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Cranberry Juice

It always somewhat surprises me how some interventions never seem to die. Theophylline seems to have disappeared in the medical pantheon, but what comes around, goes around.  I predict a resurgence of theophylline this century.  Despite the recent study that shows, yet again, echinacea has no effect on colds, I predict the study will neither decrease the sales of echinacea nor prevent further funds being spent on clinical trials on its efficacy.  Hear that JREF?  I made predictions.  I will await my million dollar check. Make it out to Mark Crislip.

Another therapy that refuses to be put to rest, or even to be clarified, is the use of cranberry juice for urinary tract infections.  Pubmed references go back to 1962, and there are over 100 references.  Firm conclusions are still lacking.

There is a reasonable, but incomplete,  basic science behind the use of the cranberry juice for urinary tract infections.E. coli , the most common cause of urinary tract infections, causes infection in the bladder by binding to the uroepithelial cells.  To do this, they make  fimbriae,  proteinaceous fibers on the bacterial cell wall. Fimbriae are adhesins that attach to specific sugar based receptors on uroepithelial cells.  Think Velcro.  Being able to stick to cells is an important virulence factor for bacteria, but not a critical one; it is not the sine qua non of bladder infections.

Are all E. coli causing UTI’s fimbriated?  No.  It is the minority of E. coli that cause UTI that have fimbria, and the presence of fimbriae may be more important for the development of pyelonephritis (kidney infection) than cystitis (bladder infection).

The prevalence of uropathogenic Escherichia coli bearing type 1 and/or p fimbriae was assessed in 179 adult women with urinary tract infections, and the presence of specific fimbriae types was correlated with results of localization studies. E. coli with p fimbriae occurred more frequently in patients with clinically defined pyelonephritis (13 of 23 [57%]) than in women with cystitis (22 of 116 [19%]; P = .0004) or asymptomatic bacteriuria (6 of 40 [15%]; P = .0008), whereas organisms with type 1 fimbriae were equally distributed in these three patient groups. In contrast, the presence of p-fimbriated strains was not correlated with infection localized to the upper urinary tract by either the antibody-coated bacteria technique (among symptomatic women) or ureteral catheterization (among asymptomatic women). Thus although p fimbriation seems to be an important virulence factor associated with development of acute pyelonephritis in adult women, its detection appears not to be a useful localization test per se, and efforts to prevent these infections should not be directed against this factor alone.

and in children

P-fimbriae were present in 91% (33/35) of the urinary strains causing acute pyelonephritis. Among strains causing cystitis and asymptomatic bacteriuria P-fimbriae were found in 19% and 14% of cases, respectively.

So fimbriated E. coli account for a distinct minority of urinary tract infections.

What is the alleged mechanism by which cranberry juice is  beneficial in preventing urinary tract infections?   Cranberry juice, and some other fruits, contain  proanthocyanidins.  There is reasonable data that demonstrates that proanthocyanidins block adherence, usually of p fimbriated E. coli , to uroepithelial cells.  But not all E. coli:

Interestingly, proanthocyanidin shows a very strong inhibitory activity against mannose-resistant adhesins produced by urinary isolates of E. coli  but shows only moderate anti adherent activity against fecal E. coli isolates.

So the theory is that by taking cranberry juice, or cranberry pills, you will block the E. coli sticking to bladder cells and that will decrease the number of UTI’s.  The use of cranberry should be more beneficial as a preventative than as a treatment of cystitis and should be effective for a minority of patients.

There have been a variety of clinical trials, in different populations, to see if cranberry products are of benefit in the prevention of UTI’s and there has been variable efficacy.

There are, I am shocked, shocked to find,  problems with the studies.

First, no one has ever done basic pharmacokinetics on proanthocyanidins to see if there is, indeed, proanthocyanidins in the urine of patients who take cranberry products.

The closest they have come is that the urine of patients who consume cranberry juice  inhibits E coli binding to bladder epithelial cells.  Close.  But it may be something else in the urine that is leading to the decreased E. coli adherence.  I may complain about the pharmaceutical companies and the spin they put on their clinical studies, but at least they are nice (1) and methodical in elucidating the basic pharmacokinetics of their preparations.

Doing clinical trials without determining first if there is sufficient material that  CAN be effective, before showing that it IS effective,  is the homeopathic, and most SCAM, method of research.  No one has been methodical in their evaluation of cranberry juice, so we are left with a hodgepodge of incomplete  studies.

