coffee consumption chronic kidney dz

 A recent article found that coffee intake may lead to hypertension and kidney dysfunction, depending on the CYP1A2 genetic variation that affects caffeine metabolism (see ckd coffee intake jama2023 in dropbox, or doi:10.1001/jamanetworkopen.2022.47868)

 

Details:

-- 604 individuals aged 18-45 who had stage I hypertension in the Hypertension and Ambulatory Recording Venezia Study (HARVEST) in Italy were recruited in 1990 and prospectively followed up for approximate 10 years until 2006 (median of 7.5 years). Patients who develop sustained hypertension and were put on meds were followed up only until that time, with one last clinical assessment done

  -- exclusion criteria included: baseline nephropathy, diabetes, urinary tract infection, and cardiovascular disease  

-- 73% male, mean age 33, BMI 25, 40% drank alcohol, 20% smoked

-- eGFR 101 ml/min/1.73m²,  albumin excretion rate 13 mg/24 hr, blood pressure 144/93 mmHg,

    -- those who were heavy consumers of caffeine tended to be older (4 years) and have a higher BMI (about one point)

-- blood pressure and biochemical data were collected during the first three months then every six months thereafter. No one was on medications for hypertension

-- genotyping, lifestyle questionnaires, and urinalysis data were obtained

    -- they specifically assessed the CYP1A2 genotype rs762551 variant, which determined the rapidity of caffeine metabolism

        -- rapid metabolizers: genotype AA (no variant)

        -- slow metabolizers: genotype AC (heterozygous: mixed normal and variant), and genotype CC (homozygous for variant)

-- caffeine consumption was determined by the number of cups of Italian espresso coffee (each cup having 100 mg of caffeine) but did not include decaffeinated coffee, tea, and other caffeinated drinks

-- Main outcomes: albuminurea (albumin level of at least 30mg/24h) and hyperfiltration (eGFR calculated from creatinine clearance of at least 150ml/min/1.73m²)

 

Results:

-- coffee intake habits did not change substantively over the time of follow-up

-- coffee consumption:

    -- <1 cup a day: 158 participants (26%)

    --1-3 cups per day: 379 participants (63%)

    -- at least 3 cups per day: 67 participants (11%)

-- genotype frequencies:

    -- AA (rapid metabolizers, no variant): 260 participants (43%)

    -- AC (heterozygous for variant): 247 participants (41%)

    -- CC (homozygous for variant): 97 participants (16%)

-- slow metabolizers did not differ significantly in the amount of caffeine consumed as compared to rapid metabolizers

 

Albuminuria:

-- no difference at baseline, but increased from 6.1% to 8.1% of slow metabolizers and no change in fast metabolizers

-- risk of albuminuria: slow metabolizers vs fast metabolizers: aHR 2.74 (1.63-4.62), p<0.001, after adjusting for age, sex, baseline BMI, baseline clinic systolic blood pressure, and baseline eGFR

 

Hyperfiltration:

-- was not present at baseline: at follow-up 16.9% of fast metabolizers and 18.0% of slow metabolizers

-- risk of developing hyperfiltration in slow metabolizers: aHR 2.11 (1.17-3.80), p=0.01

 

Hypertension:

-- Risk of developing hypertension in slow metabolizers increased significantly with heavy coffee drinking: aHR 2.81 (1.51-5.23), p=0.001

 

 

This graph is for albuminuria, though they were quite similar graphs for the risk of hyperfiltration as well as the risk for hypertension

 

Commentary:

-- more than 95% of caffeine is metabolized by the cytochrome CYP1A2, and the common rs762551 variant decreases the enzyme activity, leading to slower metabolism (in this case of caffeine)

-- This CYP1A2 rs762551 variant has been associated with:

    -- risk of myocardial infarction, hypertension, and impaired fasting glucose, in a dose-dependent manner, in studies over the past 20 years

    -- and is associated with an increased risk of cancer (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526566/ ), most notably in breast and colorectal cancers

        -- these associations are not so striking since this variant decreases the metabolism of many medications as well as several carcinogens (e.g. benzopyrene and aflatoxin, as well as nicotine) and, some nephrotoxins (eg aristolochic acids, which are plant-based nephrotoxic phytochemicals). See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758120/ . And, this decreased metabolism likely leads to prolonged/increased toxic effects in the body

