Recent clinical trials* provide further evidence for the role of cranberry (Vaccinium macrocarpon, Ericaceae) preparations in preventing urinary tract symptoms in a variety of circumstances, including radiation-induced cystitis, lower urinary tract infections (UTIs), infections after ureteral catheter placement, UTIs after gynecological surgery, and lower urinary tract symptoms (LUTS) in men. A growing body of scientific work supports the simple strategy of using appropriately manufactured cranberry preparations for lower urinary tract health.
Acute radiation cystitis (i.e., inflammation of the bladder caused by radiation therapy) is a common complication in men receiving external beam radiation for prostate cancer. Although several treatments provide symptomatic relief, there is no consensus treatment or standard prevention measure for radiation cystitis.
A New Zealand study aimed to determine the effect of a standardized cranberry extract encased in coated capsules (Naturo Pharm Ltd.; Rotorua, New Zealand; each capsule containing 72 mg proanthocyanidins [PACs]) on the incidence and severity of radiation cystitis.1 Forty-one men with prostate cancer participated in this randomized, double-blinded, placebo-controlled (RDBPC) clinical trial. Participants took one capsule per day at breakfast during radiation treatment and for two weeks after treatment completion. They also were asked to follow a hydration regimen (8 cups [1.9 L] of water per day), but a low-hydration regimen (4-6 cups [0.9-1.4 L] of water per day) was added during the course of the trial since some patients, older men in particular, experienced discomfort with the recommended hydration protocol. Severity of urinary symptoms was measured using a modified version of the Expanded Prostate Cancer Index Composite (EPIC). At the end of the study, men in the cranberry group had lower incidences of cystitis and severe cystitis (65% and 30%, respectively) compared with those in the placebo group (90% and 45%, respectively), although these differences were not statistically significant (P = 0.058 and P = 0.30, respectively). Overall, the incidence of pain/burning was significantly lower in the cranberry group (P = 0.045) compared with the placebo group. Men on the low-hydration regimen in the cranberry group had less pain/burning (P = 0.038), stronger urine stream (P = 0.030), and used significantly fewer pads/liners (P = 0.042) compared to the placebo group. The authors concluded that men receiving radiation therapy for prostate cancer may benefit from using cranberry supplements, particularly those on low-hydration regimens or with baseline urinary symptoms.
In two recent clinical studies it was also found that cranberry may be able to effectively prevent recurrent lower UTIs. The first study was a small Italian study in which 22 people were offered a standardized cranberry extract (Anthocran; Indena SpA; Milan, Italy) with lifestyle advice, and 22 people were offered lifestyle advice without the cranberry extract (the control group).2 The cranberry group experienced a 73.3% reduction (P < 0.05) in the frequency of UTI episodes during the study period compared with the two months before the trial, and the control group had a 15.4% reduction in frequency compared with the same period, a significant difference between groups (P = 0.012). Seven (31.8%) people in the cranberry group were symptom-free at the end of the study, but no patients in the control group were symptom-free, a significant between-group difference (P < 0.05). During the study period, the mean duration of UTI episodes was 2.5 ± 1.3 days in the cranberry group, compared with 3.6 ± 1.7 days in the control group, a significant difference (P < 0.05). Urine evaluation for blood or bacteria was completely negative in 90.9% of those in the cranberry group and in 50% of those in the control group (P < 0.005). No adverse events were observed. The authors asserted that these preliminary results, which were obtained in a field-practice setting, indicate that a standardized cranberry extract can be effective and safe in the prevention of recurrent UTIs.
In the second, and much larger, study, 928 older adults (median age of 84; 703 women) living in nursing home facilities in the Netherlands took 500-mg cranberry capsules (containing 9 mg of PACs) or placebo capsules (both supplied by Springfield Nutraceuticals; Oud-Beijerland, Netherlands) twice daily for 12 months.3 Participants were stratified according to UTI risk (risk factors included long-term catheterization, diabetes mellitus, and one or more UTIs in the preceding year). In participants with a high UTI risk at baseline (n = 516), the incidence of clinically defined UTIs was significantly lower with cranberry capsules than with placebo (P = 0.04). The treatment effect was 0.74 (95% confidence interval [CI] = 0.57-0.97), meaning the treatment reduced the risk of a clinically defined infection by 26%.
