In a recent article published in the journal Nutrients, researchers estimated the association of coffee consumption and genetic predisposition to caffeine metabolism on kidney function.

Study: Caffeine Intake, Plasma Caffeine Level, and Kidney Function: A Mendelian Randomization Study. Image Credit: Aleksey Korchemkin/Shutterstock.com

Background

Caffeine-containing drinks such as coffee and tea are widely consumed worldwide. Caffeine is also present in everyday life in energy drinks, carbonated drinks, and analgesic drugs.

Given the increasing prevalence of kidney diseases, researchers postulate that increasing caffeine consumption has adverse effects on kidney structure and function. However, the exact effects of caffeine intake on kidney function remain unclear.

Experimental studies using animal models have cited that caffeine consumption increases renal vascular resistance and proteinuria, leading to kidney failure.

Likewise, studies among human subjects have suggested that in patients with polycystic kidney disease (PKD), caffeine intake can increase the risk of cyst enlargement compared to those who do not consume caffeine. However, data from observational studies appears skewed due to the design and assessment methods used. 

About the study

In the current Mendelian Randomization (MR) study, researchers obtained genetic association summary statistics for plasma caffeine levels and caffeine intake from genome-wide association studies (GWAS) meta-analyses encompassing 9,876 and >47,000 individuals of European descent, respectively. 

Previous GWASs conducted among human subjects of European descent have shown cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AHR) genes are linked to caffeine metabolism. CYP1A2 metabolizes more than 95% of caffeine in humans, and the AHR regulates its expression. 

Thus, in this study, the researchers adopted a two-sample MR approach to analyze the single nucleotide polymorphisms (SNPs) within a 100-kilobase window of the CYP1A2 and AHR gene regions. Specifically, they selected the strongest signal at each locus, specifically rs242297 and rs4410790, respectively. 

They investigated these effects on kidney functions, including estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), urinary sodium, albumin-creatinine ratio (UACR), and chronic kidney disease (CKD) risk.

Finally, they pooled estimates for both genetic instruments using the random effects inverse-variance weighted method to derive Wald ratios with the MR standard errors.

Adopting an MR approach helped the researchers overcome the limitations of observational methods, including bias due to environmental factors and reverse causation and selecting genes encoding enzymes with an established role in caffeine metabolism. Genetic instruments minimized the pleiotropic effects of the MR design in this study.

Results

Consistent with experimental studies, higher genetically predicted plasma caffeine levels showed an adverse effect on eGFR measures determined using creatinine or cystatin C.

Conversely, a higher genetic predisposition to caffeine intake exerted a protective effect on kidney function. It increased eGFR and lowered the risk of CKD. According to the authors, the observed discrepancy is likely attributable to fast metabolizers of caffeine requiring a greater caffeine intake to achieve the same psychostimulant effect as slow metabolizers. 

In addition, higher genetically predicted plasma caffeine levels showed adverse associations with two biological markers of CKD progression, urinary sodium and BUN, but not UACR. However, researchers found no evidence of any harmful effect of genetically predicted plasma caffeine levels on albuminuria.

The CKDGen Consortium GWAS selected 25 SNPs, including the ones considered in this study, and found that an extra cup of coffee per day conferred a protective effect against CKD, an important finding that needs to be factored into future works.

Conclusions

To summarize, the current MR study evidenced that coffee consumption and genetic predisposition to caffeine metabolism have contrasting effects on kidney function, with the former having a protective and the latter having a detrimental effect on kidney function.

However, the current study could not determine whether the observed effects on kidney function were driven by the adverse effects of higher caffeine levels in plasma or the protection conferred by greater consumption of caffeinated beverages; thus, future studies should investigate the same.

Journal reference:

• Giontella A, de La Harpe R, Cronje HT, et al. (2023). Caffeine Intake, Plasma Caffeine Level, and Kidney Function: A Mendelian Randomization Study. Nutrients, 15, 4422. doi: 10.3390/nu15204422. https://www.mdpi.com/2072-6643/15/20/4422