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Urinary Tract Infection 363
Table 9.5 Organisms causing urinary tract infection in
domiciliary practice
Organism Approximate
Escherichia coli and other ‘coliforms’
Proteus mirabilis 12
Klebsiella aerogenes* 4
Enterococcus faecalis* 6
Staphylococcus saprophyticus or S. epidermidis
*More common in hospital practice.
†More common in women.
Recurrent infection causes considerable morbidity and infection can lead to
life-threatening Gram-negative septicaemia and kidney failure.
†
frequency (%)
68+
10
Pathogenesis
Infection is most often caused by bacteria from a patient’s own bowel flora
and infection usually ascends up the urethra. In women, the short urethra
makes ascending infection more likely. Rarely, infection may arise from
the bloodstream, lymphatics or by direct extension (e.g. from a vesicocolic
fistula). For Escherichia coli, the presence of flagellae (for motility), aerobactin (used to acquire iron), haemolysin (to form pores) and, above all, the
presence of fimbriae (adhesins which attach organisms to the perineum
and urothelium) on the cell surface make E.coli such a common pathogen
(Table 9.5).
Risk factors for UTI
• Women (especially during pregnancy or post-menopause)
• New sexual activity, particularly in young women
• Indwelling urinary catheter or instrumentation of the urinary tract
• Urinary tract stones
• Urinary tract stasis (incomplete bladder emptying)
• Diabetes mellitus or immunosuppression.
Clinical features
The symptoms of lower UTI are frequency of micturition, dysuria, suprapubic
pain and tenderness, haematuria and smelly urine. The clinical features of
acute pyelonephritis are loin pain and tenderness, nausea, vomiting and
fever. Localization of the site of infection on the basis of symptoms alone is
unreliable. UTI can also present with few or no symptoms (particularly in the
immunocompromised), or with abdominal pain, fever or haematuria in the
absence of frequency or dysuria. In the elderly, new confusion may be the only
364 Renal disease
symptom of UTI. The possibility of UTI must always be considered in the fretful,
febrile sick child who fails to thrive.
Natural history
Uncomplicated versus complicated infection. Uncomplicated infection
refers to a UTI in an otherwise healthy non-pregnant woman with a
functionally normal urinary tract and will rarely result in serious kidney
damage. Complicated infection refers to infection in patients with abnormal
urinary tracts (e.g. stones, obstruction) or systemic disease involving the
kidney (e.g. diabetes mellitus, sickle cell disease/trait). They are more likely
to fail treatment and develop complications which include renal papillary
necrosis (p. 351) and the development of a renal or perinephric abscess with
the risk of Gram-negative septicaemia. Most UTIs in men are considered
complicated since they are often associated with urological abnormalities
such as bladder outlet obstruction.
Acute pyelonephritis. This condition is associated with neutrophil
infiltration of the renal parenchyma; small cortical abscesses and streaks
of pus in the renal medulla are often present. There may be an acute
deterioration in renal function but significant permanent kidney damage in
adults with normal renal tracts is rare.
Reflux nephropathy. Previously called chronic pyelonephritis or atrophic
pyelonephritis, reflux nephropathy arises from childhood UTIs in combination
with vesicoureteric reflux, leading to progressive renal scarring and presenting
as hypertension or CKD in childhood and adult life. Vesicoureteric reflux refers
to an incompetent valve between bladder and ureter, allowing reflux of urine
up the ureter during bladder contraction and voiding. Reflux usually ceases
around puberty but by that time the damage is done.
Recurrent UTI. Recurrent UTI with the same or a different organism
more than 2 weeks after stopping antibiotic treatment is considered to be
reinfection, whereas relapse is diagnosed by recurrence of bacteriuria with
the same organism within 7 days of completion of treatment. Relapse implies
failure to eradicate the organism usually in association with anatomical renal
tract abnormality, e.g. polycystic kidneys.
Investigations
Diagnosis
Uncomplicated UTIs in younger women (age ≤65 years old) can be diagnosed in patients without known urinary tract abnormalities, recent urinary
tract instrumentation or systemic illness if they exhibit at least two of three
cardinal symptoms – dysuria, urgency or frequency – along with absence of
vaginal discharge. Neither urine dipstick testing for leucocyte esterase nor
urine culture enhances diagnostic sensitivity.