UTIs are among the most frequent complications after urinary tract surgical procedures, mainly when catheter placement is necessary. Although the use of cranberry has been linked to a reduced risk of UTIs, there has been no published study, until recently, reporting the value of its preventive effect against catheter-associated UTIs. A prospective trial of patients with double J catheters compared the UTI rate (confirmed by positive urine culture) of patients taking a cranberry extract (Urosens; Laboratorios Salvat; Barcelona, Spain) (120 mg per day) in addition to their routine prophylactic therapy (n = 31) to the rate of those receiving only routine prophylactic therapy (n = 31).4 When the catheters were removed approximately 30 days after the start of the study, the UTI incidence was found to be significantly lower (P = 0.04) in the cranberry group (12.9%) compared to the placebo group (38.7%).
UTIs are a common hospital-acquired infection, and the risk is high after gynecological surgery during which a catheter is placed. Women (N = 160) undergoing such elective surgery were randomly assigned to take either TheraCran cranberry capsules (provided by Theralogix, LLC; Rockville, Maryland; equivalent to 480 mL per day of cranberry juice) or a matched placebo for six weeks after surgery.5 The occurrence of UTIs during the study period was significantly lower (P = 0.008) in the cranberry group (19%) compared with the placebo group (38%) (odds ratio, 0.38; 95% CI = 0.19-0.79). After adjustment for known confounders, including the frequency of intermittent self-catheterization in the postoperative period, the protective effect of cranberry remained (odds ratio, 0.42). There were no significant differences between groups in terms of adverse events, such as gastrointestinal upset (56% in the cranberry group and 61% in the placebo group).
Finally, a cranberry powder (Flowens; supplied by Naturex-DBS LLC; Sagamore, Massachusetts) produced a clinically relevant, dose-dependent reduction in LUTS in men over 45.6 This six-month, RDBPC study aimed to evaluate the effect of 250 mg or 500 mg cranberry powder on LUTS and urinary flow. A total of 124 volunteers with prostate-specific antigen (PSA) levels less than 2.5 ng/mL of blood and International Prostate Symptom Scores (IPSSs) of 8 or higher were recruited for the study. The primary outcome measure was the IPSS, evaluated at three and six months. Secondary outcome measures included quality of life, bladder volume (Vol), maximum urinary flow rate (Q max), average urinary flow rate (Q ave), ultrasound-estimated post-void residual urine volume (PVR), and levels of serum PSA, selenium, interleukin 6, and C-reactive protein, at six months. At the end of the study, volunteers in both cranberry groups had significantly lower IPSSs (-3.1 in the 250 mg group [P = 0.05] and -4.1 in the 500 mg group [P < 0.001]) compared to the placebo group, and a dose-response effect was observed. There were significant, favorable differences in Q max, Q ave, PVR, and Vol in the 500 mg cranberry group versus baseline (P < 0.05). A dose-dependent effect on Vol was observed, as well as on PVR for participants with a non-zero PVR. There was no effect on clinical chemistry or hematology markers.
Complex Mechanisms of Action
One of cranberry’s most-studied mechanisms of action for preventing UTIs involves increasing the capacity of urine to prevent certain uropathogenic bacteria from adhering to epithelial cell receptors in the urinary tract. Many pathogenic bacteria contain fimbriae (thread-like appendages) that allow them to attach to epithelial cells. For example, the strains of Escherichia coli that cause UTIs can attach to uroepithelial cells. Cranberry’s ability to prevent the P-fimbriated E. coli bacterium from adhering to these cells has been attributed to its content of A-type proanthocyanidins (A-PACs). PACs typically consist of molecules of catechin and epicatechin joined by carbon-carbon or carbon-oxygen bonds. Hence, catechin and epicatechin are referred to as monomers, and those polyphenols containing two to four of these monomers are referred to as oligomeric (meaning “a few”) proanthocyanidins. In cranberry, they are also called procyanidins because they release colored cyanidin upon boiling with acid, hence the prefix “pro” (meaning “forming”). The linkage between the monomers in PACs can be either through one (B-type) or two covalent bonds (A-type). B-type PACs occur in grape (Vitis vinifera, Vitaceae) seed and pine (Pinus spp., Pinaceae) bark, whereas A-type PACs are found in cranberries.
