The urinary system is comprised of two kidneys, two ureters,
the bladder and urethra. It has three primary
functions: (1) the removal of organic
waste materials from body fluids through excretion, (2) the discharge of these
waste materials through elimination; and (3) the homeostatic regulation of
blood volume, blood pressure, and the concentration of solutes in plasma. Other homeostatic mechanisms work to
stabilize blood pH, conserve nutrients through reabsorption, and assist the
liver in detoxification.
A urinary tract infection (UTI) is caused when a pathogen
invades the urothelial cells anywhere along the urinary tract. The location of where the infection takes
place has different names, such as cystitis for a bladder infection or
pyelonephritis for a kidney infection.
This paper will focus on uncomplicated acute cystitis.
Urinary tract infections are the second highest occurring
infection in humans, following respiratory tract infections. UTIs result in as many as seven million
office visits and more than one million emergency room visits each year. UTIs are more common in women than in men
because of differences in anatomy, and changes in sexual maturation, pregnancy
and childbirth. 50% of all women will
experience an UTI within her lifetime, while 25% of those women will experience
recurrence. Others at risk are those with
catheters, obstructions such as kidney stones, or those with diabetes mellitus. For uncomplicated acute cystitis, 90% of
those infections are caused by uropathogenic Escherichia coli (UPEC).
There are several symptoms that occur when the bladder is infected. These include a strong, frequent urge to
urinate even though the bladder is empty, pain or burning when urinating,
pressure or cramping in the lower abdomen, and the presence of cloudy or bloody
urine that may have a strong odor. If
left untreated, the infection can spread to the kidneys resulting in more
severe symptoms including chronic renal failure. Speaking from personal experience, UTIs are
aggravating and they do hurt. The
frequent, strong urges to pee can really disrupt one’s day making it nearly
impossible to get any work done.
HOMEOSTASIS
The body has several defenses in place to combat invasion by
pathogens in order to maintain homeostasis.
With the UTI, such defenses include the composition of urine, the
micturition reflex, and the innate and adaptive immune responses.
In The Journal of Clinical Investigation, Donald Kaye, in
his article Antibacterial Activity of Human Urine, wrote, “In discussing the
kinetics of urinary tract infection O’Grady and Cattell emphasized as a host
defense mechanism the importance of the mechanical effect of urine flow in
diluting and removing bacteria from the urinary tract . . . in the present
study, urine from normal individual is often inhibitory and sometimes
bactericidal for growth of these organisms.”
From Kaye’s research study, it is noted that the pH and the
concentration of urea provide an inhibitory effect on bacteria. The data showed that at a pH of 5.0, the
strongest inhibitory effect was found.
Additionally, the greater the concentration of urea, the greater the
inhibitory effect on bacterial growth.
According to the textbook used for Anatomy and Physiology,
the normal range for urine pH is 4.5 – 8.0, osmolarity ranges from 855-1335
mOsm/L, and the concentration of urea is typically 1.8g/dL. The research study referenced above showed in
their data that antimicrobial properties of urine is optimal at 5.0 but still
demonstrated inhibitory activity up to 6.0.
At a pH greater than 6.0, the inhibitory effect against bacteria
declined. It also demonstrated that as
the osmolarity increased, so did the concentration of urea. Kaye concluded, “The results of the present
study provide evidence for the role of urea in human urine as an antibacterial
agent. They also suggest that within the
ranges of concentration commonly achieved in human urine, antibacterial
activity is more a function of urea content than of osmolality, organic acid
concentration, or ammonium concentration.”
As water is reabsorbed in the nephron, the concentration of
urea increases where membranes in the ascending limb of the nephron loop, the
DCT, and the collecting ducts are impermeable to urea. The volume of urine is dependent on the
movement of water within the nephron.
85% of this water is involved in obligatory water reabsorption. The other 15%, about 27 liters per day, is
under the influence of ADH, which is secreted by the hypothalamus. This hormone inserts water channels
(aquaporins) along the membranes. This
affects the osmotic concentration and as ADH increases, more water channels
appear and more water is reabsorbed, thus concentrating the urine with solutes
because it is less diluted by water. In
the case of a UTI, based on the study mentioned above where the concentration
of urea had the greatest inhibitory effect, the body could respond by
increasing ADH, which decreases the volume of urine making it more concentrated
with urea. This could inhibit bacterial
growth in the bladder restoring homeostasis.