Imagine doing an antibiotic study where you neither tested the susceptibility of the organisms to the antibiotic before nor after you treated an infection.  It would be stupid.  You would have no idea if the therapy should or could have been effective.

Some populations where cranberry prodcuts has been tried, the neurogenic bladder, spinal cord injury and the elderly, have a radically different microbiology and epidemiology and one wonders if the basic principals behind the rationale for cranberry juice are even remotely applicable.  Fimbriated E. coli are the least of the reasons why these patients get cystitis.  It would have been nice if they had done the groundwork first.  It is the usual throw the feces at the wall, uncertain if feces are even the correct projectile,  see if anything sticks, and then trying to draw a target around it.

One study found  trimethoprim and cranberry juice equivalent in preventing recurrent UTI.  There was no placebo wing and  at best chronic antibiotics has only modest efficacy in preventing UTI’s, depending on the population studied.

So when the Cochrane review says

Cranberries (usually as cranberry juice) have been used to try and prevent urinary tract infections (UTIs). Cranberries contain a substance that can prevent bacteria from sticking on the walls of the bladder. This may help prevent bladder and other urinary tract infections. This review identified 10 studies (1049 participants) comparing cranberry products with placebo, juice or water. There was some evidence to show that cranberries (juice and capsules) can prevent recurrent infections in women. However, the evidence for elderly men and women was less clear, and there is evidence that is not effective in people who need catheterization. Many people in the trials stopped drinking the juice, suggesting it may not be a popular intervention. In addition it is not clear how long cranberry juice needs to be taken to be effective or what the required dose might be.

I think, well, the studies are so fundamentally flawed who knows what can really be said about the efficacy of cranberry juice.

As noted in the 2004 CID review,

Furthermore, results of the reviewed studies should not be viewed as conclusive because many of the trials suffer from various limitations, including lack of randomization, no or improper blinding, small number of subjects, short trial duration, large number of dropouts, and no reported intent-to-treat analysis. Perhaps the single most consistent limitation of these trials is the lack of uniformity regarding the intervention, including the particular cranberry product evaluated (juice, sweetened cocktail, or capsules/tablets), concentration, dosing regimen, and duration of the intervention, which greatly differed from study to study.

What good is a meta-analysis on crap?  If you collect individual cow pies into a larger pile, it does not transmogrify into gold.  Can you make any conclusions under those circumstances?  GIGO. Garbage in, garbage out, which, I am starting to think, should be the motto for some of the Cochrane reviews.

Which brings us to the most recent cranberry juice study,  Cranberry Juice Fails to Prevent Recurrent Urinary Tract Infection: Results From a Randomized Placebo-Controlled Trial, which has all the SBM words: prospective, randomized, double-blind comparison of the therapeutic efficacy of 8 oz of CJC drunk twice daily in preventing recurring UTI.

The cranberry juice “consisted of one 8-oz bottle (240 mL) containing a mean proanthocyanidin concentration of 112 mg per dose (range, 83–136 mg; standard deviation, ±14.1 mg),” but we have no idea there was any product in the urine.

At the end of the 6 month study period, there was no difference in relapsing UTI  between those who consumed cranberry juice and placebo.

We report results of a double-blind, randomized, placebo controlled trial of the effects of drinking cranberry juice on risk of recurring UTI among college-aged women. The trial was developed to detect a 2-fold difference in incidence of recurring UTI with alpha of .05 and power of 99%. The power was estimated assuming we would observe a 30% recurrence rate among controls, consistent with that reported in observational studies. Contrary to expectation, we found that drinking an 8-oz dosage of cranberry juice twice per day gave no protection against the risk of recurring UTI among college-aged women.

Does this put the issue to rest?  No.

You do not know if the formulation led to active drug in the urine and you do not know if the E. coli that predominated  as a cause of the UTI could have been prevented.  Were there recurrent infections the same E. coli ?  Or a new E. coli .  Were any of the E. coli fimbriated?  Given that the minority of E. coli should be inhibited by cranberry juice, it would be nice to know if the pre-study bacteria were fimbriated and if the post-therapy infections were also fimbriated.

And to complicated matters, ascorbic acid is found in both products which has been associated with decreased in UTI’s, although the studies have even less rigor than the cranberry juice studies.

But I would predict that the use of cranberry juice will have little effect on either the treatment or prevention of cystitis.  When it comes to infection prevention, targeting the bacteria rather that the underlying predisposing cause, is doomed to failure.  If you target the bacteria with an antibiotic, the organisms rapidly evolve resistance and you end up with the same infections rates, only with resistant organisms.

