Practice Essentials

Nephrolithiasis specifically refers to calculi in the kidneys, but renal calculi and ureteral
calculi (ureterolithiasis) are often discussed in conjunction. The majority of renal calculi
contain calcium. The pain generated by renal colic is primarily caused by dilation, stretching,
and spasm because of the acute ureteral obstruction.

Signs and symptoms

The classic presentation for a patient with acute renal colic is the sudden onset of severe pain
originating in the flank and radiating inferiorly and anteriorly; at least 50% of patients will
also have nausea and vomiting. Patients with urinary calculi may report pain, infection, or
hematuria. Patients with small, nonobstructing stones or those with staghorn calculi may be
asymptomatic or experience moderate and easily controlled symptoms.
The location and characteristics of pain in nephrolithiasis include the following:

Stones obstructing ureteropelvic junction: Mild to severe deep flank pain without
radiation to the groin; irritative voiding symptoms (eg, frequency, dysuria);
suprapubic pain, urinary frequency/urgency, dysuria, stranguria, bowel symptoms
Stones within ureter: Abrupt, severe, colicky pain in the flank and ipsilateral lower
abdomen; radiation to testicles or vulvar area; intense nausea with or without
vomiting

Upper ureteral stones: Radiate to flank or lumbar areas

Midureteral calculi: Radiate anteriorly and caudally

Distal ureteral stones: Radiate into groin or testicle (men) or labia majora (women)

Stones passed into bladder: Mostly asymptomatic; rarely, positional urinary retention

Diagnosis
The diagnosis of nephrolithiasis is often made on the basis of clinical symptoms alone,
although confirmatory tests are usually performed.
Examination in patients with nephrolithiasis includes the following findings:

Dramatic costovertebral angle tenderness; pain can move to upper/lower abdominal

quadrant with migration of ureteral stone
Generally unremarkable abdominal evaluation: Possibly hypoactive bowel sounds;
usually absence of peritoneal signs; possibly painful testicles but normal-appearing

Constant body positional movements (eg, writhing, pacing)

Tachycardia

Hypertension

Microscopic hematuria

Testing
The European Association of Urology recommends the following laboratory tests in all
patients with an acute stone episode[2] :

Urinary sediment/dipstick test: To demonstrate blood cells, with a test for bacteriuria
(nitrite) and urine culture in case of a positive reaction
Serum creatinine level: To measure renal function

Other laboratory tests that may be helpful include the following:

CBC with differential in febrile patients

Serum electrolyte assessment in vomiting patients (eg, sodium, potassium, calcium,
PTH, phosphorus)

Serum and urinary pH level: May provide insight regarding patients renal function
and type of calculus (eg, calcium oxalate, uric acid, cystine), respectively

Microscopic urinalysis

24-Hour urine profile

Imaging studies
The following imaging studies are used in the evaluation of nephrolithiasis:

Noncontrast abdominopelvic CT scan: The imaging modality of choice for assessment

of urinary tract disease, especially acute renal colic
Renal ultrasonography: To determine presence of a renal stone and the presence of
hydronephrosis or ureteral dilation; used alone or in combination with plain
abdominal radiography

Plain abdominal radiograph (flat plate or KUB): To assess total stone burden, as well
as size, shape, composition, location of urinary calculi; often used in conjunction with
renal ultrasonography or CT scanning

IVP (urography) (historically, the criterion standard): For clear visualization of entire
urinary system, identification of specific problematic stone among many pelvic
calcifications, demonstration of affected and contralateral kidney function

Plain renal tomography: For monitoring a difficult-to-observe stone after therapy,

clarifying stones not clearly detected or identified with other studies, finding small
renal calculi, and determining number of renal calculi present before instituting a
stone-prevention program

Retrograde pyelography: Most precise imaging method for determining the anatomy
of the ureter and renal pelvis; for making definitive diagnosis of any ureteral calculus

Nuclear renal scanning: To objectively measure differential renal function, especially

in a dilated system for which the degree of obstruction is in question; reasonable study
in pregnant patients, in whom radiation exposure must be limited

Management
Supportive care and pharmacotherapy
Medical treatment of nephrolithiasis involves supportive care and administration of agents,
such as the following:

