The Caffeine Problem

Popular perception of caffeine is as variable as the weather and for every person that claims caffeine is detrimental to health there will be another claiming it does no harm. Many PKD patients will have been told at some stage to limit their caffeine intake – an assortment of physicians, dieticians and academics will propound the idea in clinics, websites and papers to the extent that some 63% PKD patients state they have been told to avoid caffeine containing substances. (Vendramani, 2012)

I set out in researching this post to get to “the bottom line”, though I recognise I may have a conflict of interests: I drink coffee – actually quite a lot of it.

Some background
Caffeine has a chemical name of 1,3,7-trimethylxanthine.
It looks like this:

Caffeine (Image: chem242.wikispacesclassroom.com)

Caffeine
(Image: chem242.wikispacesclassroom.com)

Wikipedia  gives a whistlestop tour of the actions of caffeine, but the one most relevant to PKD is that it increases cAMP (cyclic adenosine monophosphate).
cAMP does two things in PKD

  • exerts a proliferative effect on renal tubule epithelial cells (the ones that forms the cysts)
  • upregulates cystic fibrosis transmembrane conductance regulator (CFTR) that promotes chloride transport into the cysts

So the expected effect of increasing cAMP would be an increase in the number of cysts (more cells) and an increase in the size of the cysts (more fluid).

Caffeine is absorbed rapidly and enters all tissue compartments. It is metabolised in the liver, a process that is slower in heavy smokers and people with cirrhosis.

In theory caffeine will trigger a rise in blood pressure (BP) by raising peripheral vascular resistance but no consistent relationship has been found between caffeine intake and BP and this may indicate that regular intake leads to tolerance. (Bolignano te al, 2007)

How much caffeine is there in a cup of coffee?

The answer depends on where you look.

The Caffeine Poster
This suggests that it can range from an 8oz instant coffee containing around 50mg to a 12oz Starbucks coffee at over 250mg.

PKDCure.org uses a 5oz cup as measure which is about 150ml, stating a very wide range of concentrations. It does however include tea and differentiates between a 3-minute-steeped tea and a 5-minute-steeped tea, the latter potentially containing as much caffeine as a percolated coffee of the same size.

The Mayo Clinic include decaffeinated drinks which might contain as much as 15mg caffeine.

The most comprehensive chart comes from the Center for Science and Public Interest  where I learned that Pepsi Max has 69mg in one can and Coke-Zero 35mg. It is an American site however so lists Hershey’s chocolate (9mg) but not the much better-tasting Dairy Milk!

Does caffeine cause dehydration?

This is a reasonable question to ask because theophylline (1,3-dimethylxanthine) closely related to caffeine, was for many years used to increase urine output until more potent diuretics became available in the middle of last century.

A group from Birmingham, UK, (Killer et al, 2014) undertook a study of 50 male coffee drinkers to compare coffee with water. It was counterbalanced crossover study meaning that all fifty subjects were assessed after 3 days of coffee drinking (4x200ml at 4mg/kg caffeine concentration) and also after 3 days of water (4x200ml water) instead of coffee. Parameters measured were nude body mass, total body water using deuterium oxide and usual hydration markers in urine and blood. They found no significant changes in total body water from pre to post trial, haematological and urinary markers were stable and body mass was stable. The conclusion from this is that coffee, in moderation, in caffeine-habituated males provides similar hydrating qualities to water.

This study supports the findings of a literature review from 2003 on caffeine-containing drinks and hydration.

Despite this at least one website  that professes to be a resource for PKD patients states dogmatically that coffee intake leads to dehydration. But I will talk about the websites later.

Does caffeine increase blood pressure?

I don’t want to spend too long on this one as the short answer is “yes it can” but there are so many variables and riders to that statement that it really requires a whole post to itself. I will mention one study by Corti et al where they looked at those accustomed to caffeine compared people who didn’t usually drink it. The rise in blood pressure only occurred in the coffee-drinking group if the caffeine was administered intravenously (IV). So perhaps there was substance to the comment we all made as students that we needed IV caffeine pre-exams! Whether there is a chronic effect on BP from regular coffee-drinking and whether that could translate into an “avoid caffeine” message is not something I am going to consider here.

Does caffeine increase cyst growth in PKD?

Now this is the big question.

