Investigating the Role of Hyperparathyroidism in the Cardiovascular Burden of Chronic Kidney Disease

Abstract

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is associated with increased cardiovascular mortality. Parathyroid hormone (PTH) is a regulatory hormone and it is hypothesized that effective control of PTH in the context of secondary hyperparathyroidism (SHPT) will lead to improved cardiovascular outcomes. Vascular stiffness, a non-invasive surrogate measure of vascular calcification, further reflects the cardiovascular burden of CKD-MBD. It can therefore be hypothesized that a correlation may exist between PTH and vascular stiffness measurements, and that any association between PTH and mortality could at least partly derive from its effect on vascular calcification. These hypotheses were explored using data from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a prospective epidemiological study that investigates progression of renal disease in a non-dialysis CKD population.The first study explored which clinical parameters were associated with higher serum PTH levels in a cross-sectional analysis of 2509 patients. A number of potentially modifiable and non-modifiable associates of PTH were found: female gender, increasing age, creatinine and alkaline phosphatase were all positively associated with above the median PTH. However, above median PTH was associated with both decreased phosphate and corrected calcium. Non-caucasian ethnicity was also found to be independently associated with above median PTH. Although phosphate, and calcium are all potentially modifiable parameters, in this study their relationships with PTH were potentially confounded by treatment bias. The second study demonstrated an independent association between PTH and long-term mortality outcomes in a multivariate Cox regression model. The key finding was that annualized change in PTH of greater than or equal to10%, either increasing or decreasing, was significantly associated with increased all cause and cardiovascular mortality. This provides some validation for PTH as a therapeutic target in CKD cardiovascular risk reduction.The third study showed that when the same measurement of vascular stiffness (augmentation index, AIx) was recorded using two different devices (Vicorder and SphygmoCor) interchangeable results were not obtained, leading to the conclusion that vascular stiffness measurements assessed by different devices are not comparable. The final study included Pearson correlation analysis between PTH and longitudinal change in AIx (n=275) and also pulse wave velocity (PWV) (n=147). PTH did correlate with change in PWV (r=0.14, p=0.04), but not change in AIx (r=0.24, p=0.69). Neither AIx nor PWV were associated with all-cause mortality in multivariate Cox regression models. However, both absolute PTH and change in PTH were independently associated with all cause mortality (HR:1.01 CI:1.00,1.01 p

Date of Award	1 Aug 2017
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Philip Kalra (Supervisor) & Darren Green (Supervisor)