Urinary tract infection causes and risk factors

UTIs are one of the most common infections the world over, estimated to affect close to 150 million individuals every year. ⁽⁷⁾ Females have a significantly higher risk than males of developing UTIs, especially during their reproductive years. This is due to the fact that sexual intercourse may increase the likelihood of bacteria entering the urethra (whose opening is located in close proximity to the vaginal opening).

Worldwide, it is estimated that between 40% and 50% of females, and 5% of males are likely to develop a UTI at least once during their lifetime. ⁽⁸⁾

1. General causes and risk factors in the development of UTIs affecting both genders and all ages

Colonisation of uropathogens (bacteria, fungi and viral influences):

• Pathogens present around the urethral tissues can travel upward to the bladder. These pathogens can travel further into the kidneys causing pyelonephritis or bacteraemia (the presence of bacteria in the blood) if an infection extends into the bloodstream.
• Bacterial entry can occur as a result of turbulent flow during normal bladder emptying, dysfunction that occurs during bladder emptying, the insertion of a catheter for medical condition treatment (and to drain the bladder of urine), or sexual activity / intercourse.
• Bacterial proliferation may be encouraged by difficulties with bladder emptying (as a result of spinal cord injuries or conditions that involve nerve damage which affects the bladder) or bladder incontinence, a urinary blockage affecting urine flow (due to tumours, an enlarged prostate or kidney stones), and medical conditions which lead to impaired immune system function (such as diabetes and HIV).
• The most common bacterial pathogens include E. coli (this is a culprit in up to 80% of cases) ⁽⁹⁾ or ‘bowel flora’, as well as species of Klebsiella, Proteus, Enterococcus, Staphylococcus saprophyticus, group B Streptococcus and Pseudomonas aeruginosa.
• Fungal causes are typically as a result of candida species (Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida lusitaniae and Candida krusei).
• Adenovirus (a rare underlying cause but on which can result in haemorrhagic bladder infections).

There are three main components of a UTI – a host, a pathogen and the environment. The severity of an infection has much to do with the body’s innate defence mechanisms and the destructive nature of the infecting pathogen (i.e. virulence of the infectious agent).

The main physiological mechanisms of pathogen infection are:

• Colonisation of the lower urinary tract that spreads upwards (i.e. ascends the urinary tract)
• Hematogenous spread (wherein the pathogen is carried in the bloodstream)
• Peri-urogenital spread (i.e. affecting the urinary tract and reproductive organs)

Genetic influences

Genes (and gene combinations) are an ongoing area of research as potential biomarkers for UTI susceptibility in some individuals, especially those who experience recurrent or serious infections. So far research has been able to determine the following possiblities in identifying individuals who may be most at risk:

• HSPA1B (Heat shock 70kDa protein 1B)
• CXCR1 (C-X-C motif chemokine receptor 1)
• CXCR2 (C-X-C chemokine receptor type 2)
• TLR2 (Toll-like receptor 2)
• TLR4 (Toll-like receptor 4)
• TGFβ1 (Transforming growth factor beta 1)

The genetic make-up of a person may have an influence on a person’s susceptibility to developing (recurrent or severe) UTIs, especially since genes (like the six previously mentioned which research has shown may alter a host / person’s physical responses to pathogens) can play a role in regulating innate immune responses to signs of infection in the body (i.e. a person’s natural ability to defend against pathogenic organisms). ⁽¹⁰⁾ Some genes may even favour excess numbers of bacteria in urine (bacteriuria). By isolating genetic factors, researchers may be able to help improve diagnosis and treatment in those who are prone to recurrent or severe infections and by extension, more serious UTI-related complications.

Genes are regarded as a factor that play a role in the cause of recurrent or severe UTIs but the precise reasons as to why are not yet entirely known. It is also not known why certain individuals appear to experience UTIs in clusters. Women, in particular, are prone to recurrent infections. This, many medical researchers believe is suggestive of a familial genetic predisposition to the condition. Further research is still to determine exact causal links in this regard.

