Outcome predictability of serum alkaline phosphatase in men with pre-dialysis CKD

Abstract

Background: Serum alkaline phosphatase (ALP) increases in patients with chronic kidney disease (CKD) and high-turnover bone disease. ALP may represent an adjunct marker of high bone turnover devoid of drawbacks of serum parathyroid hormone (PTH), and it may also be associated with cardiovascular calcification in CKD. Higher ALP has been recently associated with increased mortality and coronary calcification in dialysis patients. In pre-dialysis CKD patients, this association is not clear.

Methods: We examined the association of baseline, time-varying and time-averaged ALP with all-cause mortality and the composite of pre-dialysis mortality or end-stage renal disease in a historical prospective cohort of 1158 male veterans with pre-dialysis CKD from a single institution by using multivariable-adjusted Cox models.

Results: Higher ALP was associated with increased mortality irrespective of the statistical model. Time-averaged ALP displayed a consistent linear association with mortality: a 50-U/L higher serum ALP was associated with a multivariable-adjusted death hazard ratio (95% confidence interval) of 1.17 (1.08-1.28), P < 0.001. Baseline and time-varying ALP showed non-linear associations with mortality, with serum levels above 70 U/L in all models and with lower levels in time-varying models. Associations between ALP levels and the composite outcomes were similar. However, compared to serum PTH, mortality predictability of ALP appeared more incremental.

Conclusions: Elevated ALP is associated with increased mortality in patients with pre-dialysis CKD. Low ALP appears to be associated with short-term mortality.

Fig. 1

Unadjusted (A) and multivariable-adjusted (B) log hazards (solid lines) and 95% CI (dashed lines) of all-cause mortality associated with baseline levels of serum ALP in Cox models. Multivariable models were adjusted for age, race, comorbidities, blood pressure, BMI, smoking status, medication use, enrolment period, estimated GFR, serum albumin, bicarbonate, AST, ALT, calcium, phosphorus, blood haemoglobin, WBC, percentage of lymphocytes in WBC and 24-h urine protein. P-values represent the joint significance of the polynomial terms for ALP by the Wald test.

Fig. 2

Unadjusted (A) and multivariable-adjusted (B) log hazards (solid lines) and 95% CI (dashed lines) of all-cause mortality associated with time-varying levels of serum ALP in Cox models. Multivariable models were adjusted for age, race, comorbidities, blood pressure, BMI, smoking status, medication use, enrolment period, estimated GFR, serum albumin, bicarbonate, AST, ALT, calcium, phosphorus, blood haemoglobin, WBC, percentage of lymphocytes in WBC and 24-h urine protein. P-values represent the joint significance of the polynomial terms for ALP by the Wald test.

Fig. 3

Unadjusted (A) and multivariable-adjusted (B) log hazards (solid lines) and 95% CI (dashed lines) of all-cause mortality associated with time-averaged levels of serum ALP in Cox models. Multivariable models were adjusted for age, race, comorbidities, blood pressure, BMI, smoking status, medication use, enrolment period, estimated GFR, serum albumin, bicarbonate, AST, ALT, calcium, phosphorus, blood haemoglobin, WBC, percentage of lymphocytes in WBC and 24-h urine protein. P-values represent the joint significance of the polynomial terms for ALP by the Wald test.

Fig. 4

Multivariable-adjusted associations between quartiles of time-averaged serum ALP and serum PTH and all-cause mortality. Patients in the first quartiles served as the reference group. Multivariable models were adjusted for age, race, comorbidities, blood pressure, BMI, smoking status, medication use, enrolment period, estimated GFR, serum albumin, bicarbonate, AST, ALT, calcium, phosphorus, blood haemoglobin, WBC, percentage of lymphocytes in WBC and 24-h urine protein.

Fig. 5

Multivariable-adjusted hazard ratios (95% CI) of all-cause mortality associated with a 50-U/L higher time-averaged serum ALP level in select subgroups. Multivariable models were adjusted for age, race, comorbidities, blood pressure, BMI, smoking status, medication use, enrolment period, estimated GFR, serum albumin, bicarbonate, AST, ALT, calcium, phosphorus, blood haemoglobin, WBC, percentage of lymphocytes in WBC and 24-h urine protein.