25-Hydroxyvitamin D levels and chronic kidney disease in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study

<p>Abstract</p> <p>Background</p> <p>Low 25-hydroxy vitamin D (25(OH)D) levels have been associated with an increased risk of albuminuria, however an association with glomerular filtration rate (GFR) is not clear. We explored the relationship between 25(OH)D levels and prevalent chronic kidney disease (CKD), albuminuria and impaired GFR, in a national, population-based cohort of Australian adults (AusDiab Study).</p> <p>Methods</p> <p>10,732 adults ≥25 years of age participating in the baseline survey of the AusDiab study (1999–2000) were included. The GFR was estimated using an enzymatic creatinine assay and the CKD-EPI equation, with CKD defined as eGFR <60 ml/min/1.73 m². Albuminuria was defined as a spot urine albumin to creatinine ratio (ACR) of ≥2.5 mg/mmol for men and ≥3.5 for women. Serum 25(OH)D levels of <50 nmol/L were considered vitamin D deficient. The associations between 25(OH)D level, albuminuria and impaired eGFR were estimated using multivariate regression models.</p> <p>Results</p> <p>30.7% of the study population had a 25(OH)D level <50 nmol/L (95% CI 25.6-35.8). 25(OH)D deficiency was significantly associated with an impaired eGFR in the univariate model (OR 1.52, 95% CI 1.07-2.17), but not in the multivariate model (OR 0.95, 95% CI 0.67-1.35). 25(OH)D deficiency was significantly associated with albuminuria in the univariate (OR 2.05, 95% CI 1.58-2.67) and multivariate models (OR 1.54, 95% CI 1.14-2.07).</p> <p>Conclusions</p> <p>Vitamin D deficiency is common in this population, and 25(OH)D levels of <50 nmol/L were independently associated with albuminuria, but not with impaired eGFR. These associations warrant further exploration in prospective and interventional studies.</p

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. <br> <br> 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. <br> <br> 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. <br> <br> 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. <br> <br> 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. <br> <br> 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

Management of mineral and bone disorders in renal transplant recipients

The management of post-transplantation bone disease is a complex problem that remains under-appreciated in clinical practice. In these patients, pre-existing metabolic bone disorder is further impacted by the use of immunosuppressive medications (glucocorticoids and calcineurin-inhibitors), variable post-transplantation renal allograft function and post-transplantation diabetes mellitus. The treatment of post-transplantation bone loss should begin pre-transplantation. All patients active on transplant waiting lists should be screened for bone disease. Patients should also be encouraged to take preventative measures against osteoporosis such as regular weight-bearing exercise, smoking cessation and reducing alcohol consumption. Biochemical abnormalities of disordered mineral metabolism should be corrected prior to transplantation wherever possible, and because these abnormalities commonly persist, post transplant hypophosphatemia, persistent hyperparathyroidism and low vitamin D levels should be regularly monitored and treated. Bone loss is greatest in the first 6-12 months post-transplantation, during which period any intervention is likely to be of greatest benefit. There is strong evidence that bisphosphonates prevent post-transplantation bone loss; however, data are lacking that this clearly extends to a reduction in fracture incidence. Denosumab is a potential alternative to vitamin D receptor agonists and bisphosphonates in reducing post-transplantation bone loss; however, further studies are needed to demonstrate its safety in patients with a significantly reduced estimated glomerular filtration rate. Clinical judgement remains the cornerstone of this complex clinical problem, providing a strong rationale for the formation of combined endocrinology and nephrology clinics to treat patients with Chronic Kidney Disease-Mineral and Bone Disorder, before and after transplantation

The stability and variability of serum and plasma fibroblast growth factor-23 levels in a haemodialysis cohort

Abstract Background Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialysis patients and have been linked to mortality outcomes. Small studies in health and chronic kidney disease, have demonstrated marked intra- and inter-individual variability in measured FGF-23 levels, and variable degradation in serum as compared to plasma samples. In end-stage kidney disease (ESKD), the intra- and inter-individual variability of FGF-23 levels, and the optimal collection methods remain poorly characterized. In this study we assessed the variability of FGF-23 levels in a cohort of stable haemodialysis patients. Secondly, in a subset of patients, we assessed the effects of different collection methods on measured FGF-23 levels. Methods To assess the variability of FGF-23, pre-dialysis blood samples were collected over 3 consecutive weeks from 75 haemodialysis patients. The effects of different specimen collection methods were examined in a subset of patients (n = 23), with pre-dialysis blood collected into different tubes: plain (serum), EDTA (plasma) and EDTA with the addition of a protease inhibitor (EDTA-PI). All analyses were performed in the main cohort and repeated in each subgroup. Variability over a 3-week period was assessed using repeated measures ANOVA and random effects linear regression models. Intra-class correlation coefficients were calculated to assess agreement, and coefficients of variation were calculated to assess intra- and inter-individual variability. Results Over the 3-week study period the mean FGF-23 levels were not significantly different in the serum (p = 0.26), EDTA (p = 0.62) and EDTA-PI (p = 0.55) groups. FGF-23 levels demonstrated marked intra- and inter-individual variability with a CV of 36 and 203.2%, respectively. In the subgroup analysis, the mean serum FGF-23 levels were significantly lower than the EDTA (p < 0.001) or EDTA-PI (p < 0.001) groups, however there was no difference in mean FGF-23 levels between EDTA and EDTA-PI (p = 0.54). Conclusions The measured FGF-23 levels were significantly lower in serum as compared to plasma, and the addition of a protease inhibitor did not confer an additional benefit. Importantly in this cohort of ESKD patients, FGF-23 levels showed marked intra- and inter-individual variability. The routine measurement of FGF-23 in ESKD remains challenging, however this study suggests the plasma is the optimal collection method for FGF-23 analysis

Serum 25-hydroxyvitamin D deficiency and the 5-year incidence of CKD

Low serum 25-hydroxyvitamin D (25[OH]D) levels have been associated with chronic kidney disease in cross-sectional studies. However, this association has not been studied prospectively in a large general population&ndash;based cohort.This prospective cohort study shows that vitamin D deficiency is associated with a higher annual incidence of albuminuria and reduced eGFR and independently predicts the 5-year incidence of albuminuria. These associations warrant further exploration in long-term prospective clinical trials