Association between Folic Acid Treatment and CKD Progression Varies by Vitamin B12 Level

Compared with the general population, patients with chronic kidney disease (CKD) have a substantially increased risk for kidney failure, cardiovascular disease, and mortality despite standard  interventions for the management of traditional risk factors associated with CKD. According to Youbao Li, MD, and colleagues, new treatment approaches are needed.

Hyperhomocysteinemia is prevalent and significantly related to decline in kidney function among patients with CKD. Homocysteine is a sulfur-containing acid. The remethylation pathway of homocysteine metabolism is regulated by folate and vitamin B₁₂ (B12). In populations with fortification or supplementation of folic acid, the main nutritional determinant of total homocysteine (tHcy) level is B12 status.

Results of the renal substudy of the China Stroke Primary Prevention Trial (CSPPT) suggest that treatment with folic acid can significantly delay CKD progression by 55% among hypertensive patients with mild-to-moderate CKD. There are few data on the effect of naturally occurring serum B12, without supplements, on the association between folic acid treatment and  CKD progression. Dr. Li et al. conducted a post hoc analysis of the renal substudy of the CSPPT. Results were reported in the American Journal of Kidney Diseases [2020;75(3):325-332].

Of the 20,702 hypertensive adults enrolled in the CSPPT trial, 15,104 were enrolled in the renal substudy. Results of the renal substudy found no significant difference in the odds of progression to CKD in the enalapril-folic acid group compared with the enalapril-alone group in the total population. However, among participants with CKD at baseline (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m² and/or proteinuria), the odds of CKD progression (primary outcome) were reduced by 55% with folic acid treatment. The odds of the composite outcome of the primary outcome and all-cause death were reduced by 35%.

For the current analysis, only patients with CKD at baseline were included. A total of 1374 participants with CKD and B12 measurements at baseline were included in the analysis of the primary outcome, and 1445 participants with CKD and B12 measurements at baseline were included in the analysis of the composite outcome analysis.

The primary outcome, progression of CKD, was defined as a decrease in eGFR of ≥30% and to a level of <60 mL/min/1.73 m² at the exit visit if baseline eGFR was ≥60 mL/min/1.73 m²; or a decrease in eGFR ≥50% at the exit visit if the baseline eGFR was <60 mL/min/1.73 m²; or kidney failure (eGFR <15 mL/min/1.73 m² or the need for dialysis). Secondary outcomes were (1) a composite outcome of the primary outcome and all-cause death; (2) rapid decline in eGFR (average decline ≥5 mL/min/1.73 m² per year; and (3) the annual rate of relative decline in eGFR.

Participants were stratified by tertiles of B12. Overall, mean eGFR at baseline was 86.1 mL/min/1.73 m². Those with higher levels of B12 were less likely to be carriers of MTHFR 677 TT (the gene encoding methylenate-trahydrofolate reductase); had higher levels of fasting glucose, total cholesterol, and folate; and had higher living standards. They also tended to consume more red meat; but had lower tHcy levels and lower prevalence of proteinuria at baseline. Within each baseline B12 stratum, nearly all baseline characteristics were comparable between the two treatment groups (enalapril-folic acid group and enalapril-alone group).

Median duration of treatment was 4.4 years. Mean treatment adherence (percentage of the study medication actually taken during the trial) was approximately 80% in both treatment groups within each baseline B12 stratum. Patient withdrawal was defined as discontinuing the use of study drugs for any reason more than 180 days prior to termination of the study; the rates of patient withdrawal ranged from 6.0% to 11.7% within treatment groups among each baseline B12 stratum. All participants were included in the analysis irrespective of treatment withdrawal. The two treatment groups were similar in use of concomitant medication use during the trial.

There were no associations between baseline B12 levels and the primary or secondary renal outcomes. Among participants with higher baseline B12 levels (≥248 pmol/L), compared with enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary renal outcome (1.6% in the enalapril-folic acid group vs 7.8% in the enalapril alone group; odds ratio [OR], 0.17; 95% confidence interval [CI], 0.07-0.40). Among those with metabolic B12 deficiency (B12 levels <248 pmol/L), there was no significant difference in the primary outcome between the two groups (OR, 1.21; 95% CI, 0.51-2.85).

Among participants with baseline B12 levels in tertiles 2 or 3 (≤244 pmol/L), there was an association between treatment with enalapril-folic acid and an 80% reduction in the odds of the primary outcome (OR, 0.20; 95% CI, 0.09-0.45) compared with enalapril alone. Among those in the lowest tertile of B12 level (<244 pmol/L), there was no significant difference between the two groups in the primary outcome (OR, 1.07; 95% CI, 0.45-2.57).

Following exclusion of participants with B12 levels >555 pmol/L or exclusion of participants who withdrew from the study treatment, similar results were observed. Similar trends were also seen in participants with eGFRs of 30 to <60 mL/min/1.73 m².

The researchers cited some limitations to the findings, including the possibility of residual confounding due to the post hoc analysis design; only assessing participants’ eGFR at baseline and the exit visit; the study cohort being limited to Chinese hypertensive patients with low baseline folic acid levels; and the relatively small sample size.

In conclusion, the researchers said, “Compared with enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of CKD progression among patients with mild-to-moderate CKD with B12 levels ≥248 pmol/L. The potential benefits of B12 (in the form of methylcobalamin) with a higher dosage of folic acid on CKD outcomes warrants further investigation, especially in those with low B12 levels.”

Takeaway Points

1. Researchers conducted a post hoc analysis of data from an interventional trial to assess the modifying effects of vitamin B₁₂ (B12) levels on the association between treatment with folic acid and progression of chronic kidney disease (CKD).
2. Compared with treatment with enalapril alone, treatment with enalapril + folic acid was associated with an 83% reduction in the odds of CKD progression among patients with higher baseline B12 levels.
3. Among patients with baseline B12 levels <248 pmol/L, there was no significant difference between the group treated with enalapril alone and the group treated with enalapril + folic acid.