Otherwise, diagnosis is based on culture of a clean-catch mid-stream
specimen of urine (MSU) and the presence or absence of pyuria. Most
Urinary Tract Infection 365
Gram-negative organisms reduce nitrates to nitrites and produce a red colour
in the reagent square. False-negative results are common. Dipsticks that
detect significant pyuria depend on the release of esterases from leucocytes.
Dipstick tests which are positive for both nitrite and leucocyte esterase are
predictive of acute infection (sensitivity of 75% and specificity of 82%).
Routine renal tract imaging of young women with UTI has a low diagnostic
yield and is not indicated. Women with uncomplicated pyelonephritis who
have persistent fever or clinical symptoms after 48–72 hours of appropriate
antibiotic treatment require renal tract imaging to look for an abscess
that requires drainage. Women with recurrent UTIs and all patients with
complicated UTIs also require renal imaging. Contrast-enhanced CT scans
give greater anatomical detail of the renal parenchyma and the perirenal
areas than other imaging methods.
Management
Pre-treatment urine culture is essential. In patients with an indwelling urinary
catheter, antibiotic treatment is indicated only in the presence of symptoms,
and should be accompanied by replacement of the catheter.
Treatment of single isolated attack
• Antibiotic choice should be guided by local antimicrobial guidelines.
Common first-line antibiotic choices for uncomplicated UTIs include
trimethoprim and nitrofurantoin. Most patients who delay antibiotic
treatment to encourage spontaneous resolution eventually receive
antibiotics and have longer times to resolution. The antibiotics used can
be modified following the result of urine culture and sensitivity testing.
• A high (2 L daily) fluid intake should be encouraged during treatment and
for some subsequent weeks. Urine culture should be repeated 5 days
after treatment.
• If the patient is acutely ill with high fever, loin pain and tenderness (acute
pyelonephritis), antibiotics are given intravenously before switching to
oral therapy to complete the course. Intravenous fluids may be required
to achieve a good urine output.
• In patients presenting for the first time with high fever, loin pain and
tenderness, renal ultrasound examination is required to exclude an
obstructed pyonephrosis. If this is present it should be drained by
percutaneous nephrostomy.
Recurrent infection. In patients with a relapse of infection, a search
should be made for any treatable underlying cause, e.g. removal of stones.
Reinfection where there is usually no underlying renal tract abnormality is
managed initially with lifestyle advice (2 L daily fluid intake), voiding before
bedtime and after intercourse, and avoidance of spermicidal jellies and
constipation.
Colonization of the bladder by a pathogen is common after a urinary
catheter has been in situ for more than a few days, partly due to organisms
forming biofilms. So long as the bladder catheter is in place, antibiotics
366 Renal disease
are likely to be ineffective and will encourage the development of resistant
organisms. Only treat if the patient has symptoms or evidence of infection,
and replace the catheter. When changing catheters, a single dose of antibiotic
(e.g. gentamicin) is recommended.
Infection by Candida is a frequent complication of prolonged bladder
catheterization. Treatment should be reserved for patients with evidence of
invasive infection or those who are immunosuppressed. The catheter should
be removed or replaced. In severe infections, continuous bladder irrigation
with amphotericin is useful.
UTI in pregnancy
Approximately 6% of pregnant women have significant bacteriuria; if
untreated, 20% of these will develop acute pyelonephritis with significant
risk to both mother and fetus (e.g. septic shock, low birthweight and prematurity). Early detection of asymptomatic bacteriuria and antibiotic treatment
is necessary.
Abacteriuric frequency or dysuria (‘urethral syndrome’)
This occurs in women and presents with dysuria and frequency but in
the absence of bacteriuria. It may be associated with vaginitis in postmenopausal women, irritant chemicals (e.g. soaps) and sexual intercourse.
Bacterial prostatitis
Bacterial prostatitis is a relapsing infection which presents as perineal pain,
recurrent epididymo-orchitis and prostatic tenderness, with pus in expressed
prostatic secretion. Treatment is for 4–6 weeks with drugs that penetrate
into the prostate, such as trimethoprim or ciprofloxacin. Long-term low-dose
treatment may be required. Prostadynia (prostatic pain in the absence of
active infection) may persist long after the infection. Amitriptyline and carbamazepine may alleviate the symptoms.
