Joint Longitudinal Low Calcium High Phosphorus Trajectory Associates with Accelerated Progression, Acute Coronary Syndrome and Mortality in Chronic Kidney Disease

Abstract

The effects of long-term disturbance of the mineral metabolism on patients with chronic kidney disease (CKD) are unclear. We investigated whether the longitudinal Ca-P (joint calcium and phosphorus) trajectories are associated with incident end-stage renal disease (ESRD), acute coronary syndrome (ACS), and all-cause mortality in patients with CKD. We conducted a prospective cohort study by using data from a 13-year multidisciplinary pre-ESRD care registry. The final study population consisted of 4,237 CKD patients aged 20-90 years with data gathered from 2003 to 2015. Individuals' Ca-P trajectories were defined using group-based multi-trajectory modeling into three distinct patterns: reference, moderately abnormal, and severely abnormal. Times to ESRD, ACS, and death were analyzed using multiple Cox regression. Compared with those with a "reference" Ca-P trajectory, the adjusted hazard ratios (aHRs) (95% confidence interval [CI]) for incidental ESRD were 5.92 (4.71-7.44) and 15.20 (11.85-19.50) for "moderately abnormal" and "severely abnormal" Ca-P trajectories, respectively. The corresponding aHRs for ACS were 1.94 (1.49-2.52) and 3.18 (2.30-4.39), and for all-cause mortality, they were 1.88 (1.64-2.16) and 2.46 (2.05-2.96) for "moderately abnormal" and "severely abnormal" Ca-P trajectories, respectively. For outcomes of progression to ESRD, the detrimental effects of abnormal Ca-P trajectories were more substantial in patients with CKD stage 3 than those with CKD stage 4 or 5 (p-value for interaction < 0.001). Future studies should validate reliable longitudinal cut-offs of serum phosphorus and consider the "lowering phosphorus- the lower the better, the earlier the better" approach to phosphorus control in CKD.

Figure 1

Calcium, phosphors, and Ca×P trajectories defined by group-based multi-trajectory modelling (GBMM) of serial quarterly average levels of calcium, phosphorus, and Ca×P. The solid line is the averaged estimated trajectory, whereas the points represent the averaged observed trajectory (N = 4,237). Reference Ca-P trajectory: Normal calcium/ mildly high phosphorus trajectory; Moderately abnormal Ca-P trajectory: Mildly low calcium/ moderately high phosphorus trajectory; Severely abnormal Ca-P trajectory: Low calcium/ high phosphorus trajectory.

Figure 2

Adjusted hazard ratios (HRs) for end-stage renal disease (ESRD) requiring dialysis, Acute coronary syndrome (ACS) and all-cause mortality according to the baseline levels of calcium, phosphorus, and calcium-phosphorus (Ca×P) product. Solid lines represent adjusted HRs based on restricted cubic splines for baseline calcium, phosphorus and Ca×P, with knots at the 10th, 50th, and 90th percentiles. Shaded areas represent upper and lower 95% confidence intervals. Reference was set at 10th percentile of baseline calcium, phosphorus and Ca×P. Upper panel: risk of progression to ESRD requiring dialysis (blue); middle panel: risk of ACS (orange); lower panel: all-cause mortality (red). Variables adjusted are the same as those shown in Model 3 in Table 2.

Figure 3

Kaplan-Meier curves of dialysis-free survival, ACS-free survival and overall survival, according to Ca-P trajectories generated by group-based multi-trajectory modelling (N = 4237). ACS, Acute coronary syndrome.

Figure 4

Subgroup analysis for associations between Ca-P trajectories and adverse outcomes according to baseline characteristics. Reference Ca-P trajectory: Normal calcium/ mildly high phosphorus trajectory; Moderately abnormal Ca-P trajectory: Mildly low calcium/ moderately high phosphorus trajectory; Severely abnormal Ca-P trajectory: Low calcium/ high phosphorus trajectory.

Figure 5

Flow diagram of the study selection process.