Coronary Artery Calcification and Serum Calcification Propensity in Patients with CKD

The leading cause of death among patients with chronic kidney disease (CKD) is cardiovascular disease. Patients with CKD may develop vascular calcification, one mechanism that increases the cardiovascular disease risk in that patient population. Medial calcification is associated with increased arterial stiffness and heart failure; patients with CKD are also at risk for intimal calcification, indicative of atherosclerosis.

The coronary artery calcium (CAC) score includes both types of calcification. There is a strong association between CAC presence and progression and cardiovascular disease in the general population. Earlier studies have shown an association between reduced kidney function and more severe calcification as well as more rapid progression of CAC. In patients with CKD stages 2 to 4, CAC score is an independent risk predictor for cardiovascular disease and all-cause mortality.

The Chronic Renal Insufficiency Cohort (CRIC) study provided an opportunity for Joshua D. Bundy, PhD, MPH, and colleagues to examine the associations between transformation time (T₅₀) and the presence and progression of CAC in a diverse sample of patients with CKD stages 2 to 4. Higher calcification propensity is denoted by lower T₅₀. The researchers utilized CRIC data to test the hypothesis that there would be an association between low T₅₀ values and prevalent and incident CAC in patients with CKD stages 2 to 4. Results of the prospective cohort study were reported in the American Journal of Kidney Diseases [2019;73(6):806-814].

Of the total CRIC cohort, 1274 participants had available data for computed tomography (CT) and T₅₀ and were included in the current analysis. Mean age was 57.5 years, 46.9% were women, 44.3% had diabetes, 27.2% had a history of cardiovascular disease, and mean estimated glomerular filtration rate (eGFR) was 44.5 mL/min/1.73 m².

Median T₅₀ was 321 minutes. Participants with low T₅₀ were more likely to be non-Hispanic black (P<.001), have a history of cardiovascular disease (P=.004) and diabetes (P<.001), and be taking antihypertensive (P<.001), statin (P=.01), and active vitamin D medications (P<.001). On average, those with low T₅₀ had higher systolic blood pressures (P=.006), 24-hour urine protein excretion (P<.001) and phosphate (P<.001), fibroblast growth factor 23 (FGF-23) (P<.001), parathyroid hormone (PTH) (P<.001), interleukin 6 (IL-6) (P=.001), and high-sensitivity C-reactive protein (hsCRP) (P=.002) levels, and lower eGFR (P=.001), bicarbonate (P<.001), calcium (P=.006), magnesium (P=.005), serum albumin (P<.001), and fetuin-A (P<.001) values.

A total of 824 of the 1274 participants had CAC at baseline. Participants were stratified into quartiles based on T₅₀: 367-600; 322-366; 270-321; and 72-269 minutes. Mild CAC severity (<100 Agatston units) was similar among the T₅₀ quartiles; lower quartiles were more likely to have severe CAC (>400 Agatston units).

In cross-sectional associations of T50 with prevalence and severity of CAC, following multivariable adjustment there was no association between T₅₀ and the prevalence of CAC score >0. However, there was an association between lower T₅₀ and greater CAC severity among participants with baseline CAC. Following multivariable adjustment, one standard deviation lower T₅₀ value was associated with 21% greater CAC severity. There were also graded associations across T₅₀ quartiles. There was a significant association between lower T₅₀ and greater prevalence of moderate and severe CAC.

In examination of longitudinal associations of T₅₀ with the incidence and progression of CAC among 780 participants with follow-up CT an average of 3.2 years later, among the 320 participants without CAC at baseline, 65 developed CAC during follow-up. There was no association between T₅₀ and incident CAC. Among 460 participants with baseline CAC, 89 had an annual increase of ≥100 Agatston units and 37 had an annual increase of ≥200 Agatston units; there was an association between T₅₀ and both definitions of progression. Following multivariable adjustment, there was an association between one standard deviation lower T₅₀ value and 28% higher risk for progressing ≥100 Agatston units per year. There were graded associations across T₅₀ quartiles.

There were no significant associations between T₅₀ and age, sex, race/ethnicity, or diabetes. Following adjustments for potentially associated variables (calcium, phosphate, bicarbonate, magnesium, serum albumin, fetuin-A, FGF-23, and PTH levels as well as use of medications including warfarin, active vitamin D, phosphate binders, and calciferols and inflammatory variables (IL-6 and hsCRP levels), results were similar to the primary analyses.

The researchers cited possible limitations to the study, including conducting the T₅₀ test in vitro with supersaturation of calcium and phosphate that results in synthetic calciprotein particles, the possibility of selection bias, the relatively small sample size, the inability to evaluate some additional markers, the inability to distinguish between intimal and medial calcification due to limitations of CT technology, and limiting CT measurement to one point during follow-up.

The researchers said, “In conclusion, higher serum calcification propensity, denoted by lower T₅₀, was significantly associated with the severity and progression of CAC among patients with CKD. However, T₅₀ was not associated with the incidence of CAC. These findings provide valuable insights into the development of calcification and atherosclerosis in patients with CKD and highlight potential pathways for risk stratification and therapeutic intervention. Future research should evaluate these associations in other CKD populations and the general population, and clinical trials may be warranted to establish causality.”

Takeaway Points

1. Patients with chronic kidney disease (CKD) have a high prevalence of coronary artery calcification (CAC ), increasing the risk for cardiovascular disease events and mortality. Researchers conducted a prospective cohort study to test the hypothesis that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4.
2. The study included participants from the CRIC (Chronic Renal Insufficiency Cohort) study with baseline (n=1274) and follow-up (n=780) CAC measurements. At baseline, 65% (n=824) of the cohort had prevalent CAC.
3. Following multivariable adjustment, there was no association between transformation time (T₅₀) and CAC prevalence; there was an association between T₅₀ and greater severity of CAC among the patients with prevalent CAC.