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The bladder might be one of the body’s most underappreciated organs. It is far more than a simple muscular sack holding sterile urine until we find a suitable place to pass water. The anatomy and physiology of the bladder and the surrounding organs are complex, with a labyrinthine network of nerves carrying signals to and from the brain mediated by a cocktail of neurotransmitters.
When urinary function goes awry – as it does all too often – the lack of control can ruin patients’ social and daily lives. A postal questionnaire involving 10,116 people aged 40 years or older living in Leicestershire found that 28.5 per cent of men and 38.8 per cent of women experienced clinically significant urinary symptoms. For example, 19.9 per cent of men and 20.9 per cent of women reported nocturia at least twice a night, while 8.9 and 20.2 per cent respectively reported urinary incontinence several times a month or more.1
Bladder problems can cause considerable distress: 5.6 per cent of men and 7.0 per cent of women described their urinary symptoms as either moderate or severe. Many reported that the symptoms caused “a lot” of upset or distress (1.6 per cent), or affected their relationships (0.7 per cent), daily activities (1.4 per cent), social life and quality of life (both 1.6 per cent) “a lot”.1 Occasionally, the consequences can be more serious than a disrupted social life. Older women who experience incontinence or other lower urinary tract symptoms are about twice (1.5 to 2.3 times) as likely to fall as controls.2
Yet urinary incontinence remains under-diagnosed and under-treated,2 which means patients endure distressing and embarrassing symptoms. The persistent symptomatic burden partly reflects limitations in the efficacy of medicines, while concerns over the safety of surgical procedures and drugs mean that patients may be reluctant to agree to certain treatments.
The symptom burden also reflects the lag between current management strategies and new research that is overturning some widely held beliefs about the bladder. Indeed, we could be on the verge of a paradigm shift – in the true sense of that clichéd phrase – in our understanding of bladder diseases.
Linda Cardozo, professor of urogynaecology and consultant gynaecologist at King’s College Hospital, London, has already witnessed some marked changes since she first became interested in bladder problems in the 1980s.
“People now know what urinary incontinence is,” she says. “They recognise that incontinence is not an inevitable consequence of ageing or having a child. And they recognise that a lot can be done to help using lifestyle and behavioural changes, pelvic floor physiotherapy, drugs and surgery.”
For example, people with stress urinary incontinence (SUI) involuntarily pass urine as abdominal pressure rises, such as when exercising, laughing or coughing.2 A year after supervised pelvic floor muscle training, 58.8 per cent of women were completely continent or had no evidence of SUI on physical testing, with a significant reduction in their incontinence episodes. Adding other approaches – such as vaginal weighted cones or biofeedback – may improve the cure rates produced by pelvic floor muscle training alone.2
Pharmacological management and surgical procedures for urinary incontinence have also advanced considerably, Professor Cardozo comments, and have “markedly improved” patients’ quality of life.
People with urge incontinence, for instance, report a desire to pass urine that is difficult to resist.2 Anticholinergics block muscarinic receptors in the smooth muscle of the bladder. This inhibits detrusor contraction and moderately reduces urgency, frequency and the number of urgency episodes.2
Beta3-adrenergic agonists relax smooth muscle, which increases the amount of urine the bladder can store.2 So “combining anticholinergics and beta3-adrenergic agonists is a promising approach”, Professor Cardozo suggests.
Nevertheless, surgical and pharmacological treatments of bladder weakness aren’t perfect. Using tape or mesh to support the urethra improves SUI symptoms in between 48 and 90 per cent of women,2 but can cause serious complications including haemorrhage, organ perforation, mesh erosion, infection and pain.
To examine the risks, researchers retrospectively studied 92,246 first-time tape or mesh procedures between April 2007 and March 2015 in England. Of these, 68,002 were not potentially confounded by concomitant procedures.3
Peri-procedural and 30-day complication rates in the cohort that were not confounded by concomitant procedures were 2.4 and 1.7 per cent respectively. About one woman in every 17 (5.9 per cent) was readmitted at least once within five years for another mesh procedure or because of complications. Not surprisingly, the risks were higher in operations confounded by concomitant procedures: peri-procedural and 30-day complication rates were 5.2 and 3.0 per cent respectively. The five-year readmission rate was 6.4 per cent.3
Against this background, the Scottish Government suspended the use of mesh for SUI in 2014. This July, the Department of Health and Social Care and NHS England accepted recommendations made by the Independent Medicines and Medical Devices Safety Review to pause the use of surgical mesh for SUI until several changes to reduce the risk are in place (which should be by March 2019).
