Time to Think About Nutrient Needs in Chronic Disease

Abstract

There is renewed interest in health benefits of folic acid supplementation since the China Stroke Prevention Primary Prevention Trial (CSPPT) showed the potential benefits of folic acid inpreventing stroke in Chinese adults with hypertension.1 It has long been known that folic acid prevents neural tube defects, which are among the most severe anddebilitating congenital birth defectsworldwide. The CSPPTwas terminated earlywhen800μgof folic acid in combination with 10 mg of enalapril significantly reduced primarystroke incidencecomparedwith theenalapril alone treatment arm. This finding was unexpected as other studies had failed to find a preventive effect of folic acid supplementation on cardiovascular events.2 In this issue of JAMA Internal Medicine, Xu et al3 report findings from a prespecified CSPPT substudy that demonstrated that the folic acid–enalapril combination was more effective than enalapril alone in the secondary prevention of renal function decline among Chinese adults with hypertension across a spectrum of mild to moderate chronic kidney disease (CKD). Folic acid is commonly administered to treat hyperhomocysteinemia, but thebenefits ofhomocysteine loweringon the prevention or management of most chronic diseases associatedwith hyperhomocysteinemia remains unproven.2 In the renal substudy of the CSPPT,3 Xu and colleagues report that 42% of participants with CKD exhibited hyperhomocysteinemia (serum homocysteine ≥15 μM) and 24% had diabetes, comparedwithonly26%withhyperhomocysteinemiaand12% with diabetes in those without CKD. Individuals who were homozygous for theMTHFR C677T polymorphism, a genetic variant that expresses anenzymewith reduced5-methyltetrahydrofolate synthesis activity, exhibited the greatest reduction inserumhomocysteine followingfolicacid–enalapril treatmentbecause theirbaseline levelsof circulatinghomocysteine werehigher. This finding is consistentwith other studies suggesting that the current recommended dietary intake for folatemaynotbeadequate for individualshomozygous for the MTHFR 677T variantwhen homocysteine lowering is used as the functional biomarker to assess folate status.4 Importantly, the folicacid–enalapril combinationwasmore effective in reducing rates of renal dysfunction in individuals with CKD (odds ratio [OR], 0.44; 95% CI, 0.26-0.75) compared with enalapril treatment alone, with the primary outcome measure being a prespecified level of decline in the estimated glomerular filtration rate (eGFR).3 The folic acid– enalapril treatment significantly reduced other measures of renal dysfunction in addition to the 21% reduction in risk for theprimaryoutcomecomparedwith theenalapril-onlygroup. These included secondary outcome measures of rapid decline in renal function (OR,0.67;95%CI,0.47-0.96) andacomposite eventmeasure (OR,0.62;95%CI,0.43-0.90); bothwere significantly reduced in the group receiving the folic acid– enalapril combination compared with the enalapril group. Therewasnoevidence forprimarypreventionofCKD ineither arm of the study. Hyperhomocystenemia is a common finding in patients with CKD. However, folic acid–induced reductions in serum homocysteine levels did not affect kidney function in other studies.5,6Xuet al hypothesized that thesedifferencesmaybe owing to the inclusion of other B vitamins, including vitamin B12, in previous vitamin supplementation trials on renal function.Also, the level of folic acid supplementationvariedmarkedly among these trials. The study by Xu et al administered folic acid at levels below 1 mg/d, whereas other studies administered folic acid at much higher levels. Dose may be an importantmodifier of efficacy and toxic effects, especially for specific clinical populations.Forexample, inpatientswithdiabetic nephropathy, subjects receiving 2.5 mg/d folic acid, 25mg/d vitamin B6, and 1mg/d vitamin B12 exhibited greater decreases in serumhomocysteine thandid those receivingplacebo, but kidney function (measured by eGFR) unexpectedly decreased more in the treatment group than in the placebo group.5 In a related study, patients with advanced kidney or end-stage renal diseaseswere treatedwith40mg/d folic acid, 100mg/d vitaminB6, and 2mg/d vitaminB12 daily. Therewas no effect of treatment on all-cause mortality, stroke, or amputation of lower extremities compared with placebo.6 Folic acid is a synthetic, provitamin formof folate that is processed tonatural folate by the enzymedihydrofolate reductase. Very high intakes of folic acid may result in saturation of dihydrofolate reductase activity. Folic acid binds tightly to the folate receptor (FRα), aglycoprotein that is anchored to thecellmembrane of epithelial cells. It is possible that because FRα is expressed in the kidney, the kidneymaybemoreharmedbyunmetabolized folic acid, especially in subjects with kidney disease or impaired kidney function, as observed in a population with diabetic nephropathy.5 Folic acid–induced nephrotoxic effects has been demonstrated in mouse models.7 AnothermajordifferenceamongtheCKDtrialswas theuse of enalapril in the studydesign byXuet al.3 The results of this studydemonstrated that enalapril interactswith folate in human physiology, as enalapril treatment alone in the absence of supplemental folic acid increased serumfolateby5.1 ng/mL (to convert ng/mL to nmol/L,multiply by 2.266), with amodest decrease in serum homocysteine (0.2 μM). While the mechanisms for this interaction are unknown and should be explored, this drug-nutrient interactionmayunderlie the secondary prevention of renal function decline observed in this study. Dietary reference intakes are established to give guidance foradequate intake levelsofessentialnutrients forhealthy individuals, but there is increasing awareness that these recommendations may not apply to populations with chronic Related article page 1443 Effects of Folate on Chronic Kidney Disease Progression Original Investigation Research