Tuberculosis of the urinary tract
Presentation is with symptoms of a UTI and should be particularly considered in the Asian immigrant population of the UK and in countries with a
high prevalence of tuberculosis. Classically, there is sterile pyuria (p. 353).
Diagnosis depends on culture of mycobacteria from early-morning urine
samples. Treatment is as for pulmonary tuberculosis (p. 529).
Hypertension and the Kidney 367
TUBULOINTERSTITIAL NEPHRITIS
Tubulointerstitial nephritis is primary injury to the renal tubules and interstitium that results in decreased renal function. It is a feature of bacterial
pyelonephritis but in this context it rarely, if ever, leads to renal damage in the
absence of reflux, obstruction or other complicating factors.
Acute tubulointerstitial nephritis
Most cases of acute tubulointerstitial nephritis (TIN) are due to an allergic
drug reaction (e.g. penicillins, NSAIDs) with infections (e.g. streptococci)
being a less common cause. Patients present with fever, eosinophilia and
eosinophiluria, normal or only mildly increased urine protein excretion
(<1 g/day) and AKI. Renal biopsy shows an intense interstitial cellular infiltrate and variable tubular necrosis. Management involves withdrawal of the
offending drug, treatment of any underlying infection and treatment of the
AKI (p. 375). High-dose prednisolone therapy is often used, although its value
has not been proven. The prognosis is generally good; patients should avoid
further exposure to the offending drug.
Chronic tubulointerstitial nephritis
There are many causes of chronic TIN, including prolonged consumption of
large amounts of analgesics, particularly NSAIDs (‘analgesic nephropathy’),
diabetes mellitus and toxins, e.g. lead. Presentation is usually with polyuria,
proteinuria (usually <1 g/day) or uraemia. Polyuria and nocturia are the result
of tubular damage in the medullary area of the kidney, leading to defects in
the renal concentrating ability. Necrosis of the papillae, which may subsequently slough off and be passed in the urine, sometimes causes ureteric
colic or acute ureteral obstruction. Management is largely supportive. In
cases of analgesic nephropathy the drug should be stopped and replaced if
necessary with an alternative (e.g. paracetamol).
HYPERTENSION AND THE KIDNEY
Hypertension can be the cause or the result of renal disease (renal hypertension), and it is often difficult to differentiate between the two on clinical grounds.
Essential hypertension
Hypertension leads to characteristic histological changes in the renal vessels
and intrarenal vasculature over time. These include intimal thickening with
reduplication of the elastic lamina, reduction in kidney size and an increase
368 Renal disease
in the proportion of sclerotic glomeruli. The changes are usually accompanied
by some deterioration in renal function, which is much more common in the
black African population.
Accelerated or malignant-phase hypertension is marked by the
development of fibrinoid necrosis in afferent glomerular arterioles and fibrin
deposition in arteriolar walls. A rapid rise in blood pressure may trigger these
arteriolar lesions, and a vicious circle is then established whereby fibrin
deposition leads to renal damage, increased renin release and a further
increase in blood pressure. There is progressive uraemia and, if untreated,
fewer than 10% of patients survive 10 years.
Treatment of hypertension is described on page 369. The outlook is good
if treatment is started before renal impairment has occurred.
Renal hypertension
Bilateral renal disease
Hypertension commonly complicates bilateral renal disease, such as in
chronic glomerulonephritis, reflux nephropathy or analgesic nephropathy.
Two main mechanisms are responsible:
• Activation of the renin–angiotensin–aldosterone system
• Retention of salt and water, leading to an increase in blood volume and
hence blood pressure.
Good control of blood pressure will prevent further deterioration in renal
function, with ACE inhibitors or angiotensin II blockers being the drugs of choice.
These drugs confer an additional renoprotective effect for a given degree of
blood pressure control when compared with other antihypertensive drugs.
Renovascular disease
Narrowing of the renal arteries (renal artery stenosis, RAS) is usually due
to atheroma and classically occurs in patients with evidence of generalized
atheroma, e.g. peripheral vascular disease and coronary artery disease. In
younger patients, particularly women, it is more commonly due to fibromuscular hyperplasia. Renal perfusion pressure is reduced and renal ischaemia
results in a reduction in the pressure in afferent glomerular arterioles. The
mechanism of hypertension with RAS is illustrated in Fig. 9.5.