People get UTI’s for a reason: catheters, sex (not both at once), and/or genetics.  The bacteria take advantage of the underlying pathology  to infect people.  Even if the use of cranberry juice may decrease the number of UTI’s due to fimbriated E. coli, if the underlying reason for the cystitis is not addressed, then there will only be a substitution in the species of  bacteria causing infections, not a decrease in the rates of infection.

In the end, I would conclude that cranberry juice probably does not prevent UTI, and any effects are likely of little clinical value, given the relative rarity of organisms for which it could be effective. It would require a much larger study to prove or disprove efficacy, and not having proper microbiology renders all the studies to date probably worthless for coming up with worthwhile conclusions.

Forty years of evaluation and we are still left wanting. Still, I am sticking with the cranberry juice in my Cosmopolitan, but not for its UTI prevention.

Clarifications

(1) Nice as in The Nice and Accurate Prophecies of Agnes Nutter, Witch.

Posted in: Herbs & Supplements

Leave a Comment (23) ↓

23 thoughts on “Cranberry Juice

  1. tuck says:

    Terrific post.

    At least cranberries taste nice. I’ve never tried echinacea, but perhaps one might also make a cocktail out of that?

  2. drjaylee says:

    The internet assures me that raisins soaked in gin are very effective for relieving joint pain. One is suppose to eat the raisins rather than rub them on the joints or burn them at midnight during a full moon.

    To me, raisins are ok. But gin just tastes nasty. Not being a fan of gin, I tried making my arthritis pain-remedy raisins with rum instead. Then I tried drinking the rum and found that consuming the rum worked better than eating the raisins. Alas, the effects were iffy at best and despite my belief that rum was a purely “natural” product, the rum produced undesirable sideeffects.

    I’ve recently started small trials with single malt scotch and will post an update soon. And,…of course, there’s always purely natural, simply organic, Mother Nature’s marijuana.

  3. Jan Willem Nienhuys says:

    Hey Mark,

    you get Randi’s million only for paranormal tricks! Prediction heat in summer and frost in winter doesn’t count. If you look at

    http://ec.europa.eu/food/food/labellingnutrition/claims/community_register/rejected_health_claims_en.htm

    for details see:
    http://www.efsa.europa.eu/en/scdocs/scdoc/943.htm

    you’ll see that the European Commision has rejected the cranberry health claim. It was the first claim on reducing health risk that was rejected (presumably because it was the first submitted).

  4. Draal says:

    Hell, if proanthocyanidins (aka tannins) worked, then so should chocolate, wine, and green tea.
    The body’s ability to absorb polyphenols is very low, that is the bio-availability is low. Less than 2% even shows up in the blood unadulterated (i.e. no modifications by the liver’s P450 enzymes). The vast majority of polyphenols are decomposed in the small intestine by the gut microflora.

  5. “(1) Nice as in The Nice and Accurate Prophecies of Agnes Nutter, Witch.”

    Thanks, you made my day.

    Also, “People get UTI’s for a reason: catheters, sex (not both at once), and/or genetics. The bacteria take advantage of the underlying pathology to infect people.” etc.

    I don’t typically suggest that a SBM article should be longer and I don’t feel it’s necessary, but a brief explain or links on how the catheters, sex and or genetics issues are addressed, might be a nice complement to the article.

  6. skeptyk says:

    A friend who has been self catheterizing for 20 years (since he was five years old) has been on various antibiotic regimens over the years (none for quite awhile now). He has also occasionally added cranberry juice to his diet. Can’t hurt, tastes good.

    In twenty years you can count the number of UTIs he has had on one hand, but he and his parents attribute that to good old hygiene: wash your hands, wash your willy and browbeat your insurance provider to cover new catheters for each use.

  7. Scott says:

    What, you mean it isn’t guaranteed to work just because it’s natural? What an idea!

  8. desta says:

    A UROLOGIST recommend that I drink cranberry juice for my uti a few years ago.
    I had just been reading up on it on quack watch, so I said something to the effect of ‘really? I didn’t think there was much going on with that research.’

    (Whenever I question an md who give me goofball advice, I can see them making a mental note to write “problem patient” in the folder. )

    I asked him if he knew of any studies that showed efficacy (of course not), and finally asked him what the mechanism might be, to which he responded ‘well, it acidifies the bladder.’ Apparently, that’s good? In any case, if it does help, why won’t any acid work? Why can’t I just drink orange juice? Lemonade? Vinegar? At that point he just wanted me out of there, so he agreed that any acid will do and sent me away.