General factors

• Infrequent urination (holding in urine for too long or not urinating often enough during the day retains bacteria in the urinary tract and increases the risk of infection).
• Hygiene issues (females especially need to be careful with wiping following bowel movements – wiping from front to back instead of back to front, as the latter can encourage bowel flora / bacteria to enter the urinary tract)
• Obstruction of the urinary tract (i.e. catheterisation or following urologic surgery) and reduced mobility
• A history of UTIs
• Age (older adults) – Males 50 years of age and older are more prone to partial obstructions and problems with prostatic hypertrophy (age-related enlargement of the prostate gland) which can lead to UTIs. In general, seniors with urinary or bowel incontinence problems, cognitive impairments and more frequent use of catheters to assist with emptying the bladder experience an increase in infections.
• Comorbid (chronic) medical conditions, such as diabetes and those with spinal cord injuries.
• Elevated levels of serum creatinine in the bloodstream

2. Paediatric UTIs

For every 100 children, it is estimated that 3 will develop UTIs, mostly affecting the bladder. Babies (before the age of 1) are more at risk of infection than older children, with boys experiencing infections more frequently than girls. Boys who have been circumcised appear to have a reduced risk in comparison to those who are uncircumcised. After the age of 1, UTIs are more frequently experienced by girls with risk increasing as a little one ages into their teens. ⁽¹¹⁾

Bacterial pathogens

• Pathogens as a cause of UTIs in infants is fairly common. Low-level bacteraemia is a common underlying cause, especially in infants younger than 2 months. Sepsis can occur in infants due to bacterial colonisation (faecal / perineal / urethral spreading), although this is fairly rare.
• 65% to 90% of paediatric UTIs are caused by E. coli bacteria / bowel flora. ⁽¹²⁾
• Group B Streptococcus is a common bacterial cause among new-born infants.
• Staphylococcus saprophyticus is a common bacterial cause among female teenagers (including those who are sexually active).
• Antibiotic therapy that is used to treat other types of infections in children may make them more prone to UTIs. Antibiotics such as amoxicillin or cephalexin may play a role in altering the flora balance in the gastrointestinal (GI) tract and peri urethral area. This then alters the body’s ability to defend against the proliferation of pathogens in the urinary tract.

Structural or functional abnormalities

• Anatomical / structural problems in the urinary tract which may be congenital in nature, such as vesicoureteral reflux or ureters which are too narrow (resulting in reduced urine flow) can lead to the increased frequency of, or susceptibility to UTIs.
• Functional abnormalities of the bladder, such as an overactive bladder, insufficient emptying of the bladder, infrequent urination habits or urinary blockages (like kidney stones) restricting the normal flow of urine can all increase the risk of pathogen proliferation and infection.
• Constipation can also impact bladder emptying capabilities – A rectum that becomes dilated with faeces (stools) may cause restriction and impact the normal flow and frequency of urine.

3. Adult – Female UTIs

Bacterial pathogens

• Females are more commonly susceptible to UTIs as the shorter length of the urethra provides easier access to the bladder. Also, the female urethra is located closer to the source of bacteria which originates from the anus / rectum.
• Secretory immunoglobulin A (IgA) is an antibody that normally helps to reduce the number of bacteria in the urinary tract. These secretions provide a defence barrier that helps to promote the clearance of bacteria. Females who do not naturally secrete ABH blood antigens (i.e. ABO blood group system antigens normally found in bodily secretions like urine, saliva, sweat etc.) may experience recurrent UTIs. A lack of certain glycosyltransferases (enzymes), for instance, allows E. coli bacteria better opportunity to bind and proliferate within the urinary tract.
• Sexual activity can encourage bacterial pathogens to travel further into the urinary tract via the urethral opening.
• The risk of UTIs in women may increase with the use of certain birth control methods – The use of spermicides can result in irritation to the skin which can aid in bacterial proliferation. Spermicides can also eliminate bacteria that is necessary for the optimum health of the urinary tract and that provide some protection against infection. Slowed urinary flow can occur with the use of diaphragms and this can also result in bacterial proliferation. Condom use without lubrication or those with spermicidal agents can also result in irritation, promoting bacterial multiplication and growth.
• Hormonal changes experienced during pregnancy may encourage bacterial proliferation and the spreading of an infection through the ureters and possibly to the kidneys too.
• Pregnant women tend to experience trouble completely emptying the bladder / urinary stasis when urinating (often due to the location of a developing baby in the womb which is situated on top of the bladder), which increases risk for potential bacterial proliferation.
• Increased levels of urinary amino acids (aminoaciduria) and glycosuria (excess sugar in the urine) can allow for bacterial growth and thus increase a woman’s risk of developing UTIs.
• Menopausal women may experience changes in vaginal acidity levels and flora (‘good bacteria’) which, due to the vagina’s proximal location to the urethra, can increase the risk of infections. Hormonal changes (i.e. a reduction in oestrogen) can also result in the thinning or drying out of vaginal tissue, thus allowing for bacteria to thrive a little more easily. Post-menopausal women are more prone to bladder or uterine prolapse (i.e. organs which slip out of place or fall beneath their original location in the body) which can also play a role in increasing the risk of infection.
• Bladder catheterisation (assistance with emptying the bladder, often following a surgical procedure) and caesarean deliveries (babies delivered by C-section) can increase risk for bacteriuria (bacterial presence in urine).

