The renal-bone axis: the effect of renal impairment and vitamin D supplementation on bone turnover, Wnt-signalling and inflammation markers in older people

Christodoulou, Marilena (2022) The renal-bone axis: the effect of renal impairment and vitamin D supplementation on bone turnover, Wnt-signalling and inflammation markers in older people. Doctoral thesis, University of East Anglia.

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Abstract

This PhD thesis is focused on the renal-bone axis which involves an endocrine feed-back loop and cross-talk between these two organs. Several hormones and regulators play key roles in this extensive cross-talk, including: parathyroid hormone (PTH), fibroblast growth factor-23 (FGF23), 1,25-dihydroxy vitamin D, 25-hydroxy vitamin D and Sclerostin. Ageing is associated with a decrease in both renal function (most commonly measured as the estimated glomerular filtration rate (eGFR)), bone loss and reduced tissue sensitivity to regulating hormones. The mechanisms involved in this cross-talk are poorly understood. Although changes in plasma concentrations of these factors are well-characterized in advance renal impairment, less is known in the early stages of renal impairment and how this may affect the response to vitamin D supplementation. The main aim of the research presented in my thesis was to develop a better understanding on the renal-bone cross-talk. Therefore, I investigated the consequences and changes caused by renal impairment on renal-bone axis and the effect of vitamin D supplementation on the renal-bone axis.

More specifically, the focus of my research was on the effect of vitamin D supplementation on FGF23 and markers of Wnt-signalling. FGF23 plays a key role in the renal-bone axis, together with parathyroid hormone and vitamin D metabolites. FGF23 is a phosphaturic hormone which is produced and secreted by osteocytes and acts in the kidney to induce phosphate excretion in order to maintain homeostasis. It also affects bone metabolism through its regulatory function on the Wnt-signalling pathway. In addition, recent evidence showed associations of FGF23 with iron and inflammation markers.

This study utilized data and samples from the dose-ranging vitamin D interventional randomized controlled trial ‘the VDOP study’. This study was conducted in collaboration between Medical Research Council, Human Nutrition Research, The University of Newcastle and University of East Anglia. Further, a systematic review and meta-analyses of RCTs with vitamin D and its analogues in chronic kidney disease (CKD) patients and reviewed current guidelines.

Most chapters (2-5) are based on my published papers or are currently under review for publication (references and details are provided in each chapter).

The systematic review of RCTs showed that Vitamin D treatment of CKD patients has an inconsistent effect on PTH, although meta-analysis showed a significant overall effect. Calcifediol and analogues consistently suppress PTH, but the reported increase in FGF23 with 1,25(OH)2D analogues warrants caution. Current guidelines for the first CKD stages (G1-G3a) follow general population recommendations for the prevention of vitamin D deficiency. Use of calcitriol or analogues is restricted to stages G3b-G5 and depends on patient characteristics.

The VDOP study showed that vitamin D supplementation in older people leads to a decrease in intact-PTH (iPTH) and increase in procollagen type I N-propeptide: beta-C-terminal telopeptide (PINP:CTX) ratio. This suggests a protective effect of supplementation on bone metabolism although no significant effect on bone mineral density (BMD) or pronounced changes in regulators of the Wnt-signalling pathway were found. There was an increase in FGF23. This warrants caution due to its negative associations with bone and cardiovascular health.

Further analyses with data categorised by eGFR (G1-2 >60 and G3a/b <60 ml/min/1.73m2) showed that even a moderate decline in eGFR has a negative impact on vitamin D metabolism, Wnt-signalling and bone turnover markers. Vitamin D supplementation had beneficial effects on markers of the renal-bone axis in older people of both groups. The response to vitamin D supplementation was however dependent on renal function. Supplementation improved vitamin D status and Klotho in the group with moderate renal impairment (G3a/b) to concentrations comparable to those found in the group with the higher renal function (G1-2). Plasma intact-FGF23 (iFGF23), 1,25(OH)2D, PINP increased only in the group with the higher renal function (G1-2).

Moreover, in subgroup analysis comparing people with early renal impairment (CKDG3a/b) and normal renal function (CKDG1 eGFR >90 ml/min/1.73m2), alterations in regulators of the renal-bone axis, inflammation and iron status were observed in early CKD. Early renal impairment was associated with changes in regulators of calcium, phosphate, vitamin D and bone metabolism and in iron status and inflammation. After vitamin D supplementation, differences between the two groups were no longer significant for iPTH, Klotho, iron and tumor necrosis factor-α (TNFα). The response of iron and inflammation markers, to vitamin D supplementation differed between the groups. Plasma iron, Interleukin 10 (IL10) increased and TNFα decreased in the group with renal impairment. In the group with normal renal function, no changes were observed in markers of iron status and inflammation, except for an increase in IL10. Regression analyses showed that plasma c-terminal FGF23 and iFGF23 were predominantly predicted by eGFR and regulators of calcium/phosphate metabolism.

In conclusion, this study identified changes in the renal bone-axis with early renal impairment and differences in the response between groups with normal and early CKD. Vitamin D supplementation may partly abate the effects of renal impairment. Diagnosis of renal impairment at an early stage may provide opportunities for the prevention of the progression of renal disease and CKD-Mineral Bone Disease.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	26 Apr 2023 08:16
Last Modified:	26 Apr 2023 08:16
URI:	https://ueaeprints.uea.ac.uk/id/eprint/91883
DOI:

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