Serum Alkaline Phosphatase Has Prognostic Importance in Chronic Kidney Disease

By Jonathan Taliercio, DO, and Sankar Navaneethan, MD, MPH

Elevated serum alkaline phosphatase (ALP) contributes to the development and progression of vascular calcification. Studies conducted in the general population and in the population of patients on hemodialysis have shown independent associations between ALP and an increased risk of cardiovascular events, hospitalization and death. In selective non-dialysis-dependent chronic kidney disease (CKD) populations (i.e., African Americans, males), higher ALP levels are associated with an increased risk of all-cause mortality.

The relationships between ALP and mortality and between ALP and progression to end-stage renal disease (ESRD) in a larger heterogeneous population are unclear. We therefore examined these relationships in a large, diverse non-dialysis-dependent CKD population followed in our healthcare system.

Patient identification

Using the electronic medical record-based CKD registry at Cleveland Clinic, we identified 28,678 patients who had outpatient ALP levels measured between the first and second confirmatory estimated glomerular filtration rate (eGFR) value < 60 mL/minute/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Baseline characteristics were compared between CKD patients with and without elevated ALP using Chi-square tests for categorical variables and t-tests or Wilcoxon rank-sum tests for continuous variables. Kaplan-Meier plots and logrank tests were used to analyze survival and ESRD. Patients with chronic kidney disease with measured outpatient ALP values were classified into quartiles: < 66 units/liter (U/L); 66 to 81 U/L; 82 to 101 U/L and ≥ 102 U/L.

Mean age of the study population was 72 (±12) years; 54 percent were female and 12 percent were African American. After a median follow-up of 2.2 years, 588 patients developed ESRD and 4,755 died before reaching ESRD. There were 191 patients who developed ESRD and later died. The Kaplan-Meier and competing risk analyses showed a significant difference in overall mortality and ESRD among those with different ALP levels (p < 0.001; Figure 1). The associations between ALP level and death and ALP level and ESRD were similar when examined as a continuous variable (Figure).

Figure. Kaplan-Meier and competing risk analyses show increasing probability of end-stage renal disease and mortality with increasing levels of serum alkaline phosphatase.

In the multivariate adjusted analysis, each standard deviation (SD) increase in ALP level (42.7 U/L) was associated with a 16 percent increased hazard for death and a 15 percent increased hazard for ESRD. When the analysis was restricted to those who had ALP levels within the normal range (< 149 U/L), similar results were observed.

In a subgroup analysis of patients for whom serum phosphorus data were available (n = 5,667), when adjusting for serum phosphorus level, each SD increase in ALP level was associated with a 10 percent increased hazard for mortality (95 percent confidence interval [CI]: 1.06-1.14) and a nonsignificant 9 percent increased risk for ESRD (95 percent CI: 0.99-1.19). In a subgroup analysis of patients with at least one urinary protein measure (n = 14,116), after adjusting for all covariates plus proteinuria, each SD increase in ALP level was associated with a 16 percent increased hazard for mortality (95 percent CI: 1.12-1.19) and a 17 percent increased hazard for ESRD (95 percent CI: 1.07-1.26).

Proposed renal damage mechanism

Historically, ALP level has only been considered a surrogate of bone metabolism in patients with CKD and ESRD. Alkaline phosphatase is derived from various tissues but is mostly concentrated in the liver, biliary ducts, bone and placenta. Tissue-nonspecific ALP inactivates pyrophosphate, an endogenous inhibitor of hydroxyapatite formation, resulting in medial arterial vascular calcification. Under conditions such as hypertension, aging, diabetes and CKD, vascular cells undergo osteoblastic differentiation and express several bone-associated proteins, including ALP. Subsequently, this differentiation leads to mineralization of the endothelium, arterial stiffening and vascular calcification, thereby contributing to cardiovascular disease and mortality in CKD.

We observed an independent association between higher ALP levels and ESRD. Apart from vascular calcification, arterial stiffness as measured by central pressures might contribute to the progression of CKD. The proposed mechanism of renal damage from arterial stiffness includes (a) highly pulsatile blood pressure and flow to the low-resistance renal vascular bed, and (b) defects in the filtration barrier leading to intraglomerular hypertension, hyperfiltration and eventual nephrosclerosis.

Conclusions

In summary, elevated ALP levels are associated with an increased risk of ESRD and all-cause mortality in non-dialysis-dependent CKD patients. These findings, along with previous studies, suggest that clinicians may use ALP as a risk assessment tool to identify patients with higher risk for mortality and/or progression to ESRD.

Dr. Taliericio (talierj@ccf.org) is a Physician in the Department of Nephrology and Hypertension at Cleveland Clinic’s Glickman Urological & Kidney Institute.

Dr. Navaneethan (navanes@ccf.org) is aPhysician in the Department of Nephrology and Hypertension at Cleveland Clinic’s Glickman Urological & Kidney Institute.