“We strongly believe that mesh must not be used to treat women with stress urinary incontinence until we can manage the risk of complications much more effectively. We have not seen evidence on the benefits of mesh that outweighs the severity of human suffering caused by mesh complications,” Baroness Julia Cumberlege, who chaired the review, commented in a statement.
“My team and I are in no doubt that this pause is necessary. We must stop exposing women to the risk of life-changing and life-threatening injuries. We must have measures in place to mitigate the risk and those are sadly lacking at the moment,” Baroness Cumberlege added.
“At this stage in our review we are not recommending a ban but a halt to procedures until the conditions we have laid down are met. I am pleased that both the Department of Health and Social Care and NHS England support our recommendation, and I look forward to its quick implementation.”
Drugs are the mainstay of treatment for overactive bladder. In studies used to gain regulatory approval, drugs produced a 53-80 per cent reduction in urinary incontinence episodes and a 12-32 per cent reduction in urinary frequency. However, there is a marked placebo response: 30-47 per cent for incontinence episodes and 8-15 per cent for urinary frequency.2
Overall, about half of patients taking anticholinergics for overactive bladder report symptom control but side-effects such as dry mouth and constipation mean that many people discontinue them. This lack of efficacy and tolerability helps explain why less than 50 per cent of patients take anticholinergics for more than six months and less than 36 per cent for more than a year.2
Recent investigations also raise concerns that some anticholinergics may increase the risk of dementia. According to the Anticholinergic Cognitive Burden (ACB) rating scale:
Researchers enrolled 40,770 patients aged 65-99 years in the UK with diagnosed dementia and 283,933 controls. Of these, 35.5 and 30.4 per cent respectively received at least one ACB-3 drug in the four to 20 years before the index date (i.e. being diagnosed with dementia). The median drug exposure was 7.1 years, ranging from one to 16 years.4
Compared to controls, people who took at least one ACB-3 anticholinergic in the previous 4-20 years were 11 per cent more likely to develop dementia. ACB-1 and ACB-2 drugs each increased the risk by 10 per cent. The more anticholinergics patients received, the greater the risk. The dementia risk was four per cent higher in those who received up to 13 prescriptions, but 27 and 31 per cent higher in those who received 365-1,459 and at least 1,460 prescriptions respectively. The link also emerged in people exposed to ACB-3 anticholinergics 15-20 years before a dementia diagnosis.4
Anticholinergics differed in the strength of the link to dementia. ACB-3 gastrointestinal and respiratory anticholinergics did not seem to be associated with dementia but ACB-3 antidepressants increased the risk by 11 per cent, urological drugs by 18 per cent and medicines for Parkinson’s disease by 29 per cent.4
Professor Cardozo stresses that the risks should be kept in perspective. “The dementia risk associated with antimuscarinics used to treat urinary incontinence has been over-emphasised,” she says. “There has been some scaremongering. The overall anticholinergic burden drives the risk and most people with urinary incontinence don’t take a large number of other antimuscarinic drugs.”
Nevertheless, Professor Cardozo stresses the importance of judicious prescribing, which pharmacists could consider when conducting medicines use reviews. “Because of the side-effects, I tend to avoid oxybutynin in frail, elderly people,” she says, and instead considers trospium or darifenacin (which show lower drug levels in the CNS than oxybutynin, tolterodine and solifenacin),5 and alternative formulations, such as oxybutynin patches and beta3-adrenoceptor agonists.
Such limitations regarding current surgical and pharmacological options suggest it could be time to reconsider some basic assumptions about the bladder. Increasing evidence shows, for example, that the bladder – along with the gastrointestinal tract, mouth skin and vagina – has a resident microbial community.6,7 “Research has now debunked the belief that the bladder is sterile,” says Alan Wolfe, professor of microbiology and immunology at Loyola University Chicago.
