Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Abstract

Rationale & objective: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD.

Study design: Retrospective analysis nested in a cohort study.

Setting & participants: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847).

Exposure: Years before ESKD.

Outcomes: Serial FGF-23, PTH, serum phosphate, and serum calcium levels.

Analytical approach: To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD.

Results: Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased.

Limitations: Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied.

Conclusions: Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Keywords: CKD progression; Chronic kidney disease (CKD); biomarker; calcium; disordered mineral metabolism; end-stage renal disease (ESRD); fibroblast growth factor 23 (FGF-23); incident kidney failure; kidney function; longitudinal trends; parathyroid hormone (PTH); phosphate; serial measurements.

Figure 1.. Serial eGFR and levels of mineral metabolites prior to ESRD onset.

A) Mean (standard deviation) in eGFR prior to ESRD transition; B) Box plots of ln(FGF-23), ln(PTH), phosphate, and calcium levels prior to ESRD transition; C) Repeated measures of eGFR, FGF-23, PTH, phosphate, and calcium prior to ESRD transition.

Figure 2.. Population mean levels of mineral metabolites prior to ESRD onset.

Cubic spline smoothed population mean levels (with 95% confidence intervals) in ln(FGF-23) (red), ln(PTH) (green), phosphate (blue), and calcium (orange) levels prior to ESRD transition. Shaded areas represent 95% confidence intervals.

Figure 3.. Serial calcitriol concentrations prior to ESRD onset.

Box plots of calcitriol levels prior to ESRD transition.

Figure 4.. Rates of change and acceleration in mineral metabolites prior to ESRD transition.

First and second derivatives of A) FGF-23; B) PTH; C) phosphate; and D) calcium estimated by cubic spline approach. First derivative denotes rate of change and second derivative represents acceleration. Values are shown as estimated rate of change (blue) and acceleration (red), and shaded areas represent 95% confidence intervals.

Figure 5.. Use of phosphate binders and nutritional and active vitamin D prior to ESRD onset.

Percentage of use of phosphate binders and nutritional and active vitamin D by years prior to ESRD onset.

Figure 6.. Population mean levels of mineral metabolites restricted to observations prior to initiation of phosphate binders and nutritional and active vitamin D.

Cubic spline smoothed population mean levels (with 95% confidence intervals) in ln(FGF-23) (red), ln(PTH) (green), phosphate (blue), and calcium (orange) levels prior to ESRD transition. Shaded areas represent 95% confidence intervals. The table below the plot depicts the number of participants with available measurements of FGF-23, PTH, phosphate, and calcium by years prior to ESRD transition. Repeated measures values are shown as median (interquartile range) for FGF-23 and PTH and mean ± standard deviation for phosphate and calcium.