4. Adult – Male UTIs

Incidence of UTIs in males between the ages of 3 months and 50 years is typically low. By comparison, females are 30 times more likely to experience UTIs than men during this age range. ⁽¹³⁾ As with children and females, bacterial pathogens, namely E. coli are the predominant cause of infection in men.

Bacterial pathogens

• Infectious agents in males can affect the prostate gland (mainly via the urethra and bladder) and prostatic ducts. Prostatic fluid does contain fluids with antibacterial properties (such as antibodies and zinc) but can lack adequate quantities of these to keep infection at bay, and thus result in prostatitis (inflammation of the prostate gland). UTIs affecting the prostate can also occur via the bloodstream, mainly via the lymphatic vessels in the rectum. An infection may also occur following prostate surgery. Chronic prostatitis is one of the primary underlying causes of recurring UTI in males with the most common infectious agent being E. coli.
• Inflammation of the epididymis can result in testicular swelling (referred to as acute scrotum) due to infection from bacteria. Infection generally begins in the urethra, spreading through the urinary tract and finally affecting the epididymis, causing epididymitis. Urine typically then becomes infected via the prostatic urethra and epididymis, and infection spreads into the ducts which carry sperm from the testicles to the urethra (vas deferens). Infections can sometimes occur as a result of structural or functional abnormalities in the urinary tract, or due to sexually transmitted diseases (such as gonorrhoea and chlamydia, or as a result of vaginal or anal sexual intercourse with an infected partner).
• Bacteraemia which infects the upper urinary tract can spread to the kidneys and cause pyelonephritis (kidney infection).
• Bacterial cystitis can sometimes affect males, although this infection is more prevalent in females. Males with an anatomical abnormality or defective bladder emptying mechanisms may be more prone to bladder infections. Urethral catheterisation (both short and long-term) is another way males may be affected by cystitis, leading to dysfunctional urine excretion and nosocomial infections – UTIs which take place in a hospital environment. Infections typically clear soon after the removal of a catheter and appropriate treatment is implemented. Bacteria most often seen in males with UTI / cystitis include E. coli, Enterobacter, Enterococcus, Klebsiella, Pseudomonas, Proteus, Serratia and Staphylococcus species.
• Bacterial urethritis is often seen in males as a result of a gonorrhoea infection. Infections are accompanied by a milky penile discharge and urinary problems.

Viral influences

• Now considered a fairly rare cause of genitourinary infection in males, orchitis (an inflammation or one or both testicles) is typically brought on following a mumps vaccination, or an infection with coxsackie B, varicella (chickenpox), Epstein-Barr or mononucleosis (mono). Viral pathogens or microorganisms which reach the testicles cause inflammation. Bacterial orchitis can also occur, generally as a result of the spread of infection from an infected epididymis. 

References:

^{7. US National Library of Medicine - National Institutes of Health. April 2015. Urinary tract infections: epidemiology, mechanisms of infection and treatment options: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457377/ [Accessed 28.03.2018]}

^{8. US National Library of Medicine - National Institutes of Health. December 2014. Innate immunity and genetic determinants of urinary tract infection susceptibility: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286230/ [Accessed 28.03.2018]}

^{9. US National Library of Medicine - National Institutes of Health. March 2017. The Most Frequent Isolates from Outpatients with Urinary Tract Infection: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402357/ [Accessed 28.03.2018]}

^{10. US National Library of Medicine - National Institutes of Health. March 2010. Genetic Risk for Recurrent Urinary Tract Infections in Humans: A Systematic Review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847765/ [Accessed 28.03.2018]}

^{11. National Institute of Diabetes and Digestive and Kidney Diseases. April 2017. Definition & Facts of Bladder Infection in Children: https://www.niddk.nih.gov/health-information/urologic-diseases/urinary-tract-infections-in-children/definition-facts [Accessed 28.03.2018]}

^{12. US National Library of Medicine - National Institutes of Health. February 2006. Urinary tract infection caused by bacteria other than Escherichia coli: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2082698/ [Accessed 28.03.2018]}

^{13. US National Library of Medicine - National Institutes of Health. September 2016. Urinary tract infections in adults: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027397/ [Accessed 28.03.2018]}