IV hydration
Nonnarcotic analgesics (eg, APAP)

PO/IV narcotic analgesics (eg, codeine, butorphanol,

oxycodone/APAP, hydrocodone/APAP, meperidine, nalbuphine)

NSAIDS (eg, ketorolac, ketorolac intranasal, ibuprofen)

Uricosuric agents (eg, allopurinol)

Antiemetics (eg, metoclopramide)

Antidiuretics (eg, DDAVP)

Antibiotics (eg, ampicillin, gentamicin, ticarcillin/clavulanic acid, ciprofloxacin,

levofloxacin, ofloxacin)

Alkalinizing agents (eg, potassium citrate, sodium bicarbonate): For uric acid and
cysteine calculi

Corticosteroids (eg, prednisone, prednisolone)

Calcium channel blockers (eg, nifedipine)

Alpha blockers (eg, tamsulosin, terazosin)

morphine

sulfate,

Surgical option
Stones that are 7 mm and larger are unlikely to pass spontaneously and require some type of
surgical procedure, such as the following:

Stent placement
Percutaneous nephrostomy

Extracorporeal shockwave lithotripsy

Ureteroscopy

Percutaneous nephrostolithotomy

Open nephrostomy

Pathophysiology
Development of renal colic pain and renal damage

The colicky-type pain known as renal colic usually begins in the upper lateral midback over
the costovertebral angle and occasionally subcostally. It radiates inferiorly and anteriorly
toward the groin. The pain generated by renal colic is primarily caused by the dilation,
stretching, and spasm caused by the acute ureteral obstruction. (When a severe but chronic
obstruction develops, as in some types of cancer, it is usually painless.)
In the ureter, an increase in proximal peristalsis through activation of intrinsic ureteral
pacemakers may contribute to the perception of pain. Muscle spasm, increased proximal
peristalsis, local inflammation, irritation, and edema at the site of obstruction may contribute
to the development of pain through chemoreceptor activation and stretching of submucosal
free nerve endings.
The term "renal colic" is actually a misnomer, because this pain tends to remain constant,
whereas intestinal or biliary colic is usually somewhat intermittent and often comes in waves.
The pattern of the pain depends on the individuals pain threshold and perception and on the
speed and degree of the changes in hydrostatic pressure within the proximal ureter and renal
pelvis. Ureteral peristalsis, stone migration, and tilting or twisting of the stone with
subsequent intermittent obstructions may cause exacerbation or renewal of the renal colic
pain.
The severity of the pain depends on the degree and site of the obstruction, not on the size of
the stone. A patient can often point to the site of maximum tenderness, which is likely to be
the site of the ureteral obstruction
In summary, by 24 hours after a complete ureteral obstruction, the renal pelvic hydrostatic
pressure has dropped because of (1) a reduction in ureteral peristalsis; (2) decreased renal
arterial vascular flow, which causes a corresponding drop in urine production on the affected
side; and (3) interstitial renal edema, which leads to a marked increase in renal lymphatic
drainage.

Etiology
A low fluid intake, with a subsequent low volume of urine production, produces high
concentrations of stone-forming solutes in the urine. This is an important, if not the most
important, environmental factor in kidney stone formation. The exact nature of the tubular
damage or dysfunction that leads to stone formation has not been characterized.
Most research on the etiology and prevention of urinary tract stone disease has been directed
toward the role of elevated urinary levels of calcium, oxalate, and uric acid in stone
formation, as well as reduced urinary citrate levels.
Hypercalciuria is the most common metabolic abnormality. Some cases of hypercalciuria are
related to increased intestinal absorption of calcium (associated with excess dietary calcium
and/or overactive calcium absorption mechanisms), some are related to excess resorption of
calcium from bone (ie, hyperparathyroidism), and some are related to an inability of the renal
tubules to properly reclaim calcium in the glomerular filtrate (renal-leak hypercalciuria).
Magnesium and especially citrate are important inhibitors of stone formation in the urinary
tract. Decreased levels of these in the urine predispose to stone formation.