Imaging for RAS is indicated in the following circumstances:
• Evidence of atheromatous vascular disease in patients with hypertension
or progressive CKD
• A rise in the serum creatinine by more than 30% after introduction of an
ACE inhibitor or angiotensin II receptor antagonist (an increase of 30% is
acceptable and reflects reduction of glomerular perfusion)
• Abdominal bruits in a patient with hypertension or CKD
• Recurrent flash pulmonary oedema without cardiopulmonary disease
• Renal asymmetry of >1.5 cm in length on imaging.
Hypertension and the Kidney 369
)
secretory granules
Proximal
tubule
Myoepithelioid
cells with
Macula
densa
Afferent
arteriole
Fig. 9.5 The mechanism of hypertension in unilateral renal artery stenosis.
(Adapted from Davidson (1991). Principles and practice of medicine. Edinburgh:
Churchill Livingstone.)
Stenosis
Renal ischaemia as a result of renal artery
stenosis leads to an increase in production and
release of renin from juxtaglomerular apparatus
with a consequent increase in angiotensin II
Distal
convoluted
tubule
Options for renal artery imaging
The gold standard for diagnosing renal artery stenosis is renal arteriography.
This requires cannulation of the femoral artery, so less-invasive imaging with
MR or CT angiography or Doppler ultrasonography is often used in the first
instance. The choice of test is based on institutional expertise and patient
factors, e.g. CT with intravenous contrast is avoided in patients with poor
renal function. If non-invasive imaging is inconclusive and clinical suspicion
is high, conventional arteriography is necessary.
Management
Standard medical therapy for atherosclerotic vascular disease is indicated in
all patients and includes lifestyle modification (increased exercise and smoking cessation), statins, antiplatelet therapy (p. 443) and antihypertensives
for effective blood pressure control. Transluminal angioplasty (to dilate the
stenotic region) and stent placement is used in patients with fibromuscular
hyperplasia but does not offer any additional benefit (to medical treatment)
in most patients with atheromatous stenosis.
Glomerular
capillaries
Lacis cells
(secrete renin
Efferent
arteriole
370 Renal disease
RENAL CALCULI AND NEPHROCALCINOSIS
Renal (nephrolithiasis) and ureteral stones (urolithiasis) are very common
worldwide, with a lifetime risk of about 10%, and in many patients it is a
recurrent problem. The male:female ratio is 2:1. Prevalence of stone disease
is much higher in the Middle East due to a higher oxalate- and lower calciumcontaining diet (see below). There is also an increased risk of dehydration in
hot climates.
Aetiology
Most stones are composed of calcium oxalate and/or calcium phosphate.
Other types are uric acid, struvite (composed of calcium, magnesium and
ammonium phosphate) and cystine stones. Stone formation occurs when
normally soluble material, e.g. calcium, supersaturates the urine and begins
the process of crystal formation. In normal urine, inhibitors of crystal formation also prevent stone formation.
Calcium stones
Hypercalciuria. Increased urinary calcium excretion is the most common
metabolic abnormality in calcium stone-formers. Causes of hypercalciuria
are:
• Hypercalcaemia, of which the most common cause leading to stone
formation is primary hyperparathyroidism (p. 631).
• Excessive dietary intake of calcium.
• Excessive resorption of calcium from bone, e.g. with prolonged
immobilization.
• Idiopathic hypercalciuria, in which there is increased absorption of
calcium from the gut and in turn increased urinary excretion. Serum
calcium levels are normal.
• Primary renal disease, such as medullary sponge kidney and polycystic
renal disease.
• Alkaline urine (such as in the renal tubular acidosis) favours the
precipitation of calcium phosphate.
Hyperoxaluria. Increased oxalate excretion favours the formation of
calcium oxalate, even if calcium excretion is normal. The main causes are:
• Dietary hyperoxaluria: a high dietary intake of oxalate-rich foods (e.g.
spinach, rhubarb and tea) results in hyperoxaluria. Low dietary calcium
intake can also result in hyperoxaluria via decreased intestinal binding of
oxalate (by calcium) and the resulting increased oxalate absorption and
urinary excretion.
• Enteric hyperoxaluria: chronic intestinal malabsorption of any cause leads
to reduced levels of intestinal calcium for oxalate binding (see above).
