Evolution of Markers of Mineral Metabolism in Patients with CKD Stage 3b

Patients with chronic kidney disease (CKD) commonly experience disordered mineral metabolism, a complication that is associated with increased risk for cardiovascular disease events, progression to end-stage renal disease (ESRD), and mortality. Changes in levels of markers of mineral metabolism evolve over time and understanding those changes will provide insights into the pathogenesis of the condition in CKD, enable epidemiologic analyses that relate temporal trends to the risk for adverse events, and facilitate identification of high-risk patterns of changes that can be targeted for interventions.

To date, the pathogenesis of disordered mineral metabolism in CKD has been informed by cross-sectional studies in humans and longitudinal studies in animals. Tamara Isakova, MD, MMSc, and colleagues recently conducted a retrospective analysis nested in a cohort study to characterize the longitudinal evolution of the condition during the course of CKD. Results of the analysis were reported in the American Journal of Kidney Diseases [2020;75(2):235-244].

Cross-sectional data from the CRIC (Chronic Renal Insufficiency Cohort) Study reported that elevated levels of fibroblast growth factor 23 (FGF-23) were more prevalent at higher estimated glomerular filtration rates (eGFR) than secondary hyperparathyroidism or hyperphosphatemia. The findings suggested that FGF-23 excess preceded the onset of secondary hyperparathyroidism or hyperphosphatemia in patients with CKD. For the current analysis, the researchers examined a subset of CRIC participants who developed ESRD to test the hypothesis that in the prelude to ESRD, FGF-23 levels would increase more rapidly compared with changes in levels of other mineral metabolites.

The study population included 847 individuals who progressed to ESRD during CRIC follow-up. Participants had advanced CKD (identified by low eGFR and high urinary albumin-creatinine ratio) and a high prevalence of comorbidities and risk factors for progression of CKD. Fewer than 10% of participants were prescribed nutritional vitamin D (7.7%), phosphate binders (8.0%), or active vitamin D (5.2%) at enrollment.

The mean age of the cohort was 55.5 years, 40% were women, 52.3% were black, 17.4% were Hispanic, and 16.3% were current smokers. Overall, 93.7% had hypertension, 65.4% had diabetes, 12.9% had heart failure, 9.8% had peripheral vascular disease, and 23.9% had coronary artery disease.

In the longitudinal analyses, time was expressed as years before ESRD onset rather than being anchored to the CRIC Study annual visits in order to assess levels of mineral metabolites spanning 8 years of CKD progression prior to development of ESRD. The analyses revealed the rates of change in the levels, provided an assessment of how rapidly the changes developed during a time frame when eGFR declined progressively, and identified when change points occurred in relation to years before ESRD.

Overall, there was a steeper increase in FGF-23 levels over time compared with more modest elevations in parathyroid hormone (PTH) and phosphate levels. Levels of calcium were predominately stable; as ESRD neared, calcitriol levels steadily declined.

To estimate rates of change of concentrations of FGF-23, PTH, phosphate, and calcium, the researchers calculated the first and second derivatives of the longitudinal functions over time as CKD progressed to ESRD: (1) velocity and (2) magnitude of acceleration.

Compared with the other metabolites, levels of FGF-23 demonstrated the highest rate of change (first derivative) and magnitude of acceleration (second derivative). The changes became apparent approximately 5 years prior to ESRD and persisted without deceleration through onset of ESRD. At approximately the same time, there were modest increases in levels of PTH and phosphate, with modest deceleration immediately prior to ESRD when use of Vitamin D and phosphate binders increased.

The researchers cited some limitations to the study findings, including the inability to assess changes in levels of  a-klotho and intake FGF-23 because those measurements were not available in the CRIC Study; the lack of measurements of serial levels of urinary phosphate excretion, dietary phosphate intake, 25-hydroxyvitamin D, and iron status; and lack of data on the heterogeneity by CKD subtype. In addition, the study included only participants who progressed to ESRD during follow-up, excluding participants who entered the CRIC Study at early stages of CKD who did not progress to ESRD during follow-up.

In summary, the researchers said, “Disordered mineral metabolism is a progressive disorder that develops early in the course of CKD, continues through the period of ESRD, and often persists into the post-transplantation period. Based on a cross-sectional analysis of the CRIC Study, we previously concluded that patients with eGFR <60 mL/min/1.73 m² could be targeted for clinical trials testing interventions for disordered mineral metabolism. Our findings from ESRD-anchored longitudinal analyses suggest that a critical period in the pathogenesis is approximately 5 years before ESRD, or at CKD stage 3b. Although the necessity to intervene is debated by guideline groups, our current results would suggest that it is prudent to consider close surveillance of disordered mineral metabolism in patients with CKD stage 3b. Because this population is likely to experience dynamic changes in levels of markers of mineral metabolism over time, clinical investigators may opt to target patients with CKD stage 3b for future trials aimed at testing novel interventions for disordered mineral metabolism.”

Takeaway Points

1. Researchers analyzed data from the CRIC Study to characterize the longitudinal evolution of disordered mineral metabolism during the course of chronic kidney disease.
2. There was a marked increase in mean levels of fibroblast growth factor 23 (FGF-23) as time to end-stage renal disease (ESRD) decreased; there was a modest increase in levels of parathyroid hormone and phosphate and a minimal decrease in calcium.
3. Compared with the other markers, FGF-23 levels showed the highest rate of change and magnitude of acceleration of disordered mineral metabolism; the changes were evident ~5 years prior to the onset of ESRD.