This statement is made by several authorities (uwmedicine.org, pkdcure.org) and where it is supported by academic references they usually quote the paper from 2002 by Belibi et al. It is important to look at what this study actually did and to understand its limitations. Firstly it is a study of cells in a petri dish, not actual kidneys in a human. The cells were cultured from ADPKD tubular cell samples after nephrectomy (from 3 patients) and the control were cultured from a cadaveric kidney of one normal patient (albeit not alive). I’d like to highlight the numbers here – 3 kidneys, just 3.

Although they titled this paper “The effects of caffeine on renal epithelial cells from patients with PKD” it was one of several they produced from the dataset of results and they were also exploring effects of other substances such as desmopressin, prostaglandinE2 and isoprotenerol. Their relevant finding was that caffeine SLIGHTLY increased basal levels of cAMP, an effect that was potentiated by adding in other phosphodiesterase inhibitors (as might be expected). From this they seem to have taken a huge leap and concluded “caffeine is a risk factor for the promotion of cyst enlargement in patients with ADPKD”

Another paper from 2001 by Tanner et al, found that there was no increase in cyst size or total kidney volume (TKV) following the administration of caffeine to ADPKD rats. Rats are actually quite a good model for PKD, but it is still not the same as investigating ADPKD in the general free-living human population.
The most recent paper on caffeine and PKD

Vendramini and a group from Brazil published their research on caffeine and PKD in 2012.

They studied 102 people with ADPKD and 102 controls, matched for age and sex. They assessed exposure to caffeine by dietary recall over 3 non-consecutive days. The data was collected by questionnaire and interview with researchers . They used clinical records for laboratory data and measured total kidney volume using ultrasound. Caffeine intake did not correlate with renal volume in ADPKD patients. This was true for both low intake and high intake and was reflected by a lack of correlation of eGFR with caffeine intake.

In addition they took an even closer look at a subset of these patients where they had access to previous ultrasound results. From this they concluded that rate of growth did not correlate with caffeine intake.

Of course there are limitations to this study like any other:

  • The ADPKD group did show a lower consumption of caffeine containing food and drink compared with the healthy population.
  • They explained this by noting that 63% had been advised at some point in their past to reduce caffeine intake, but the lower intake itself may contribute to the lack of correlation.
  • Ultrasound as tool to measure TKV is operator dependent and doesn’t detect small changes. MRI studies would be more accurate but also more expensive. In addition the investigators wanted to reflect investigations commonly used and in Brazil MRI is not routine.
  • Does a Brazilian population permit translation of results into the rest of the world? Preparation methods and cup sizes may differ.
  • Coffee was a major source of intake in this study. They claim that in UK tea is a predominant source of caffeine but the supporting reference for this is from 1996.
  • The average intake of caffeine in this study was 171mg/day. This is low compared with US (200mg) and UK (280mg) and much lower than in Denmark (490mg)

Nonetheless, it is so far one of the larger studies on this topic and it does look at humans and actual patients with ADPKD, not just rats or cell cultures.
What are the websites saying?

I looked at 15 different websites, all to be found in the first 5 pages of a Google search using terms “polycystic + kidney + caffeine”, that is, sites that people are likely to use to obtain information on ADPKD and caffeine. I searched those sites specifically for the advice they give on caffeine.

1. Renal Resource Centre
This is an Australian community health page. They reference the Tanner paper from 2001 – that’s one in ADPKD rats that found BP could be related to caffeine intake but not cyst numbers, TKV or GFR. They advise ADPKD patents to “monitor the effect of caffeine on BP” or to “limit caffeine intake”

2 – 6. Kidney Service China
pkdclinic.org
kidneyservicechina.com
renaldiseases.org
kidney-cares.org
kidney-support.org

These appear to be five different sites but when you delve into the “about” and “contact” pages they all relate to the same hospital in China – Shijiazhuang Kidney Disease Hospital. I found the information on these was mixed – some seemed quite reputable, but it stood alongside some dubious statements. For example “Caffeine promotes calcium loss and PKD patients can easily catch osteoporosis” or “Coffee may accelerate the progression of PKD”. They stop short of saying caffeine causes renal failure but it is easy to see how you can leave the website with that message. Their one clear promoted message is that caffeine is a poor choice for patients with ADPKD and should be avoided. The information pages are presented in slightly different format on each site but the wording uses identical phrases and most of the statements are not referenced to any academic papers.