But on the other hand, increasing urine volume to cause a person to pee
more will provide more bacterial cleansing of the bladder and urethra.
Aside from the composition of urine, the flow of urine
through the micturition reflex is another important defense against invading
pathogens. Urine is the end product
after the blood has gone through filtration in the nephrons, the functional
units of the kidneys. After the bodily
fluid is filtered in the proximal convoluted tubule, it then goes through
reabsorption in the Loop of Henle in which water, ions, metabolites and
nutrients are reabsorbed into the vasa recta.
Finally, in the distal convoluted tubule, the active secretion of ions,
acids, drugs and toxins takes place. The
fluid that is left is what makes up urine as it now flows into the collecting
ducts of the nephron, then to the papillary duct and on to the minor
calyx. The minor calyces join to form a
major calyx and two or three major calyces form the renal pelvis, which is
connected to the ureter. Urine then
flows down the ureters, one from each kidney, to fill the urinary bladder.
The micturition reflex begins when the stretch receptors in
the bladder are stimulated as the bladder become full. This sends an impulse along the afferent
fibers in the pelvic nerve to the sacral spinal cord. Parasympathetic motor neurons are stimulated
and send the signal along the interneurons that relay sensation to the thalamus,
then through the projection fibers and on to the cerebral cortex. This is when one feels the urge to urinate
and the conscious decision is made to go to the bathroom. While sitting on the toilet, one voluntarily
relaxes the external urethral sphincter, which then causes the internal
urethral sphincter to relax as well. At the
same time, parasympathetic preganglionic motor fibers in the pelvic nerve delivers
an impulse to the postganglionic neurons that stimulate the detrusor muscle to
contract. (The detrusor muscle is the
name for the muscle fiber of the bladder.) This elevates the hydrostatic
pressure in the bladder and with the sphincters relaxed, urination takes
place. It is this act of urination that
works to flush out any pathogens that may be present; thus maintaining
homeostasis.
With a UTI, a patient can experience dysuria, which is pain
as a result of inflammation. Moreover,
urinalysis from a patient with a UTI will often show a higher than normal count
of white blood cells (pyuria) as well as a higher than normal count of red
blood cells (hematuria). All of this is
evidence of the body’s defenses working to restore homeostasis upon bacterial
infection.
Attached to this report is an actual urinalysis from a
family member who recently recovered from her first acute bout of
cystitis. She is a health-conscience,
physically fit, 39 year old female with a very busy schedule who is under a lot
of stress. She called me to ask about
some symptoms she was experiencing. She
described pain in her lower abdomen and the constant urge to pee with hardly
anything coming out. I asked her if she
noticed her urine appearing cloudy or red.
She said yes to both and added that there were blood clots in her urine
as well. I advised her to go to her
doctor as soon as possible because she had a bladder infection and she needed a
course of antibiotics to help her immune system fight off the bacteria. The battle waging inside her bladder was
between UPEC and her body’s innate and adaptive immune responses working to
restore homeostasis.
Uropathogenic E. coli (UPEC) must face the innate immune
defenses of the body upon invasion. But
one virulent strain has multiple ways to evade the host’s defenses. The first step in the pathogenesis of UPEC is
the portal of entry. UPEC lives in the
human gut’s flora and if microscopic amounts of feces come into contact with
the urethra, the UPEC can then enter, traveling up the urethra to the
bladder. As mentioned earlier, UTIs
affect more women than men. Women can
become infected if they wipe from back to front or as a result of sexual
intercourse.
E. coli are a Gram-negative bacillus that grows well under
various environmental conditions. These
rod-shaped bacteria have fimbriae, or pili, which function to bind to the
receptor sites on the host cell membrane.
This report will focus on UPEC strain NU14. The filamentous type 1 pili have a FimH
adhesion which binds to mannose-containing glycoprotein receptors. Research of Martinez et al, published in the
European Molecular Biology Organization Journal states, “Interactions between
FimH and receptors expressed on the luminal surface of the bladder epithelium
appear to be critical to the ability of many uropathogenic E. coli (UPEC)
strains to colonize the bladder and cause disease.”
As the photo illustrates, UPEC is able to penetrate into the
cell through membrane ruffling and is able to evade host defenses by leaving
the lumen of the bladder where flow of urine would flush them out of the
body. Once in the urothelial cell, the
bacteria have a source for nutrients and the opportunity to proliferate.
