Modest Doses of Folic Acid Slow CKD Progression

Norra MacReady

August 24, 2016

A daily dose of folic acid may slow the decline of renal function in people with chronic kidney disease (CKD) who live in areas without folic acid fortification, the authors of a new study report.

In a randomized, double-blind, actively controlled trial, patients who received enalapril plus folic acid experienced slower progression of CKD and decline of estimated glomerular filtration rate (eGFR) compared with patients taking enalapril alone, Xin Xu, MD, PhD, from the National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China, and colleagues report in an article published online August 22 in JAMA Internal Medicine.

The trial was a renal substudy of the China Stroke Primary Prevention Trial (CSPPT), which showed that adding folic acid to enalapril significantly reduced the risk for a first stroke in adults with hypertension. People with and without CKD were included in CSPPT.

In the renal substudy, the greatest treatment effects were seen in patients who had mild to moderate CKD at baseline, the authors write. These patients "benefited the most from the folic acid therapy with a 56% and 44% reduction in the risk for progression of CKD and the rate of eGFR decline, respectively. In contrast, the renal protective effect in those without CKD was nominal."

People with CKD have a high prevalence of hyperhomocysteinemia, which is associated with folate deficiency and an increased risk for stroke. Based on that observation, researchers have suggested that hyperhomocysteinemia is a risk factor for CKD progression, according to the authors.

Previous studies have suggested that supplements have no or even a negative effect on renal outcomes, but they were conducted in regions with folic acid fortification and involved supplements not just of folic acid but also of the other B vitamins. The CSPPT study investigated the effects of moderate doses of folic acid in a population without folic acid fortification.

The CSPPT was conducted from May 2008 to August 2013 in 32 communities in Anhui and Jiangsu provinces in China, on hypertensive adults with no history of major cardiovascular disease. This substudy included CSPPT participants whose eGFR was at least 30 mL/min/1.73 m2. The participants were randomly assigned to receive one daily tablet containing either 10 mg enalapril alone or enalapril plus 0.8 mg folic acid. Patients could also take other antihypertensive medications if necessary.

Researchers measured participants' pulse and blood pressure every 3 months and collected serum and urine samples at an exit visit to assess renal outcomes.

A total of 15,104 patients began the substudy, including 1671 (11.1%) with CKD at baseline, and 12,917 completed the renal outcome assessment. The median participation time was 4.4 years. Mean treatment compliance, determined by counting the number of pills patients had at each 3-month assessment, was 76%.

At baseline, the mean age was 60 years, but ranged from 45 to 75 years. People with CKD had higher blood pressure and fasting glucose levels than those without CKD. Forty-two percent of the people with CKD also had hyperhomocysteinemia, defined as serum homocysteine levels of 15 μmol/L or more, compared with 26% of people who did not have CKD. The time-averaged blood pressure during the trial was 140/84 mm Hg, which represented an average decrease of 28/12 mm Hg from baseline, but there were no significant differences in blood pressure observed in the two treatment groups throughout the trial.

CKD progression, which was the primary endpoint of the substudy, occurred in 164 people taking enalapril alone and 132 people taking enalapril plus folic acid. Progression was defined as a decrease in eGFR of 30% to 50% or more, depending on the baseline eGFR.

Folic acid was associated with a 21% decrease in risk for progression after adjustment for age, sex, eGFR, proteinuria, serum glucose, total cholesterol, systolic blood pressure, baseline body mass index, and time-averaged systolic blood pressure during treatment (odds ratio, 0.79; 95% confidence interval [CI], 0.62 - 1.00; P = .05).

Among the secondary outcomes, a significant effect of folic acid was seen only in the rate of annual decline in eGFR (1.42% per year vs 1.28%; P = .02). No effect was seen in all-cause mortality or rapid decline in renal function.

When the researchers analyzed the outcomes according to baseline CKD or no CKD, they found that the benefit of folic acid was restricted to those with CKD. Specifically, among people with CKD, disease progression occurred in 24 (3.3%) taking folic acid compared with 46 (6.8%) taking enalapril alone (adjusted odds ratio, 0.45; 95% CI, 0.27 - 0.76; P = .003; P value for interaction = .02). No significant treatment effects between groups were seen in people who did not have CKD.

Similarly, secondary outcomes were improved among people with CKD who received folic acid. Again, the most striking finding was in the rate of eGFR decline: folic acid was associated with a rate of 0.96% per year compared with 1.72% among patients in the control group (adjusted odds ratio, −0.62; 95% CI, −0.95 to −0.29; P < .001; P value for interaction = .002).

At baseline, the mean serum homocysteine level for all patients was 14.7 μmol/L. This had dropped to 12.7 μmol/L at exit among people taking folic acid compared with 14.5 μmol/L for the control group. Among people with CKD, the mean for the control group was 16.8 μmol/L at baseline and 16.2 μmol/L at exit compared with 17.1 and 14.0 μmol/L, respectively, in the group taking folic acid.

These findings emphasize the need to better understand the role of nutrients in disease prevention and management, Patrick J. Stover, PhD, and Martha S. Field, PhD, from the Division of Nutritional Sciences, Cornell University, Ithaca, New York, and Robert J. Berry, MD, MPHTM, from the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities, Atlanta, Georgia, write in an accompanying editorial.

For example, "folic acid-induced reductions in serum homocysteine levels did not affect kidney function in other studies," possibly because those studies also included other B vitamins as part of the intervention. Also, although the folic acid-enalapril combination proved more effective at preventing CKD progression and eGFR decline, "[t]here was no evidence for primary prevention of CKD in either arm of the study." The earlier studies also employed higher doses of folic acid in countries that provided folic acid fortification. "Dose may be an important modifier of efficacy and toxic effects, especially for specific clinical populations," the editorialists write.

Study limitations include renal function assessment only at the baseline and exit visits and exclusion of 12% of the original participants because of incomplete outcome data, the authors write.

"Given the magnitude of renal protection suggested by this study as well as the safety and low cost, the potential role of folic acid therapy in the clinical management of patients with CKD in regions without folic acid fortification should be vigorously examined," they conclude.

The authors disclosed no relevant financial conflicts of interest. Dr Stover is a member of the scientific advisory boards of Chobani, BioFortis, and the Maribou Foundation, and consults for Raze Therapeutics and Pamlab, Inc. Dr Berry and Dr Field disclosed no relevant financial conflicts of interest.

JAMA Intern Med. Published online August 22, 2016. Article full text, Editorial extract

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