7. livestrong.com
Once again this site uses the phrase “poor choices” describing caffeine in the diet and even says it is “one of the worst foods for a polycystic kidney diet” . The evidence they choose to back this statement is again the Belibi study (you remember – the one with cultured cells from just 3 patients)

8. dailystrength.org
This link led to a support group for PKD patients discussing the issues back in 2012. None is linked to any actual research though it does highlight what people have been advised by their physicians i.e.. don’t drink coffee.

9. uwmedicine.org
This website states in PKD you should “avoid or limit caffeine (coffee, tea or chocolate) because caffeine increases cyst growth in animal models” Maybe it pained me because it included chocolate here, (I love chocolate) but you will recall that the animal models did not show an increase in cyst growth attributable to caffeine intake, merely an increase in cAMP and that was only slight.

10. askanaturopath.com
I found this to be an alarming website: it states “PKD is a genetic disorder of unknown cause” – what textbook were they looking at, one from the 1950s? It implies that cysts are aspirated or treated surgically as a matter of routine and uses that as the horror scenario from which to contrast the reportedly natural and thus safe (note my sarcasm) herbal remedies – such as parsley, clergy, spiralling and chlorophyll. Now I have nothing against these herbs – actually I know very little about any of them so maybe a future post – but the whole tone of the site was jarring with my scientific training, or at least with my need for an evidence based knowledge in the area.

11. kidneydoctorbradenton.org
Written by a physician in renal specialist training, it is not a long article but it comes down on the side that currently there is nothing against 3-4 cups of coffee a day.

12. pkdcure.org
The link led me directly to their patient manual for ADPKD where, buried within some really useful stuff, is the statement that “caffeine-like substances result in increased cyst growth”. Having read thus far on this post you will know that isn’t particularly well supported by the evidence.

13. kidneyfailureweb.com
Oh no, this is that Chinese one again. They are really keen to acquire new patients!

14. nutrition411.com
A dietitian website that says: “People with PKD generally are advised not to drink or eat any caffeine containing beverages or foods” This is unsupported by references.

15.PKDDiet
Now there is a vast amount of information in this website, much of it supported by references and links to relevant papers. Most people will like the little GIF of myocytes excited by caffeine. What concerns me though is that despite having a “contact” page and an “our stories” category I could not find out who is behind the website and who is giving the advice. Anyhow, they focus more on caffeine and its effect on pain levels, which is beyond the remit of this post.
You may notice I have not included the PKD Charity (UK) or the National Kidney Foundation (US) – the main reason is that they have not made any dogmatic statements regarding caffeine and cysts. In my opinion they are correct – there is no basis for advice against it but of course, the lack of evidence is not the same as saying it is quite harmless.
List of papers mentioned, primary author and main message :

Hartley, 2000: The increase in BP triggered by caffeine is more if already hypertensive
Tanner, 2001 : ADPKD rats given caffeine had raised BP but no increase in cyst size or TKV
Corti, 2002: Habitual coffee drinkers only experience increased BP after IV,not oral, caffeine
Belibi, 2002: Cell study, caffeine led to slight increase in cAMP; reasoned that it might increase cyst fluid and growth
McCusker, 2006: Decaffeinated coffee may contain 0 -13.9mg caffeine per 16oz
Bolignano, 2007: Literature review; effects of caffeine depend on dose, genetics, drugs, previous exposure; no evidence against 3-4 cups/day in healthy or nephropathic subjects
Vendramani, 2012: No correlation between TKV or GFR and caffeine intake
Killer, 2014: Caffeine is not dehydrating

No strong evidence for avoiding caffeine in PKD

No strong evidence for avoiding caffeine in PKD

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6 responses to “The Caffeine Problem

  1. Yay for coffee! 🙂 I so agree with everything you say. I might be biased too, but there really is no good evidence to advise against coffee in moderate amounts, and I got peeved at people making these recommendations. Didn’t realise just how widespread this practice was though. I think every person with PKD must have come across that chinese website! And the askanaturopath.com one is well dodgy, I agree – they completely contradict themselves on the subject of diuretics. They recommend herbs which are ‘gently’ diuretics (which they are not – dandelion leaf is equal in action to furosemide), but to cut down on sugar, alcohol, etc because they are diuretic and lead to dehydration and stress on the kidneys! But anyway, maybe one day there will be good evidence, but that goes for a lot of dietary advice, and you can’t follow it all ‘just in case’!

    Like

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