However, UPEC still has to overcome the obstacles of the
body’s first line of defense, which are the pH and the concentration of urea
present in urine as well as the flow of urine to flush out the bladder and
urethra. As will be discussed, UPEC RU14
has virulence factors that enable it to evade the host defenses but note that
research has revealed “in recent years important advances in our understanding
of the molecular mechanisms governing host resistance and in maintaining tissue
homeostasis in the urinary tract to ultimately prevent constant microbial
invasion have been made.”
The body’s innate immune response to this strain of UPEC
infection begins with the physical barriers of the urothelial cells. In Billips’, et al. research on the Molecular
Basis of Uropathogenic E. coli Evasion of the Innate Immune Response in the
Bladder, it is reported that the body’s robust innate immune response produces
the inflammatory cytokines and chemokines in the urothelium. The production of these chemical messengers
“results in the rapid recruitment of neutrophils into the bladder lumen and in
bacterial clearance.” The activation of
this response in the urinary tract depends upon recognition by the pattern
recognition receptors (PRR) of the pathogen-associated molecular patterns
(PAMPs) such as lipopolysaccharide (LPS) or type 1 pili.
In addition to this recognition mechanism, toll-like
receptors (TLRs) function in a similar way through a signaling cascade to
produce inflammatory cytokines and chemokines.
However, some UPEC can suppress the activation of these components. Specifically, UPEC strain NU14 can suppress
the secretion of interleukin-6 (IL-6) and IL-8 and the proinflammatory
transcription factor NF-KB. When UPEC
suppresses NF-KB, there is enhanced type 1 pilus-mediated apoptosis, which
decreases the levels of inflammatory cytokines and thus neutrophil recruitment.
The proinflammatory transcription factor NF-KB is an example
of a localized inflammatory tissue response resulting in the release of
histamine. The cardinal signs of
inflammation are redness, pain, heat, and swelling. (The reason for dysuria with an UTI is
because the inflammation causes the detrusor muscle of the bladder to spasm and
that creates even more irritation. Also
the inflammation of the lining of the bladder and urethra is what causes the
burning sensation upon urination.) The
adherence of UPEC to the bladder lining initiates this inflammatory
response. Mast cells respond by:
- Increasing blood flow resulting in swelling
- Activating phagocytes which engulf and destroy pathogens
- Increasing capillary permeability
- Activating complement for pore formation, enhanced phagocytosis, and histamine release
- Initiating the clotting reaction to wall off region (if there is hematuria)
- Increasing local temperature to disrupt pathogen
- Activating adaptive defenses with specificity, versatility and memory
Depending on the amount of inflammation, the vasodilation
that results will affect the afterload of the heart, peripheral blood pressure,
and capillary blood flow. Vasodilation
lowers blood pressure which decreases afterload, the amount of pressure needed
by the ventricle to open the semilunar valve to eject blood. A decrease in afterload provides less time
for isovolumetric contraction and leads to a decrease in end-systolic volume
(ESV). This in turn equals to an
increase in EDV, stroke volume and cardiac output. This is another way a connected body system
works to maintain homeostasis.
These innate immune defenses are critical to
homeostasis. Additional immune responses
by the body to remove pathogens in order to maintain health involve the cell-mediated
and the antibody-mediated response of adaptive immunity. When the uropathogenic E. coli enter the host
cell, the host releases IL-6 and IL-8 which operate to recruit macrophages to
the affected area. Additionally, the
infected cell will present a major histocompatibility complex (MHC) on its
surface. This is a signal for a
lymphocyte to bind and activate.
T cell lymphocytes are cell-mediated so upon encountering an
infected cell presenting a Class I MHC, the T cell will bind at its CD8 marker
to the MHC glycoprotein and will activate.
Upon activation, the T cells divide forming active cytotoxic T cells
(Tc) and memory Tc cells. The cytotoxic
T cell destroys the infected cell in one of three ways. First the Tc can release perforin, which essentially
punches holes in the cell membrane causing water to flow into the cell until it
bursts. Second, the release of cytokines
may stimulate apoptosis. Finally,
lymphotoxins may be released, which interfere with cellular metabolism.
Other T cells with CD4 markers will bind to infected cells
that present a Class II MHC on its surface.
When activated, they divide into helper T cells (TH) and
memory helper T cells. The TH
cell secretes cytokines which stimulates T cell division, attracts macrophages,
attract and stimulate the action of Tc cells, and promotes the activation of B
cells. B cells are responsible for
antibody-mediated immunity. They are
sensitized when exposed to antigens in the interstitial fluid. The antibodies of the B cell bind to the antigens
and then present them on their cell membrane.