Dehydration secondary to fluid loss from the gut also plays a part in
stone formation.
Renal Calculi and Nephrocalcinosis 371
• Primary hyperoxaluria: this is a rare autosomal recessive enzyme
deficiency resulting in high levels of endogenous oxalate production.
There is widespread calcium oxalate crystal deposition in the kidneys,
and later in other tissues (myocardium, tissues and bone). CKD develops
in the late teens or early 20s.
Uric acid stones
Uric acid stones are associated with hyperuricaemia with or without clinical
gout (p. 291). Patients with ileostomies are also at risk of developing urate
stones, as loss of bicarbonate from gastrointestinal secretions results in the
production of an acid urine and reduced solubility of uric acid.
Infection-induced stones
UTI with organisms that produce urease (Proteus, Klebsiella and Pseudomonas
spp.) is associated with stones containing ammonium, magnesium and calcium. Urease hydrolyses urea to ammonia and this raises the urine pH. An
alkaline urine and high ammonia concentration favour stone formation. These
stones are often large and fill the pelvicalyceal system, producing the typical
radiopaque staghorn calculus.
Cystine stones
Cystine stones occur with cystinuria, an autosomal recessive condition
affecting cystine and dibasic amino acid transport (lysine, ornithine and
arginine) in the epithelial cells of renal tubules and the gastrointestinal tract.
Excessive urinary excretion of cystine, the least soluble of the amino acids,
leads to the formation of crystals and calculi.
Clinical features
Most people with urinary tract calculi remain asymptomatic. Of those who
are symptomatic, pain is the most common clinical feature. Large staghorn
renal calculi cause loin pain while ureteric stones cause renal colic, a severe
intermittent pain lasting for hours and felt anywhere between the loin and the
groin, radiating into the scrotum, tip of the penis or labiam. Nausea, vomiting
and sweating are common. Haematuria often occurs. There will be features
of acute pyelonephritis or Gram-negative septicaemia if there is associated
infection in an obstructed urinary system. Bladder stones present with urinary frequency and haematuria. Urethral stones may cause bladder outflow
obstruction, resulting in anuria and painful bladder distension.
Differential diagnosis
Bleeding within the kidney, e.g. after renal biopsy, can produce clots that
lodge temporarily in the ureter and produce ureteric colic. Pain may also
occur from sloughed necrotic renal papillae. Pain from an ectopic pregnancy
or leaking aortic aneurysm should be considered in the differential diagnosis
of renal colic.
372 Renal disease
Investigations
Investigations include an MUS for culture and measurement of serum urea,
electrolytes, creatinine and calcium levels. A plain abdominal X-ray (KUB)
may show a radiopaque stone in the line of the renal tract. Unenhanced helical (spiral) CT is the best diagnostic test available; a normal CT scan during
an episode of pain excludes calculus disease as the cause of the pain.
A detailed history may reveal possible aetiological factors for stone
formation, e.g. vitamin D consumption (leading to hypercalcaemia), gouty
arthritis, recurrent UTIs, intestinal resection. A further work-up to look for
underlying metabolic risk factors is indicated in all patients other than the
elderly with a single episode (Table 9.6).
Management
Initial treatment. A strong analgesic is given to relieve the pain of renal
colic. Patients are managed at home if there is no evidence of sepsis
and they are able to take oral medications and fluids. Most small ureteric
stones (≤5 mm) will pass spontaneously. Indications for intervention include
persistent pain, infection above the site of obstruction, and failure of the stone
to pass down the ureter. The options for stone removal include the following:
• Extracorporeal shock wave lithotripsy (ESWL) will fragment most stones,
which then pass spontaneously.
• Endoscopy (ureteroscopy) with a YAG laser is used for larger stones.
• Open surgery is rarely needed.
Table 9.6 Investigations to identify the cause of stone formation
Urine
Chemical analysis of any stone passed
MSU for culture and sensitivity
24-hour urine collection for calcium, oxalate, uric acid
Screen for cystinuria (purple colour of urine after addition of sodium nitroprusside)
Blood
Serum urea and electrolytes
Serum calcium
Serum urate
Plasma bicarbonate (low in renal tubular acidosis)
Radiography
CT scan will normally have been performed at diagnosis
Imaging is also to look for a primary renal disease
CT, computed tomography; MSU, mid-stream urine specimen.