Only the A-type PACs have demonstrated anti-adherence activity (larger PACs do not get absorbed in the bloodstream and are excreted in the urine due to their size), and urinary anti-adherence activity is correlated with a dose-dependent increase in PACs in cranberry products.7 Preliminary studies suggest that larger PACs act in the gut to prevent E. coli invasion, thereby reducing the resident population capable of causing future UTIs, and may induce the indirect excretion of anti-adherence molecules into the urine. Further, the larger A-type PACs may bind to uropathogenic rectal isolates in the colon, rendering them unable to adhere in the urinary tract if they were to enter.8
A human study published in 2012 found procyanidin A2 (a dimer [i.e., a molecule composed of two identical or structurally similar, bonded monomers]) at 24 ng/mg creatinine in urine 11 hours after ingestion of cranberry.9 (Concentrations of urinary metabolites are typically expressed per mg of creatinine due to the variability of a person’s water intake, and hence excretion.) This was shared in a conference report, and the same group finally published more details of their findings in 2015, which indicate that other cranberry phytochemicals, or their metabolites, generally occur at much higher levels than procyanidin A2 (e.g., protocatechuic acid [a phenolic acid] at 21.1 mcg/mg creatinine is almost 1,000 times greater). However, these metabolites were not individually tested for anti-adherence activity.10
As studies continue to elucidate the details concerning the mechanisms of action, the anti-adherence activity of urine after cranberry consumption is now well-supported by clinical evidence. For example, two recent clinical studies from the same research group demonstrated a substantial rise in bacterial anti-adherence activity that peaked around three hours after cranberry beverage or extract consumption.11,12
Cysticlean (Vita Green Europa; Barcelona, Spain), at a dosage of 118 mg PACs per day, was found to reduce recurrent UTIs by 93% in a six-month, observational prospective study in 20 women.13 And yet, 500 mg per day of cranberry fruit powder supplied by Naturex-DBS LLC, reported to contain only 2.8 mg A-type PACs per dose, also reduced UTIs in a trial involving 182 women with two or more UTI episodes in the past year.14 Participants were randomly assigned to the cranberry (n = 89) or placebo group (n = 93) and received treatment for six months. Intention-to-treat analysis showed that in the cranberry group UTIs were significantly fewer than in the placebo group (10.8% vs. 25.8%, P = 0.04) over the course of the study. The cranberry group also experienced a longer time-to-first-UTI than the placebo group (P = 0.04).
Future Research Directions
The clinical trials summarized above add to the evidence that cranberry is a viable option for the prevention of UTIs in at-risk populations, or in those suffering from recurrent infections. The potential of cranberry for LUTS in older men is worthy of clinical consideration, and has been demonstrated in previous research.15
There is controversy about label claims for, and measurement of, A-type PACs found in cranberry. This may explain some of the discrepancies in the clinical findings, meaning that the PAC contents of tested products may have been rather different than what was claimed in the studies, depending on the analytical method(s) used. Evidence of these complexities is provided in a study in which four products on the Swiss market with labeled PAC levels were tested by two different analytical techniques.16 Results were provided by a photometric DMAC method (which uses 4-(dimethylamino)cinnamaldehyde [DMAC] as the color reagent) and an ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS2) assay. Per the DMAC method, PACs ranged from 16-61% of the label claim. The UHPLC-MS2 assay yielded an even more stunning deviation, with PAC levels found to be 1.4-7.2% of what was declared on the labels. The discrepancies between the two methods may be explained in part by the fact that the UHPLC-MS2 method quantified only catechin/epicatechin dimers and trimers, while the DMAC method included PACs of higher polymerization degrees as well. However, all results, regardless of the method used, were still short of the label claims. The DMAC method is appropriate for measuring total PACs in soluble cranberry products, but results depend on the type of standard used.17 Standardization of methods used to quantify A-type PACs in cranberry products of different tissue types (juice or pomace) and accurate labeling of products by type are essential to reduce consumer confusion and increase accuracy in reporting A-type PAC contents in clinical trials.
Many questions remain to be answered before the true mechanisms of action of cranberry in preventing UTIs are properly understood and corresponding quality/activity markers can be agreed upon with appropriate methods of analysis. Anti-adherence activity of urine is likely part, or perhaps even all, of the story, but the specific metabolites that deliver this activity remain to be unequivocally established.
Kerry Bone is the co-founder of and innovation driver at MediHerb, where he serves as director of research and development. In 2016, MediHerb was awarded the American Botanical Council’s (ABC’s) Varro E. Tyler Award for Excellence in Phytomedicinal Research. As part of his educational role, Bone is principal of the Australian College of Phytotherapy and also adjunct professor at New York Chiropractic College, providing input into their postgraduate applied nutrition program. Bone has co-authored more than 30 scientific papers on herbal research, including original research and systematic reviews. He has also written or co-written six popular textbooks on herbal medicine, including his latest with Simon Mills, the long-awaited second edition of Principles and Practice of Phytotherapy, which was awarded ABC's 2013 James A. Duke Excellence in Botanical Literature Award.
*While this review comprehensively covers most of the clinical trials on cranberry preparations from 2010 to early 2016, this article is not meant to be exhaustive; accordingly, some studies have not been included.