Professor Wolfe believes that the myth of urine sterility has contributed to the lack of innovation in incontinence therapy in recent years. “If microbes contribute to a disorder, but the microbes are not observed or they are observed but overlooked, then any attempt to understand that disorder is likely to fail and, in many cases, did,” he says. “We have now shown that some members of the bladder microbiome are associated with a variety of lower urinary tract symptoms and disorders.”
In one recent study, Professor Wolfe’s team isolated and sequenced the genomes of 149 bacterial strains in 78 species from urine collected from 77 women. “We have cultivated bacteria from more than a thousand women over the past five years,” Professor Wolfe says. “We chose the 149 isolates from 77 women based on all our studies to be representative of the general population.”
The 78 species represent about two-thirds of the bacterial diversity in the urine samples. “The genomes of urinary microbes are similar to the genomes of the vaginal microbes, but are quite different from those of the gut,” Professor Wolfe says. For instance, detailed genetic analysis of bacteria from the bladder shows that the strains of Escherichia coli, Streptococcus anginosus, Lactobacillus iners and Lactobacillus crispatus can be very similar to those in the vagina of the same woman.6 Professor Wolfe suggests this similarity probably reflects anatomy rather than another myth – poor female hygiene.
“The openings to the vagina and the bladder are next to each other,” says Professor Wolfe. “Gravity makes it easy to understand the movement of bacteria from the bladder to the vagina – it happens several times a day. The other direction is a bit more difficult to understand, but some combination of anatomy and physics is probably the answer.” This anatomical arrangement helps account for the high prevalence of urinary tract infections (UTIs) among women, most of which follow penetrative sexual intercourse, says Professor Cardozo.
Professor Wolfe dismisses suggestions that poor hygiene might be responsible. “My clinical colleagues have told me about the ‘women have poor hygiene’ hypothesis,” he says. “Really?
Half of all women will get a UTI during their lifetime and, as they age, many develop other urinary tract symptoms. Do half of all women and older women in particular have dreadful hygiene habits? I don’t believe that for a moment.”
The discovery that urine is not sterile is of more than just academic interest. “I’m speculating, but think of Clostridium difficile,” Professor Wolfe says. “C. difficile is a poor coloniser and is often present as a minor component of the gastrointestinal microbiome. However, treatment with antibiotics can kill off major members of the gastrointestinal microbiome, causing a dysbiosis [microbial imbalance], especially in older or immune-compromised individuals.
“The loss of major members of the microbiome permits C. difficile to take over. The result of that bloom can be death. So, what if, in some women, treatment with antibiotics – for acute UTI, for example – causes a dysbiosis in the bladder that never returns to normal? Could some of the chronic lower urinary tract disorders be the result of dysbioses?”
Certainly, a growing number of studies link increases in the diversity of the bladder microbiota to urge incontinence and a reduced response to anticholinergics. Some bacterial species (e.g. S. anginosus and Gardnerella vaginalis) seem to be associated with urge incontinence. Others, including L. crispatus, seem to be associated with a lack of lower urinary tract symptoms.
“We also have a paper in review that describes a urinary microbiome study of men with and without benign prostatic hyperplasia. Men with BPH often have symptoms similar to urge incontinence,” Professor Wolfe says. “We detected microbes in the bladders of some older men and also found microbes more frequently in men with enlarged prostates.”
Women with microbiota dominated by some species of Lactobacillus seem to be less likely to develop postinstrumentation and post-operative UTIs.6
Bacteriophages are viruses that infect bacteria. When bacteriophages infect Vibrio cholera or Corynebacterium diphtheria, the bacteria produce the toxins responsible for cholera and diphtheria respectively. Bacteriophages also pass genes between bacteria, which contributes to the spread of antibiotic resistance – but using bacteriophages to infect and kill specific pathogenic bacteria could help spare antibiotics.
“We are trying to understand the role of bacteriophages in the bladder’s microbiome. Until the 20th century, and in some places today, viruses chose who lived and who died – they shaped human communities,” Professor Wolfe remarks. “Bacteriophages do the same to bacterial communities and, as such, they might be useful as alternatives to antibiotics.”
