Consuming more than 3 cups of coffee per day may increase risks for kidney dysfunction in slow metabolizers of caffeine, investigators reported in JAMA Network Open.

In the study of 604 untreated patients with stage 1 hypertension, slow metabolizers of caffeine had significant 2.7-, 2.1-, and 2.8-fold increased risks of developing albuminuria, hyperfiltration, and stage 2 or higher hypertension, respectively, with a daily coffee intake of more than 3 cups compared with less than 1 cup, over a median 7.5 years of follow-up, Ahmed El-Sohemy, PhD, of the University of Toronto in Canada, and colleagues reported in JAMA Network Open. The caffeine content per cup was defined as 100 mg of Italian espresso coffee.

Albuminuria was defined as a urinary albumin excretion rate of 30 mg/24 h or higher. Hyperfiltration was defined as an estimated glomerular filtration rate (eGFR) of 150 mL/min/1.73 m2 or higher. Albuminuria and hyperfiltration mostly occurred independently of each other. The investigators found that only 6.3% of patients with hyperfiltration also had albuminuria, and only 16.7% of patients with albuminuria also had hyperfiltration. The model adjusted for age and sex as well as body mass index, clinic systolic blood pressure, and eGFR at baseline.

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The findings are from the Hypertension and Ambulatory Recording Venetia Study (HARVEST). At baseline, all patients had normal kidney function. Individuals with pre-existing nephropathy, diabetes, urinary tract infection, and cardiovascular disease were excluded from the study. The vast majority of patients were White Italians. They rarely consumed decaffeinated coffee, tea, and other caffeinated drinks.

Caffeine is predominantly metabolized by cytochrome P450 1A2 (CYP1A2), the investigators explained. The rs762551 variant of the CYP1A2 gene decreases the enzymes’ activity in clearing caffeine. Genotyping for rs762551 revealed that 43.1% of the cohort had genotype AA, 40.8% had genotype AC, and 16.1% had genotype CC. Individuals with AC and CC genotypes are slow metabolizers of caffeine, and those with the AA genotype are fast metabolizers.

Dr El-Sohemy’s team concluded that caffeine may play a role in the development of kidney disease in susceptible individuals. They noted that “the association between coffee intake and kidney dysfunction may vary according to the etiology of kidney disease, stages of kidney disease, exposure time, and genetic differences.”

“These findings have implications for DNA-based interventions, such as precision nutrition recommendations, to reduce the risk of kidney disease.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Mahdavi S, Palatini P, El-Sohemy A. CYP1A2 genetic variation, coffee intake, and kidney dysfunction. JAMA Netw Open. Published online January 26, 2023. doi:10.1001/jamanetworkopen.2022.47868