The following are the 4 main chemical types of renal calculi, which together are associated
with more than 20 underlying etiologies:

Calcium stones
Struvite (magnesium ammonium phosphate) stones

Uric acid stones

Cystine stones

Calcium stones
Calcium stones account for 75% of renal calculi. Recent data suggest that a low-protein, lowsalt diet may be preferable to a low-calcium diet in hypercalciuric stone formers for
preventing stone recurrences.[6] Epidemiological studies have shown that the incidence of
stone disease is inversely related to the magnitude of dietary calcium intake in first-time stone
formers.

Calcium oxalate, calcium phosphate, and calcium urate are associated with the following
disorders:

Hyperparathyroidism - Treated surgically or with orthophosphates if the patient is not

a surgical candidate
Increased gut absorption of calcium - The most common identifiable cause of
hypercalciuria, treated with calcium binders or thiazides plus potassium citrate

Renal calcium leak - Treated with thiazide diuretics

Renal phosphate leak - Treated with oral phosphate supplements

Hyperuricosuria - Treated with allopurinol, low purine diet, or alkalinizing agents

such as potassium citrate

Hyperoxaluria - Treated with dietary oxalate restriction, oxalate binders, vitamin B-6,
or orthophosphates

Hypocitraturia - Treated with potassium citrate

Hypomagnesuria - Treated with magnesium supplements

Struvite (magnesium ammonium phosphate) stones

Struvite stones account for 15% of renal calculi. They are associated with chronic urinary
tract infection (UTI) with gram-negative rods capable of splitting urea into ammonium,
which combines with phosphate and magnesium. Usual organisms include Proteus,
Pseudomonas, and Klebsiella species. Escherichia coli is not capable of splitting urea and,
therefore, is not associated with struvite stones. Urine pH is typically greater than 7.
Underlying anatomical abnormalities that predispose patients to recurrent kidney infections
should be sought and corrected. UTI does not resolve until stone is removed entirely.

Uric acid stones

Uric acid stones account for 6% of renal calculi. These are associated with urine pH less than
5.5, high purine intake (eg, organ meats, legumes, fish, meat extracts, gravies), or malignancy
(ie, rapid cell turnover). Approximately 25% of patients with uric acid stone have gout.
Serum and 24-hour urine sample should be sent for creatinine and uric acid determination. If
serum or urinary uric acid is elevated, the patient may be treated with allopurinol 300 mg
daily. Patients with normal serum or urinary uric acid are best managed by alkali therapy
alone.

Cystine stones
Cystine stones account for 2% of renal calculi. They arise because of an intrinsic metabolic
defect resulting in failure of renal tubular reabsorption of cystine, ornithine, lysine, and
arginine. Urine becomes supersaturated with cystine, with resultant crystal deposition.
Cystine stones are treated with a low-methionine diet (unpleasant), binders such as
penicillamine or a-mercaptopropionylglycine, large urinary volumes, or alkalinizing agents. A
24-hour quantitative urinary cystine determination helps to titrate the dose of drug therapy to
achieve a urinary cystine concentration of less than 300 mg/L.

Drug-induced stone disease

A number of medications or their metabolites can precipitate in urine causing stone
formation. These include indinavir; atazanavir; guaifenesin; triamterene; silicate (overuse of
antacids containing magnesium silicate); and sulfa drugs including sulfasalazine,
sulfadiazine, acetylsulfamethoxazole, acetylsulfasoxazole, and acetylsulfaguanidine.[7, 8, 9]

Epidemiology
International statistics
Nephrolithiasis occurs in all parts of the world. The incidence of urinary tract stone disease in
developed countries is similar to that in the United States; the annual incidence of urinary
tract stones in the industrialized world is estimated to be 0.2%. Stone disease is rare in only a
few areas, such as Greenland and the coastal areas of Japan. A lifetime risk of 2-5% has been
noted for in Asia, 8-15% for the West, and 20% for Saudi Arabia.
In developing countries, bladder calculi are more common than upper urinary tract calculi;
the opposite is true in developed countries. These differences are believed to be diet-related.

Age distribution for nephrolithiasis

Most urinary calculi develop in persons aged 20-49 years. Peak incidence occurs in people
aged 35-45 years, but the disease can affect anyone at any age. Patients in whom multiple
recurrent stones form usually develop their first stones while in their second or third decade
of life.

An initial stone attack after age 50 years is relatively uncommon. Nephrolithiasis in children
is rare; approximately 5-10 children aged 10 months to 16 years are seen annually for the
condition at a typical US pediatric referral center.

