Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis

Abstract

Background: Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies.

Methods: We updated a prior systematic review through 2010. Studies included adults receiving dialysis and reported categorical data for calcium, phosphorus, and/or parathyroid hormone (PTH) together with all-cause mortality. We performed 2 separate meta-analyses to compare higher-than-referent levels vs referent and lower-than-referent levels vs referent levels.

Results: A literature review showed that when a linear relationship between the minerals and mortality was assumed, the estimated associations were more likely to be smaller or non-significant compared to non-linear models. In the meta-analyses, higher-than-referent levels of phosphorus (4 studies, RR = 1.20, 95% CI = 1.15-1.25), calcium (3 studies, RR = 1.10, 95% CI = 1.05-1.14), and PTH (5 studies, RR = 1.11, 95% CI = 1.07-1.16) were significantly associated with increased mortality. Although no significant associations between relatively low phosphorus or PTH and mortality were observed, a protective effect was observed for lower-than-referent calcium (RR = 0.86, 95% CI = 0.83-0.89).

Conclusions: Higher-than-referent levels of PTH, calcium, and phosphorus in dialysis patients were associated with increased mortality risk in a selection of observational studies suitable for meta-analysis of non-linear relationships. Findings were less consistent for lower-than-referent values. Future analyses should incorporate the non-linear relationships between the minerals and mortality to obtain accurate effect estimates.

Figure 1

Hypothesized relationship between biochemical parameters and mortality risk.

Figure 2

Flow diagram: publications documenting the association between relatively high/low biochemical parameters and mortality.

Figure 3

Studies used in the meta-analysis of biochemical parameters and mortality. In these studies, biochemical parameter levels were analyzed as categorical variables. In order to visualize the relationship between mortality and the biochemical parameters, the values on the x-axis for each symbol in the figure represent the midpoint within each category for each study. In order to make the graphical representation more comparable across studies, we adjusted the HRs so that the midpoint of the reference range was as similar as possible. We stress that this is done just for the figures only and not for the meta-analyses. Specific adjustments are noted below.a. Phosphorus: The midpoints of reference ranges were ≈4- 4.5 mg/dL across all studies with the exception of Kalantar-Zadeh 2006 [14]. For this study, we adjusted the graphical depiction of the reference range from 5–6 mg/dL to 4–5 mg/dL. Of note, non-linear relationships were most clearly evident in the 2 studies with the largest sample sizes. b. Calcium: The midpoints of reference ranges were ≈9-9.25 mg/dL across all studies. No studies had to be adjusted for graphical display. c. PTH: The midpoints of reference ranges were ≈225-250 pg/mL across all studies with the exception of Dukkipati 2010 [29]. For this study, we adjusted the graphical depiction of the reference range from 300–600 pg/mL to 200–249 pg/mL.