UTIs are a potentially reversible cause of incontinence2 but, as Professor Cardozo comments, effective management of recurrent lower UTIs is currently the greatest unmet need in the care of people with bladder problems. “Antibiotic resistance is a major concern in these patients,” she comments.
“It was widely accepted that uropathogenic E. coli [UPEC] and other causes of acute UTIs ascend through the urethra into a sterile bladder that has few defences,” Professor Wolfe remarks. “Clearly, this is not correct and investigators who are trying to understand how UPEC and other pathogens cause UTIs must adjust their study designs. Indeed, some are doing just that.”
Understanding the interactions between members of the microbiome, the human cells that line the bladder (the urothelium) and the innate immune system might help develop new approaches to managing UTIs. “Since the microbes exist, these interactions must exist, but we know almost nothing about them,” Professor Wolfe adds. “Which of these interactions protect the bladder against invaders such as UPEC? Which cause disease or enhance the pathogenicity of UPEC and other known uropathogens?”
Research by Professor Wolfe and others also reveals that the bladder hosts several poorly understood bacterial species called ‘emerging uropathogens’. “Almost nothing is known about these bacteria,” he says. “By sequencing their genomes, as we did in our recent study,6 we can obtain new knowledge concerning the abilities of bladder bacteria, both good and bad.
“I am convinced that this new knowledge can be used to improve bladder health. For example, we might be able to restore a disrupted bladder microbiome to a healthier community – perhaps by using some ‘good’ bacteria as probiotics or by instructing the bladder’s immune system.”
Professor Wolfe’s team is studying an emerging uropathogen called Aerococcus urinae, which is associated with urge incontinence and UTIs. “Knowledge of its genome is helping to begin the process of understanding how A. urinae interacts negatively with the bladder,” he says.
“This is important because A. urinae is considerably more common than once thought and it is resistant to some antibiotics typically used to treat UPEC. New knowledge concerning the biology of A. urinae or other emerging uropathogens could result in new therapies.”
Professor Wolfe’s team is also looking at the microbiome’s role in other lower urinary tract disorders in women and men, including post-surgical UTI, bladder cancer, urinary stones and interstitial cystitis.
So how can community pharmacists help people with urinary incontinence? Pharmacists could, for instance, be vigilant for potentially reversible causes of incontinence, such as excessive fluid intake (typically more than two litres a day), UTIs, and the use and timing of diuretics. It is important to consider whether co-morbidities – such as obesity, constipation, smoking and sleep apnoea – might contribute to urinary incontinence.2
Pharmacists can reinforce lifestyle modifications that support other interventions, including stopping smoking, treating constipation and avoiding excessive fluids – especially caffeine, carbonated and diet drinks, and alcohol2 – while avoiding dehydration.
Patients should be encouraged to drink small amounts regularly rather than a few large drinks. Voiding at intervals individualised to each patient (say, every two to three hours) can reduce urgency incontinence episodes.2 Pharmacy teams can also provide discreet advice and specialist products to help improve the quality of life of bladder weakness sufferers.
Professor Cardozo stresses the importance of flagging potential interactions. “Community pharmacists need to ensure they are familiar and up-to-date with the treatments that are available and help ensure people with urinary incontinence receive the support they need,” she says.
It seems the bladder, this rather neglected organ, is beginning to receive the attention it deserves. New management approaches are needed given the uncertainty over the safety of mesh and the inefficacy of some of the drugs used. The debunking of the myth that urine is sterile could prove to be a seminal moment – provided the hypothesis proves robust when subjected to the rigours of clinical trials.
In the meantime, Professor Wolfe says pharmacists and patients should remain sceptical of any claims that jump on the bladder microbiome bandwagon. “At this point, we don’t have enough information to provide any guidance, so I would treat any advice concerning a new-fangled microbiological path to bladder health with extreme suspicion.”
1. J Public Health Med 2000; 22:427-34
2. JAMA 2017;318:1592-1604
3. Scientific Reports 2017; 7:DOI:10.1038/ s41598-017-11821-w
4. BMJ 2018; 361:DOI: 10.1136/bmj.k1315
5. British Journal of Clinical Pharmacology 2011; 72:235-246
6. Nature Communications 2018; 9:1557
7. Journal of Clinical Microbiology 2012; 50:1376-83