholecalciferol increased serum 1,25(OH)2D levels, resulting in a greater proportion of patients who reduced the dose of active vitamin D at Month 6 (31% vs. 10% in the placebo group). Cholecalciferol also suppressed intact PTH only among patients with severe vitamin D deficiency. In conclusion, cholecalciferol supplementation increases serum hepcidin-25 levels in the short term and may increase erythropoietin resistance in the long term among haemodialysis patients. Both thrice-weekly and once-monthly supplementation effectively increases serum 1,25(OH)2D levels, and hence, reduces active vitamin D drugs.Clinical Trial Registry: This study was registered at ClinicalTrials.gov and University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as NCT02214563 (registration date: 12/08/2014) and UMIN000011786 (registration date: 15/08/2014), respectively (please refer to the links below). ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/record/NCT02214563 . UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000017152&language=E .

Dataset Information

Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD.

Publications

Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD.

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