In end-stage kidney disease (ESKD) patients, elevated levels of tissue-non specific Alkaline phosphatase (ALPL) associate with mortality independent of liver function and bone mineral disorder parameters. ALPL measurements in ESKD may be confounded by various environmental. To further investigate the issue we studied the ALPL gene genetic polymorphisms adopting the Mendelian randomization approach.
We studied 265 dialysis patients who underwent echocardiography, followed-up for a mean time of 3.7 years. Eighteen polymorphisms in ALPL gene, capturing over 80% of the genetic, were investigated. The study end-points were death and LV remodeling.
We focused on two polymorphisms associated with mortality (rs1780314, P=0.02 and rs4654957, P=0.06). During the follow-up period 141 patients died, 31% of CV causes. The G allele of rs1780314 was a direct predictor of death [HR (AG+GG): 1.61, 95% CI: 1.07-2.45, P=0.02] and the A allele of rs4654957 showed the same tendency [HR (TA+AA): 1.41, 95% CI: 0.99-2.02, P=0.06]. A genetic risk score (GRS) based on the two polymorphisms significantly predicted all-cause mortality [HR: 1.35, 95% CI: 1.07-1.70, P=0.01]. Serum ALPL was higher (+14%) in patients having the highest GRS as compared to those in the lowest GRS category. At echocardiography, 65% of patients displayed LVH (46% of patients had concentric LV geometry and 38% of patients had eccentric remodeling). The ALPL-GRS was directly related to relative wall thickness (r=0.16, P=0.01) and posterior wall thickness (r=0.13, P=0.04). Accordingly, the ALPL-GRS was robustly related with LV concentric remodeling (odds ratio: 1.71, 95% CI: 1.19-2.46, P=0.004) even after extensive adjustment (odds ratio: 1.64, 95% CI: 1.12-2.41, P=0.01).
In this study the ALPL-GRS emerged as a robust predictor of death and concentric LV remodeling in ESKD patients. These findings support the contention that high ALPL levels in ESKD play a causal role in the high risk of death and cardiomyopathy in this population.