Impaired renal function is associated with increased cardiovascular and all-cause mortality. Low glomerular filtration rate and high albumin excretion rate, both measures of renal dysfunction, are independent prognostic predictors. High homocysteine and low folate concentrations relate to cardiovascular events and to all-cause mortality [1,2]. Furthermore, due to low intake, high demand, or high losses, low folate and high homocysteine concentrations are common findings in patients with chronic kidney disease. Although people in some regions of the world have high dietary folate intake and/or grain fortification, there are also large populations in developing countries in Asia and elsewhere with low dietary folate intake and no mandatory food fortification. These regional differences may have contributed to the inconclusive evidence from previous studies on the potential of folate supplementation to reduce cardiovascular events and mortality .
The China Stroke Primary Prevention Trial evaluated the effects of a fixed combination of enalapril and folic acid vs. enalapril alone in a prospective double blind randomized study conducted in China in 20 702 people with hypertension but with no previous stroke, coronary artery disease, heart failure, or congenital heart disease . Women and men aged 45–75 years with a SBP of at least 140 mmHg or a DBP of at least 90 mmHg or on antihypertensive medication were eligible. During a median treatment duration of 4.5 years, folate supplementation reduced incident stroke, the primary outcome, by 21% (hazard ratio 0.79, 95% confidence limits 0.68–0.93), suggesting that folate supplementation to a population with low folate intake can reduce cardiovascular events. In this issue of Journal of Hypertension, Li et al.  now report results from a post-hoc analysis of China Stroke Primary Prevention Trial, which extend our knowledge and understanding of the role of folate supplementation in patients with hypertension and chronic kidney disease.
Li et al.  assessed the effect of the fixed combination of enalapril and folic acid vs. enalapril on all-cause mortality during a median 4.5 years treatment duration, according to glomerular filtration rate and urine protein excretion in 19 349 patients with valid measurements. The patients were categorized into three groups of estimated glomerular filtration rate (≥90, 60–89, or <60 ml/min per 1.73 m2, according to the Chronic Kidney Disease Epidemiology Collaboration formula) and three groups of protein excretion (<100, 100–999, and ≥1000 mg/l). The patient group with the greatest proteinuria had a three-fold higher all-cause mortality (11 vs. 3% in the group with the lowest values, hazard ratio 3.30, 95% confidence limits 2.10–5.18), and patients in the group with the lowest estimated glomerular filtration rate had a two-fold higher all-cause mortality (13 vs. 2% in the group with the highest values, hazard ratio 1.93, 95% confidence limits 1.19–3.12). Both indices of renal impairment were independent predictors of mortality in multivariable analyses. Folate supplementation reduced all-cause mortality by one-half in the group with the greatest proteinuria (11 vs. 6%, hazard ratio 0.49, 95% confidence limits 0.26–0.94), with an interaction (P = 0.040) between folate supplementation and degree of proteinuria. However, there was no interaction between folate supplementation and glomerular filtration rate on all-cause mortality.
These novel results suggest that in people with inadequate folate intake, supplementation with folic acid in hypertensive patients with advanced proteinuria will reduce the risk for all-cause mortality. However, there are some potential limitations to the study by Li et al. . First, this group of patients with advanced proteinuria comprised only 2% of the study population of hypertensive patients. In this post-hoc analysis, there was no evident benefit of folate supplementation in patients with less severe proteinuria. To study this would require larger properly designed prospective studies. Second, whether these results can be extended to people without hypertension also remains to be clarified but could have major impact on the implementation of the results. Third, it was reported that only 69% of the patients in each study group were adherent to more than 70% of their study medication throughout the trial, and 14% in each study group discontinued study treatment . Furthermore, folate levels increased substantially during the course of the trial also in the control group. These confounding factors make the true magnitude of benefit of folate supplementation uncertain but may be taken to suggest a larger benefit than that observed in this study.
Humans lack the necessary enzymes to synthesize folate and depend entirely on dietary intake. Folate occurs naturally in many foods, especially liver and dark green leafy vegetables. Dietary folate is converted to the active metabolite 5-methyltetrahydrofolate, which reacts with homocysteine to form methionine and tetrahydrofolate . One of the main functions of folate metabolism is to provide one-carbon building blocks for the synthesis of purines and pyrimidine necessary in DNA replication and repair. However, the homocysteine lowering effect of folate metabolism may in itself be linked to a reduced cardiovascular risk. High levels of homocysteine are common in chronic kidney disease, are associated with inflammation, and are an established risk factor for stroke and myocardial infarction [1,7]. Despite this, most previous studies have failed to show benefit from homocysteine lowering therapy with vitamin B supplementation. The Diabetic Intervention with Vitamins in Nephropathy trial actually showed harm with high dose vitamin B (2.5-mg folic acid, 25-mg vitamin B6, and 1-mg/day vitamin B12) in patients with diabetic nephropathy, particularly among those with a lower estimated glomerular filtration rate . These doses are substantially higher than the 0.8 mg/day of folic acid alone used in the present study by Li et al., which suggests that supplementation rather than treatment is the key.
In a recent separate renal substudy of the China Stroke Primary Prevention Trial, which included 15 104 participants with estimated glomerular filtration rate at least 30 ml/min per 1.73 m2, the authors reported a greater benefit of folate supplementation in participants with chronic kidney disease at baseline (adjusted odds ratio 0.44, 95% confidence limits 0.26–0.75) . As high levels of homocystein are common in patients with chronic kidney disease and are associated with increased risk, it may be that patients with chronic kidney disease benefit more from folate supplementation than other patient categories.
Folate also improves nitric oxide production and may reduce oxidative stress. Nitric oxide is essential in the local regulation of vascular tone and is synthesized by endothelial NO-synthase. This enzyme requires the cofactor tetrahydrobiopterin (BH4) to function. In conditions of limited substrate or BH4 bioavailability or high oxidative stress, NO-synthase uncouples and produces superoxide rather than NO. Sufficient folate availability contributes to adequate levels of BH4 through, for instance, upregulated production and recycling . Folate may also directly scavenge superoxide radicals .
Folate supplementation or food fortification is a readily available and well tolerated remedy to prevent neural tube birth defects, which may also have substantial potential to reduce cardiovascular events and disease progression. Physicians in countries without mandatory folate fortification should consider supplementation, particularly in those with high cardiovascular risk and low folate levels, such as patients with chronic kidney disease. Supplementation could not only be given in the form of a tablet, but also as a healthy diet with natural sources of folate, likely to have additional health benefits.
In conclusion, results from the China Stroke Primary Prevention Trial show that in people with inadequate folate intake, supplementation with folic acid appears to reduce all-cause mortality in hypertensive patients with advanced proteinuria . In addition, previous results have indicated a reduction in incident stroke  and slower progression of renal dysfunction . If these promising findings could be extended to a larger group of patients at high risk for cardiovascular events, this may have important implications for the treatment of hypertensive patients.
Conflicts of interest
There are no conflicts of interest.
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