Folic Acid Supplementation in Chronic Kidney Disease

Folic acid (FA) is the synthetic form of vitamin B9; naturally occurring FA is known as folate. FA is crucial for the production of DNA and RNA and is especially important during times of rapid cellular and tissue growth, such as pregnancy and infancy. Due to this fact, more than 50 countries require fortification of certain foods with FA to prevent neural tube defects during pregnancy.[1]. FA is also critical in the conversion of homocysteine (HCY) to methionine. If there is not enough intake of FA, there is not enough conversion, and HCY levels are raised. Research has shown increased HCY levels suggest enhanced risks for inflammation, endothelial injury and blood clots—all of which lead to cardiovascular disease (CVD), strokes and chronic kidney disease (CKD).

CKD is defined as persistent kidney damage with a reduction in the glomerular filtration rate (GFR) and albuminuria. It is associated with numerous complications including electrolyte imbalances, mineral and bone disorders, anemia, dyslipidemia, and hypertension (HTN).  The prevalence of CKD has steadily increased over the past two decades and affects close to 20% of the US population, attributed in part to an aging population and increased rates of diabetes, obesity and primary HTN.

This sub-study analysis, in over 15,000 participants with HTN and CKD, assessed whether a combination of a standard medical therapy for hypertension (ACE inhibitor) plus FA was more effective at slowing CKD progression vs the ACE inhibitor alone.[2]  The results showed:

  • Combining standard anti-hypertensive therapy with FA led to a significant delay (10%) in the progression of CKD as compared to standard therapy alone
  • In patients with mild CKD who received the combination therapy, there was a 21% reduction in progression of their disease
  • In patients with established CKD who received the combination therapy there was a 56% reduction of disease progression
  • HCY levels remained the same regardless of supplementation

Why is this clinically significant?

As FA is metabolized, it is recycled in the body; if the individual has a defective recycling gene, the methylene tetrahydrofolate reductase (MTHFR) gene that would indicate that less FA is available, leading to raised HCY levels and the potential for increased risks for CVD and/or CKD. One of the concepts behind this study was to give FA to patients so that, even if they had the defective gene, the exogenous FA would help break down homocysteine and reduce CVD– and perhaps CKD. However, the data showed that the HCY levels didn’t predict any outcomes—regardless of the HCY levels, the results were the same—perhaps HCY was not the main ‘bad guy’ in these patients? This would suggest that further work may be needed to find out who the ‘bad guy’ actually is in the development of the CVD/CKD cycle.

What the study did show was that supplementing standard medical therapy with FA led to significant reductions in the progression of CKD at any stage of the disease.  The key takeaway is that is crucial, therefore, to supplement FA in those patients who are deficient and FA supplementation along with standard HTN therapy is an inexpensive way to slow CKD progression in ‘at risk’ patients to optimize their health outcomes overall.


Reference: PubMed Link

[1] Obeid, R; Herrmann, W. “The Emerging Role of Unmetabolized Folic Acid in Human Diseases: Myth or Reality?”. Current Drug Metabolism. 2012, 13 (8): 1184–95.

[2] Xu X, QinX, Li Y et al. “Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial”. JAMA Intern Med. 2016 Aug 22




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