- Hamilton K, Bennett NC, Purdie G, Herst PM. Standardized cranberry capsules for radiation cystitis in prostate cancer patients in New Zealand: a randomized double blinded, placebo controlled pilot study. Support Care Cancer. 2015;23(1):95-102. Available at: https://ourarchive.otago.ac.nz/bitstream/handle/10523/4839/hamiltonkatelin2014brthons.pdf?sequence=3. Accessed September 20, 2016.
- Ledda A, Bottari A, Luzzi R, et al. Cranberry supplementation in the prevention of non-severe lower urinary tract infections: a pilot study. Eur Rev Med Pharmacol Sci. 2015;19(1):77-80. Available at: www.europeanreview.org/wp/wp-content/uploads/77-80.pdf. Accessed September 20, 2016.
- Caljouw MA, van den Hout WB, Putter H, Achterberg WP, Cools HJM, Gussekloo J. Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities. J Am Geriatr Soc. 2014;62(1):103-110. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC4233974/pdf/jgs0062-0103.pdf. Accessed September 20, 2016.
- Barnoiu OS, Sequeira-García Del Moral J, Sanchez-Martínez N, Díaz-Molina P, Flores-Sirvent L, Baena-González V. American cranberry (proanthocyanidin 120 mg): its value for the prevention of urinary tracts infections after ureteral catheter placement. Actas Urol Esp. 2015;39(2):112-117.
- Foxman B, Cronenwett AE, Spino C, Berger MB, Morgan DM. Cranberry juice capsules and urinary tract infection after surgery: results of a randomized trial. Am J Obstet Gynecol. 2015;213(2):194.e1-8. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC4519382/pdf/nihms680709.pdf. Accessed September 20, 2016.
- Vidlar A, Student V Jr, Vostalova J, et al. Cranberry fruit powder (Flowens™) improves lower urinary tract symptoms in men: a double-blind, randomized, placebo-controlled study. World J Urol. 2016;34(3):419-424.
- Howell AB, Botto H, Combescure C, et al. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infections Diseases. 2010;10(94):1-11.
- Feliciano RP, Meudt JJ, Shanmuganayagam D, Krueger CG, Ree JD. Ratio of “A-type” to “B-type” proanthocyanidin interﬂavan bonds aﬀects extra-intestinal pathogenic Escherichia coli invasion of gut epithelial cell. J Agric Food Chem. 2014;62(18):3919-3925.
- Zampariello CA, McKay DL, Dolnikowski G, Blumberg J, Chen CYO. Determination of cranberry proanthocyanidin A2 in human plasma and urine using LC-MS/MS. FASEBJ. 2012;26:124.8.
- McKay DL, Chen CY, Zampariello CA, Blumberg JB. Flavonoids and phenolic acids from cranberry juice are bioavailable and bioactive in healthy older adults. Food Chem. 2015;168:233-240.
- Kaspar KL, Howell AB, Khoo C. A randomized, double-blind, placebo-controlled trial to assess the bacterial anti-adhesion effects of cranberry extract beverages. Food Funct. 2015;6(4):1212-1217.
- Mathison BD, Kimble LL, Kaspar KL, Khoo C, Chew BP. Consumption of cranberry beverage improved endogenous antioxidant status and protected against bacteria adhesion in healthy humans: a randomized controlled trial. Nutr Res. 2014;34(5):420-427.
- Sánchez Ballester F, Ruiz Vidal V, López Alcina L, et al. Cysticlean® a highly PAC standardized content in the prevention of recurrent urinary tract infections: an observational, prospective cohort study. BMC Urol. 2013;13:28.
- Vostalova J, Vidlar A, Simanek V, et al. Are high proanthocyanidins key to cranberry efficacy in the prevention of recurrent urinary tract infection? Phytother Res. 2015;29(10):1559-1567.
- Vidlar A, Vostalova J, Ulrichova J, et al. The effectiveness of dried cranberries (Vaccinium macrocarpon) in men with lower urinary tract symptoms. Br J Nutr. 2010;104(8):1181-1189.
- Chrubasik-Hausmann S, Vlachojannis C, Zimmermann BF. Proanthocyanin content in cranberry CE medicinal products. Phytother Res. 2014;28(11):1612-1614.
- 17. Krueger CG, Chesmore N, Chen X, et al. Critical reevaluation of the 4-(dimethylamino)cinnamaldehyde assay: Cranberry proanthocyanidin standard is superior to procyanidin A2 dimer for accurate quantification of proanthocyanidins in cranberry products. J Funct Foods. 2016;22:13-19.