Alkaline Phosphatase and Parathyroid Hormone Levels: International Variation and Associations With Clinical Outcomes in the DOPPS

Abstract

BackgroundSecondary hyperparathyroidism increases the risk of fractures and cardiovascular (CV) disease in hemodialysis (HD) patients. The relationship between parathyroid hormone (PTH) and outcomes has been inconsistent, possibly due to variable bone responsiveness to PTH. The KDIGO guideline suggests monitoring total alkaline phosphatase (ALP), but the role of ALP versus PTH in the management of mineral and bone disorder is not clear. MethodsThe analysis included 28,888 HD patients in 9 countries in DOPPS phase 3-7 (2005-2021). The primary exposures of interest were normalized ALP and PTH – raw values divided by facility upper normal limit – measured at study enrollment. Cox models were used to estimate hazard ratios of all-cause/CV mortality and any/hip fracture adjusted for potential confounders. Linear mixed models, adjusted for potential confounders, were employed to investigate the relationship between normalized ALP levels and patient characteristics. ResultsNormalized PTH showed a J-shaped association with all-cause/CV mortality, and a weak linear association with fracture. In contrast, normalized ALP showed a strong association with all outcomes. Factors associated with higher ALP levels after controlling for PTH included Black race, longer dialysis vintage, diabetes mellitus, hypocalcemia, hypophosphatemia, elevated C-reactive protein, and the use of cinacalcet. ConclusionsTotal ALP is a more robust exposure of adverse outcomes than PTH in HD patients. PTH responsiveness is affected by race, primary renal disease, comorbidities, and mineral metabolism and therapy. Our results indicate that it may be useful to evaluate target organ response, rather than PTH alone when considering the consequences of secondary hyperparathyroidism.