When the activated TH cell encounters this antigen-antibody
binding, it releases cytokines that costimulate the B cell resulting in B cell
activation. The activated B cell then
divides producing memory B cells and the plasma cells that secrete the
antibodies.
There are 5 classes of antibodies: IgM, IgD, IgA, IgG, and IgE. With the antigen-antibody complexes, there
are 7 ways in which these antibodies will eliminate the antigen. They are:
- Prevention of bacterial and viral adhesion
- Neutralization
- Agglutination
- Attraction of phagocytes
- Stimulation of inflammation
- Opsonization
- Activation of Complement
Upon invasion by the uropathogenic E. coli that causes the
urinary tract infection in greater than 80% of all cases, the adaptive immune
response recognizes the signals from the infected cell and activates to destroy
that cell, which in turn will destroy the bacteria. The cytotoxic T cells work directly to
destroy the infected cell. The helper T
cell releases cytokines which sensitize and activate the B cells. This is when the immunoglobulins go to
work. IgM is the first responder whose
concentration will decline as IgG production increases. Since the bladder is lined by a layer of
mucosa, IgA will also be present as it will attack pathogens before they gain
access to the internal tissue of the mucosa.
The graphic above provides a scenario of some of the innate
and adaptive immune responses involved with a urinary tract infection. The graphic depicts the blocking action of
secretory IgA and a protein called a Tamm-Horsfall Protein. These adhere to the fimbriae of the bacterium
to prevent attachment to the bladder lumen leaving the bacteria suspended in
the urine, which will be flushed out of the body resulting in bacterial clearance
For UPEC that make it past this blocking action to bind to
and invade the host, the infected cell releases cathelicidin, defensins, and
nitric oxide to directly combat the bacteria.
At the same time, the cell releases IL-6 and IL-8 to enlist the
phagocytic action of the neutrophils.
Cathelicidin is a microbial peptide that is important in maintaining the
integrity of the urinary tract by its action to destroy uropathogenic
bacteria.
In summary of homeostasis, the body has several lines of
defense against the colonization of E. coli in the urinary bladder to restore
balance back to a state of health. With
the UTI, such defenses include the composition of urine, the micturition
reflex, and the innate and adaptive immune responses.
TESTS
A CBC and/or a blood culture may be ordered by the doctor
and certainly a urine sample is collected to run a urinalysis. First the sample is visually examined for
color and clarity. A cloudy, red urine
sample, for example, indicates abnormalities.
A urinalysis testing positive for a UTI may show abnormally high levels
for white blood cell count and nitrites.
Nitrites indicate the presence of bacteria since bacteria can convert
nitrates to nitrites. Also the red blood
cell count may be high due to inflammation causing blood vessels to leak RBCs
into the urine. If bacteria are present,
a urine culture may be done to identify the type of bacteria, which knowing
this is important in prescribing the correct antibiotic for treatment.
The results of the urinalysis completed upon my family
member’s visit to the ER are listed below.
From her clean catch urine sample, the pathologist observed the color
was red and the clarity was turbid. This
indicates the presence of both red blood cells (hematuria) and white blood
cells (pyuria), which is typical when there is infection. Some of the specific components that are
indicators of infection with abnormally high levels in her urine were for
nitrites, white blood cells, red blood cells and bacteria. Upon the presence of bacteria, a urine
culture was also done. This showed the
bacteria responsible for her infection to be E. coli with a too many CFUs
(colony forming units) to count.
Also of interest with this urinalysis is the specific
gravity. A result of 1.026 is at the
high end of normal. This means there
were more solutes in her urine making it more concentrated. This also means she was not taking in enough
fluids to be properly hydrated. One risk
of limited intake of fluids is the formation of kidney stones. There needs to be enough water available to
the urinary system in order to properly flush out the solutes as well as
invading bacteria.
How was her body working to restore homeostasis? First, the pH was within the normal range at
6.0. According to the research cited
above, this measure of pH was still at a level of activity where her body was
working to inhibit the growth of the bacteria.
Second, was the frequent urge to urinate as this micturition reflex worked
to flush out bacteria in the bladder.
