Serum 1,25-dihydroxyvitamin D: an outcome prognosticator in human sepsis

Abstract

In sepsis, the vitamin D active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D) may play a crucial role by its action to produce cathelicidin and improve endothelial barrier function, such that a deficiency in 1,25(OH)2D is associated with poor outcome. To test our hypothesis, we performed analysis of stored plasma samples from a prospective observational study in 91 patients with sepsis, age of 59.1+/-2.0 years, 52.7% females, and 11.0% deaths at 30 days. Vitamin D status, including 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), and parathyroid hormone (PTH), were measured daily over 3 days after hospital admission. At baseline, 1,25(OH)2D was significantly different between survivors vs. non-survivors. But there was no significant difference in 25(OH)D, 24,25(OH)2D, and PTH. In a multivariable binomial logistic regression model, age, total calcium and 1,25(OH)2D were significant predictors of 30-day mortality. Kaplan Meier analysis showed that patients with mean 1,25(OH)2D measured over 3 days of < = 13.6 pg/mL had 57.1% 30-day survival compared to 91.7% in patients with 1,25 (OH)2D level >13.6 pg/mL (p<0.01). From repeated measures regression analysis, there was significant increase in 1,25(OH)2D for increases in 25(OH)D in both survivors and non-survivors. However, compared to survivors, the low 25(OH)D in non-survivors was insufficient to account for the larger decrease in 1,25(OH)2D, indicating a dysfunctional 1α-hydroxylase. Additionally, there was a significant negative correlation between PTH and 1,25(OH)2D in both survivors and non-survivors, suggesting a severe impairment in the effect of PTH to increase renal 1α-hydroxylase activity. In conclusion, low 1,25(OH)2D levels are associated with increased 30-day mortality in sepsis patients, likely due to impaired 25(OH)D hydroxylation and PTH insensitivity. Our data also suggest that the active metabolite 1,25(OH)2D may be an important therapeutic target in the design of sepsis clinical trials.

Figure 1. Receiver operating characteristic (ROC) curves for age, total calcium, 1,25-dihydroxyvitamin D (1,25(OH)₂D) at hour 48, and the multivariable model including these 3 variables in discriminating survivors from non-survivors at 30 days after enrollment.

AUC – Area under the ROC curve.

Figure 2. Kaplan Meier survival analysis between patients with mean 1,25-dihydroxyvitamin D (1,25(OH)₂D)<vs.>13.6 pg/mL measured over the 72-study period.

The mean survival time for patients with 1,25(OH)₂D<13.6 pg/mL was 17.6 days, compared to 24.6 days in patients with 1,25 (OH)₂D level >13.6 pg/mL (p<0.01).

Figure 3. 1,25-dihydroxyvitamin D (1,25(OH)₂D) as a function of 25-hydroxyvitamin D (25(OH)D).

In both survivors and non-survivors, there was a significant increase in ln(1,25(OH)₂D) for increases in ln(25(OH)D) (p<0.01 and p = 0.02, respectively), such that ln(1,25(OH)₂D) = 2.39+0.34(ln(25(OH)D)) for survivors, and 1.88+0.34(ln(25(OH)D)) for non-survivors. For the same level of 25(OH)D, 1,25(OH)₂D would be lower in non-survivors compared to survivors (p<0.01).

Figure 4

1,25-dihydroxyvitamin D (1,25(OH)₂D) as a function of parathyroid hormone (PTH). The plot shows that in both groups, there is a parallel decrease in ln(1,25(OH)₂D) for increases in ln(PTH). In the survivors, this relationship is significant (p<0.01). However, the change was not significant in the non-survivors possibly due to small number of subjects (p = 0.80).