        -- so, for example, was there a nephrotoxin that was naturally in the soil or added for coffee bean growth (pesticide??) that made its way into the coffee bean and then damaged the kidneys (ie absorbed from the soil, sort of like the cadmium in dark chocolate)? or some nephrotoxin added during the processing of the beans (as with the lead in dark chocolate?). see last blog on this issue

-- caffeine, in some studies, is associated with adverse effects in animals and humans, stimulating glomerular remodeling and sclerosis, worsening hypertension, proteinuria, and acceleration of pre-existing chronic renal disease. However other studies have found no association

 

-- This prospective cohort study found that consuming more than 3 cups of coffee a day was associated with increases in albuminuria, hyperfiltration, and hypertension only in those who were slow metabolizers having the common rs762551 variant, which was present in 57% of their population. And these increased bad kidney outcomes were quite high, close to three-fold that of the fast metabolizers

-- in terms of the measured markers of kidney disease in this study:

    -- hyperfiltration is is associated with kidney injury in those with hypertension and diabetes (and prehypertension and prediabetes).  other studies have found that those with hyperfiltration have a higher risk of death, heart failure, other cardiopulmonary events as well as declining eGFR

    -- albuminuria is also associated with cardiovascular disease (even at levels of 10-20 mg/24h) and kidney disease (and in this study was largely independent of hyperfiltration as a marker of renal dysfunction)

 

-- the relationship between coffee consumption and kidney disease is not so clear in other studies, with quite varying results:

    -- there have been many studies that have found coffee to be quite healthy. For example

        -- a recent NHANES study found that coffee was associated with decreased mortality in a dose-dependent fashion: http://gmodestmedblogs.blogspot.com/2022/06/coffee-and-decreased-mortality-and-it.html

        -- a British study found that coffee consumption was associated with decreased overall mortality, independent of genetic variations of caffeine metabolism,  see http://gmodestmedblogs.blogspot.com/2019/01/coffee-and-decreased-mortality.html , though the rs762551 variant was not included in this analysis

    -- a case-controlled study found coffee consumptions associated with decreased colon cancer: http://gmodestmedblogs.blogspot.com/2016/04/coffee-and-decreased-colon-cancer.html

    -- another study found decreased coronary artery calcium in coffee drinkers (though the above cited study on higher MI rates with coffee was for the rs762551 variant)

 

Limitations:

-- this was an observational study (people were not randomized to specific coffee intakes and followed for a decade), so there might well be unmeasured confounders (did those drinking >3 cups of coffee/day also do other different things that might be associated with adverse kidney outcomes??  (eg diet or exercise or stress or....). there are some suggestions that exercise can affect kidney outcomes: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242908/

--This study was in only 4 of the sites used in the larger 17-site HARVEST study, and the rs762551 variant will likely vary in prevalence in other areas of the world, affecting the generalizability of these results. This may explain some of the quite discordant results found in prior studies

-- they did not include non-espresso caffeinated products in the above analysis. did those drinking less coffee have more redbull?

-- was there some way that a nephrotoxin got into the coffee beans either naturally or in the mass growth of these beans for consumption? after all, this study was in just one country and the coffee type was just the espresso. we would need more studies in more areas to be certain it was the caffeine itself. and, so many other studies have found caffeine benefit on clinical outcomes (eg all-cause mortality). it would seem somewhat unlikely that such a common variant as the rs762551 (present in >50% of the Italians in this study) would not manifest itself in harm in some of the other caffeine studies....

    --given that the CYP1A2 rs762551 variation also affects the metabolism of many other chemicals (eg  including the plant-based aristolochic acids, known nephrotoxins) that could be associated with chronic kidney disease, this could affect their results which single out the caffeine. I am not sure how common aristolochic acids are in Italy, though they are quite present in the soil in many of the Balkan countries which surround Italy

 

so, another study trashing some of our favorite pastimes: eating dark chocolate, having an alcoholic beverage, and now waking up to that morning coffee... my sense is that the alcohol is actually not so great for us and that the zero consumption is an appropriate public health target.  But dark chocolate and coffee? it is true that the active ingredients in both are similar (xanthines), but the preponderance of prior observational studies suggest these are good for us (and that is certainly what i had hoped and assumed). However, observational studies are fraught: they can have incorrect conclusions. and it is very unlikely that there could be definitive randomized controlled trials: who would want to be randomized to specific  amounts of chocolate or coffee and followed many years at that same consumption level (or, worse, taking a placebo for the studies)??

 

geoff

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