    Anyhow, it really irked me that a specialist in the field would recommend nonsense. It’s one thing when the general public goes for this, but it’s insidious that the cranberry thing is firmly lodged in a urologist’s uroepithelial cells.

  9. Todd W. says:

    Thanks for the Agnes Nutter reference. Gave me a chuckle.

    This is one of those things that I’d heard of, but never really thought to question. Low risk (unless you have some sort of allergy), tastes good. Then again, self-reporting in lots of cases on a self-limiting problem.

  10. wales says:

    Those pesky biofilms. This article indicates that cranberry juice may be more effective against staph biofilms than e. coli biofilms.

    http://ihealthbulletin.com/blog/2010/09/02/cranberry-juice-blocks-staph-infection-biofilm/

  11. wales says:

    for those of you who object to the source of the above article, here is the original source.

    http://www.wpi.edu/news/20101/cranstaph.html

  12. apgaylard says:

    @wales
    A poster reporting, “a small clinical study.” I think I’ll wait to see if it makes it’s way into a decent peer-reviewed journal before I get too excited.

  13. superdave says:

    I appreciate this entry. The seemingly small stories can be just as important as the big ones.

  14. David Gorski says:

    One also notes that this small clinical study was ” supported by grants from the Cranberry Institute and the Wisconsin Cranberry Board.”

    This doesn’t mean that the study is hopelessly compromised because it was funded by groups whose purpose is to promote the sale of cranberry-based products like cranberry juice, but fair’s fair. If anti-pharma types always point out when a study is industry-sponsored, it’s only fair to point out the same when a study like this is presented.

  15. Jan Willem Nienhuys says:

    Actually it would be nice if every producer who wishes to make health claims about his product would provide proof, just like pharmaceutical companies do. At least the cranberry people put some effort in providing such proofs, quite in contrast with all the sellers of supplements, noni, mangosteen, colloidal silver etc.

    The anti-pharma use spurious logic, so I don’t see what’s fair about emulating them.

  16. cloudskimmer says:

    Cranberries are okay, but it takes a LOT of sugar to make their bitterness palatable, and since the recommendations are to drink a very large amount when symptoms appear, that may be a problem for people who are fighting a weight problem. And what are diabetics to do? Wouldn’t drinking huge quantities of sugar-water harm them?

    What should someone do who has occasional UTI’s? The recommendations I’ve had usually involve going to see a doctor right away, who then prescribes antibiotics, which cause a rash, and then there’s another antibiotic I can’t take… And the last time I felt horrible for a few hours, but improved during the interminable wait in the emergency room. By the time they figured out all I needed was a urine test and prescription for antibiotics, six hours had gone by, and the bloody urine was nearly gone. So after consulting with my Primary Care Physician the next day, I stopped the antibiotics and had a complete recovery. In retrospect, I would’ve done better just to stay in the hotel room and sleep, and it would have been far more comfortable (I almost froze to death in the ER–Why do they keep it so terribly cold?)

    Thanks, Dr. Crislip, for the analysis. Now I’d like to know if the more general idea of downing lots of fluids when symptoms first appear is any good, and how long to wait before running to a very expensive emergency room visit.

  17. Draal says:

    @cloudskimmer said, “Cranberries are okay, but it takes a LOT of sugar to make their bitterness palatable, and since the recommendations are to drink a very large amount when symptoms appear, that may be a problem for people who are fighting a weight problem. And what are diabetics to do? Wouldn’t drinking huge quantities of sugar-water harm them?”

    This particular study specifically used diet cranberry juice. That is, it used sucralose as a sugar substitute.

    “What should someone do who has occasional UTI’s?”
    My last girlfriend had occasional UITs. Her GYNO recommended that she pee every time after sex. Problem solved for her. Something to think about.

  18. squirrelelite says:

    @Draal,

    The gynecologist’s recommendation reminded me of this little study for some reason:

    http://blogs.discovermagazine.com/discoblog/2011/01/14/ncbi-rofl-and-the-most-pornographic-abstract-award-goes-to/

    Strange name but an interesting discovery nonetheless!

  19. BillyJoe says:

    cloudskimmer,

    Drinking lots of fluids would theoretically flush out any bacteria in the bladder thereby helping to terminate the infection. It would also help prevent bacteria travelling up the ureter to the kidney causing pyelonephritis. That would entail a very expensive hospital admission (though not in Australia).
    Whether this has been born out by clinical studies I do not know.

