American Journal of Nephrology

Patient-Oriented, Translational Research: Research Article

Tiong M.K.a,b· Holt S.G.a,b,c,d· Ford M.L.e,f· Smith E.R.a,b

Author affiliations

aDepartment of Nephrology, The Royal Melbourne Hospital, Parkville, VIC, Australia
bDepartment of Medicine (RMH), University of Melbourne, Parkville, VIC, Australia
cSEHA Kidney Care, Abu Dhabi Health Services Company, Abu Dhabi, United Arab Emirates
dDepartment of Medicine, Khalifa University, Abu Dhabi, United Arab Emirates
eDepartment of Renal Medicine, King’s College Hospital NHS Foundation Trust, London, UK
fFaculty of Life Sciences & Medicine, Kings College London, London, UK

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Article / Publication Details

First-Page Preview

Received: June 28, 2022
Accepted: August 12, 2022
Published online: December 06, 2022

Number of Print Pages: 10
Number of Figures: 1
Number of Tables: 3

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: https://www.karger.com/AJN

Abstract

Introduction: Elevated levels of fibroblast growth factor-23 (FGF23) in chronic kidney disease (CKD) are associated with progression of CKD. FGF23 inhibits proximal tubular phosphate reabsorption, raising phosphate concentrations in the tubular fluid of functioning nephrons, predisposing to spontaneous precipitation of calcium phosphate crystals and resultant tubular injury. Calciprotein monomers (CPM) form spontaneously in biological fluids when clusters of calcium phosphate ions are bound by the liver-derived glycoprotein fetuin-A. Serum CPM are elevated in CKD and are postulated to trigger FGF23 secretion. CPM are also readily filtered at the glomerulus into the tubular fluid, suggesting that higher CPM levels could be associated with progression of CKD via FGF23-mediated increased phosphate load but also through direct effects in the proximal tubule. Methods: ACADEMIC was a prospective observational study of 200 stable outpatients with CKD stages 3 and 4. Participants were followed until commencement of dialysis or death. In this study, we examined a sub-cohort of 189 participants who had baseline serum available for measurement of CPM. Cox proportionate hazard regression models were used to examine the association between CPM and a composite kidney disease outcome (commencement of dialysis or reduction in estimated glomerular filtration rate [eGFR] >30%). Linear regression models were used to examine the association between CPM and annualized eGFR slope. Results: Relative to the lowest tertile, the highest tertile of CPM was associated with increased risk of the composite kidney disease outcome in univariate models and after sequential adjustment for conventional risk factors for progression of CKD (adjusted hazard ratio 4.22; 95% confidence interval [CI] 1.91, 9.33, p < 0.001). Natural log-transformed CPM was also inversely associated with eGFR slope in univariate and multivariate adjusted models (adjusted β-coefficient −1.66, 95% CI: −3.10, −0.22, p = 0.024). In exploratory mediation analysis, the association between serum CPM and eGFR slope was partially mediated by iFGF23; however, the majority of the association was direct and independent of the iFGF23 pathway. Conclusion: Elevated levels of CPM are associated with the progression of CKD. This association was partially mediated via FGF23, consistent with recent evidence that FGF23 predisposes to spontaneous precipitation of calcium phosphate crystals leading to tubular injury. However, serum CPM also appeared to have a direct association with eGFR slope, raising the possibility that CPM may also be associated with progression of CKD through additional pathways.

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First-Page Preview

Received: June 28, 2022
Accepted: August 12, 2022
Published online: December 06, 2022

Number of Print Pages: 10
Number of Figures: 1
Number of Tables: 3

ISSN: 0250-8095 (Print)
eISSN: 1421-9670 (Online)

For additional information: https://www.karger.com/AJN

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