Finally, her body’s innate and adaptive immune responses kicked into
high gear as evident by the pain, cramping, bleeding and blood clots resulting
from inflammation. The inflammation was
necessary to bring in the white blood cells to destroy the bacteria; to
activate T cells, B cells and subsequent antibodies; and to wall off the
infected area to prevent the bacteria from spreading.
If it is a case of complicated UTI, as seen with higher risk
patients such as pregnant women, those on catheters, or those in nursing homes,
additional tests may be ordered. These
tests include a CT scan of the abdomen, kidney ultrasound, intravenous
pyelogram, or a voiding cystourethrogram.
These tests will look for other problems such as kidney infection
(pyelonephritis), kidney stones, structural abnormalities, or, in men, chronic
prostatitis.
TREATMENT
Mild cases of acute cystitis may disappear on their own
without treatment, but since there is a risk for kidney infection, treatment
with antibiotics is usually recommended.
In the case of my family member, her urine culture noted that the best
antibiotic to take to fight E. coli is a piperacillin such as tazobactam, which
is a beta-lactam effective against Gram-negative bacteria. An alternative to antibiotics for mild cases
is to drink cranberry juice. Studies
have shown that the active compound of cranberries works to prevent bacterial
adhesion. This is also useful as a
preventative measure.
The following
antibiotics are used to treat UTIs:
(Source: Medicinenet.com/urine_infection)
- Beta-lactams, including penicillins and cephalosporins (for example, Amoxicillin, Augmentin, Keflex, Duricef, Ceftin, Lorabid, Rocephin, Cephalexin, Suprax, and others); many organisms have resistance to some of these drugs.
- Trimethoprim-sulfamethoxazole combination antibiotic (for example, Bactrim DS and Septra); many organisms may show resistance.
- Fluoroquinolones (for example, Cipro, Levaquin, and Floxacin) resistance is developing; also these should not be used in pregnancy or in the pediatric population.
- Tetracyclines (for example, tetracycline, doxycycline, or minocycline) used most often for Mycoplasma or Chlamydia infections; like fluoroquinolones, they should not be used in pregnancy or by the pediatric population.
- Aminoglycosides (for example, gentamycin, amikacin, and tobramycin) used usually in combination with other antibiotics to combat severe UTIs.
- Macrolides (for example, clarithromycin, azithromycin, and erythromycin), used more often with some STD-caused urinary problems.
PROGNOSIS
Treatment with antibiotics is usually successful and
symptoms of the infection usually disappear within 24 -48 hours.
Recurrence is a possibility for about 20-30% of women who’ve
had one episode of UTI. It is considered
a recurrence if infection returns for three or more episodes with a 12 month
period. Recurrence is caused by
different bacteria than the one that caused the first infection. If a repeat episode happens because of the
same organism, it is considered a relapse as opposed to a recurrence and occurs
less often.
BIBLIOGRAPHY
Billips, Benjamin K., Anthony J. Schaeffer, and David J.
Klumpp: Molecular Basis of Uropathogenic
Escherichia coli Evasion of the Innate Immune Response in the Bladder. Infection and Immunity, Sept. 2008; Vol. 76,
No. 9: 3891-3900.
Kaye, Donald:
Antibacterial Activity of Human Urine.
The Journal of Clinical Investigation, October, 1968; 47(10): 2374-2390.
Martinez, Juan J., Matthew A. Mulvey, Joel D. Schilling,
Jerome S. Pinker and Scott J. Hultgren:
Type 1 Pilus-mediated Bacterial Invasion of Bladder Epithelial
Cells. The European Molecular Biology
Organization Journal, 2000; Vol. 19 No. 12: 2803-2812.
Martini, Nath, and Bartholomew: Fundamentals of Anatomy & Physiology, 9th
edition.
Puri, Randhir and Jaideep Malhotra: Recurrent Urinary Tract Infection (UTI) in
Women. South Asian Federation of
Obstetrics and Gynecology, January – April 2009; 1(1): 10-13.
Saemann, Marcus D., Walter H. Horl and Thomas
Weichhart: Uncovering Host Defenses in
the Urinary Tract: Cathelicidin and
Beyond. Nephrology Dialysis
Transplantation, October, 2008; 22:347-349.
Thumbikat, Praveen, Carl Waltenbaugh, Anthony J. Schaeffer,
and David J. Klumpp: Antigen-Specific
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3080-3086.
Websource:
labtestonline.org/understanding/analytes/urinalysis/tab/test
Websource:
emedicine.medscape.com/article/217485-overview#a0104
