Vitamin D, Phosphate and Fibroblast Growth Factor 23: A role in the pathogenesis and management of Chronic Kidney Disease and Chronic Kidney Disease Mineral and Bone Disorder

Chronic kidney disease (CKD) is defined by the presence of proteinuria or decreased kidney function, with a prevalence of 10-15% in the adult population. CKD can progress to end-stage kidney disease (ESKD) and is associated with progressive abnormalities of bone and mineral metabolism, defined as CKD mineral and bone disorder (CKD-MBD). The use of vitamin D in CKD, the optimal level for initiating treatment and the use of current and novel biomarkers in the management of CKD-MBD remain controversial. This thesis examines the role of three markers of CKD-MBD; vitamin D, phosphate and Fibroblast Growth Factor 23 (FGF-23), in the pathogenesis, detection and management of CKD and CKD-MBD.

Using the baseline and 5-yr Australian Diabetes Obesity & Lifestyle Study (AusDiab), I examined the prevalence and incidence of CKD by serum 25-hydroxyvitamin D level [25(OH)D]. I found that low serum 25(OH)D levels were significantly associated with prevalent CKD (albuminuria), as well as an increased incidence of albuminuria at 5-years.

The definition of the optimal target serum 25(OH)D level in health and in CKD remains unclear. Using a large community cohort I was able to determine an interaction between the effect of vitamin D and PTH by CKD stage, enabling analysis across all stages of CKD. I found no single level that can clearly define vitamin D deficiency, but rather a range of serum 25(OH)D measurements that places the patients at risk for deficiency. Furthermore in CKD there may be a benefit in targeting higher serum 25(OH)D levels.

The treatment of elevated phosphate levels remains the cornerstone of therapy for patients with ESKD, where phosphate measurements are usually collected randomly. I explored whether fasting samples are superior to random samples. My study found no difference between the two collection methods, but demonstrated marked intra-individual variability in serum phosphate levels, highlighting the need for more considered clinical decisions.

FGF-23 has been proposed as a potential biomarker for CKD-MBD, as it increases early in CKD, and has associations with morbidity and mortality outcomes. Much remains unknown about the effects of haemodialysis on FGF-23 levels, and the optimal collection and processing methods. My studies found no discernable effect of haemodialysis on FGF-23 levels. However different collection methods significantly influence measured FGF-23 values (with plasma being superior to serum), and FGF-23 levels showed high inter- and intra-individual variability.

This thesis provides further evidence for research into vitamin D deficiency as a modifiable risk factor for CKD. My studies also support the hypothesis that we should target a range of serum 25(OH)D levels, rather than aim for a single threshold level, thus providing further rationale for supplementation and target levels on CKD. My studies further question the current practice of regular phosphate measurement in ESKD, and treatment changes in response to those measures. Finally given the marked variability in measured levels, my studies examining FGF-23 suggest that at present it is not ready for routine clinical use. The work in this thesis will inform further observational and interventional studies, and provide additional data to inform clinical guidelines.