  20. Calli Arcale says:

    Being a woman with a congenital urinary diverticulum, I am more familiar with UTIs than I’d like. There are some crucial things that need to be said:

    1) Hygiene is the single biggest factor in UTI prevention, and most of it revolves around keeping fecal bacteria from gaining access in the first place.
    a) Wipe *away* from the urethra. Always.
    b) If female, wipe even after peeing; some women skip this. (I know, because they dribble all over the seat when they get up. Nasty.)
    c) Keep it dry down there; dry skin is far less hospitable to the bacteria while they wait for you to push them into someplace they can thrive. That means clean, breathable undies, preferably cotton. This is also very good advice for preventing yeast infections, so, bonus!
    d) If female, be sure to clean before sex and after, and to use the potty afterward. It also helps to make sure he keeps clean too. It’s not really rocket science; it’s just stuff one doesn’t usually think about.

    2) The second factor is sort of hygiene related; you need to pee regularly so the urethra gets flushed out before any nasties can work their way up it. Don’t hold it ridiculously long, and make sure you’re getting adequate fluid intake. For females, you should particularly make sure you pee after sex; this actually does make a difference.

    3) Make sure it really is a UTI. If your only symptom is urgency or burning during urination (what my daughter evocatively called “lava pee”), you may not have an actual infection. Certain drugs or foods can irritate the lining of the bladder, and especially as we all get older, there are plenty of other conditions which can produce UTI-like symptoms. I suspect this is why OTC herbal remedies and homeopathy for urinary tract infections seem to be so effective — most of these other conditions will resolve on their own in under a week.

    The advice for drinking lots of fluids is good for prevention but can also help reduce symptoms (both of a real UTI and a fake one) because it makes the urine less concentrated and thus less painful. From experience, it also reduces the frustration factor — the worst part about urinary urgency is that you feel like you desperately have to go, and then when you get to the bathroom, you don’t produce anything! Very annoying. At least if you’re drinking lots, you’ll have something to do when you go in there.

    I’ve tried the cranberry juice thing; it didn’t seem to make any noticeable difference either for prevention or treatment. But it is very nice mixed with ginger ale or, after hours, champagne. ;-)

  21. New RCT on this, 300+ subjects. Dr. Neil Ampel for Journal Watch: “These findings fail to demonstrate a decreased risk for recurrent UTI in those consuming cranberry juice. However, as the authors point out, something other than proanthocyanidin might be the active factor, and the placebo might inadvertently have contained this ingredient. Therefore, this study is probably not the last word on cranberry juice and UTI prevention.”

  22. Eleison says:

    I used to have mild recurrent UTIs. Drinking cranberry juice alleviated the pain somewhat, but the only alternative treatments I’ve found that really worked well (researched mainly because, lacking health insurance, I couldn’t afford a doctor’s visit) were apple cider vinegar to treat the UTI as it occurred and increasing my daily water intake while decreasing diuretic (e.g., coffee, soda, tea) intake to keep my system well-flushed. Based on this, my thoughts are that cranberry juice helped in alleviating the pain simply because it was a non-diuretic liquid.

    More than anything, I think largely removing the diuretics from my diet and dramatically increasing water intake is what has helped stop the reoccurrence, because I still sometimes get a mild UTI if I have to go several days without getting enough water.

  23. Calli Arcale says:

    Wouldn’t diuretics increase the “flushing” of your system? Diuretics tend to increase urine production. (Note also that it is a myth that drinking caffeinated beverages will lead to dehydration; the diuretic effect is more than countered by the fluid volume of the beverage, so unless you were on the very cusp of dehydration, it wouldn’t make a difference.)

    Drinking cranberry juice never did anything at all for the pain for me. Apple cider vinegar has been suggested many times as a treatment for many things, but I’ve never seen any conclusive evidence that it actually did anything at all besides give people heartburn. (When drunk straight, that is.)

    Proper hydration is helpful, though; it dilutes your urine, which makes it less irritating to an inflamed bladder.

    Note: if you did not see a doctor for your UTIs, how do you know you had UTIs? The symptoms can be mimicked by many other things, most of which resolve spontaneously. Heavy caffeine use can irritate the lining of the bladder, I seem to recall, so you may have removed an insult rather than treating an infection. Not that that’s a bad thing.

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