Sex distribution for nephrolithiasis

In general, urolithiasis is more common in males (male-to-female ratio of 3:1). Stones due to
discrete metabolic/hormonal defects (eg, cystinuria, hyperparathyroidism) and stone disease
in children are equally prevalent between the sexes. Stones due to infection (struvite calculi)
are more common in women than in men. Female patients have a higher incidence of infected
hydronephrosis.

Racial differences in incidence

Urinary tract calculi are far more common in Asians and whites than in Native Americans,
Africans, African Americans, and some natives of the Mediterranean region. White males are
affected 3-4 times more often than African American males, though African Americans have
a higher incidence of infected ureteral calculi than whites.
Although some differences may be attributable to geography (stones are more common in hot
and dry areas) and diet, heredity also appears to be a factor. This is suggested by the finding
that, in regions with both white and nonwhite populations, stone disease is much more
common in whites.

Prognosis
Approximately 80-85% of stones pass spontaneously. Approximately 20% of patients require
hospital admission because of unrelenting pain, inability to retain enteral fluids, proximal
UTI, or inability to pass the stone.
The most morbid and potentially dangerous aspect of stone disease is the combination of
urinary tract obstruction and upper urinary tract infection. Pyelonephritis, pyonephrosis, and
urosepsis can ensue. Early recognition and immediate surgical drainage are necessary in these
situations.
The usually quoted recurrence rate for urinary calculi is 50% within 5 years and 70% or
higher within 10 years, although a large, prospective study published in 1999 suggested that
the recurrence rate may be somewhat lower at 25-30% over a 7.5-year period. Recurrence
rates after an initial episode of ureterolithiasis have also been reported to be 14%, 35%, and
52% at 1, 5, and 10 years, respectively.

History
Patients with urinary calculi may report pain, infection, or hematuria. Small nonobstructing
stones in the kidneys only occasionally cause symptoms. If present, symptoms are usually
moderate and easily controlled. The passage of stones into the ureter with subsequent acute
obstruction, proximal urinary tract dilation, and spasm is associated with classic renal colic.

Acute onset of severe flank pain radiating to the groin, gross or microscopic hematuria,
nausea, and vomiting not associated with an acute abdomen are symptoms that most likely
indicate renal colic caused by an acute ureteral or renal pelvic obstruction from a calculus.
Renal colic pain rarely, if ever, occurs without obstruction.
Patients with large renal stones known as staghorn calculi (see the image below) are often
relatively asymptomatic. The term "staghorn" refers to the presence of a branched kidney
stone occupying the renal pelvis and at least one calyceal system. Such calculi usually
manifest as infection and hematuria rather than as acute pain.
Important historical features are as follows:

Duration, characteristics, and location of pain

History of urinary calculi

Prior complications related to stone manipulation

Urinary tract infections

Loss of renal function

Family history of calculi

Solitary or transplanted kidney

Chemical composition of previously passed stones

Complications
Serious complications of urinary tract stone disease include the following:

Abscess formation
Serious infection of the kidney that diminishes renal function

Urinary fistula formation

Ureteral scarring and stenosis

Ureteral perforation

Extravasation

Urosepsis

Renal loss due to long-standing obstruction

Infected hydronephrosis is the most deadly complication because the presence of infection
adjacent to the highly vascular renal parenchyma places the patient at risk for rapidly
progressive sepsis and death.

Indications for hospitalization

The decision to hospitalize a patient with a stone is usually made based on clinical grounds
rather than on any specific finding on a radiograph. Generally, hospitalization for an acute
renal colic attack is now officially termed an observation because most patients recover
sufficiently to go home within 24 hours. Admission rate for patients with acute renal colic is
approximately 20%.
Hospital admission is clearly necessary when any of the following is present:

Oral analgesics are insufficient to manage the pain.

Ureteral obstruction from a stone occurs in a solitary or transplanted kidney.

Ureteral obstruction from a stone occurs in the presence of a urinary tract infection
(UTI), fever, sepsis, or pyonephrosis.

Surgical Care
In general, stones that are 4 mm in diameter or smaller will probably pass spontaneously, and
stones that are larger than 8 mm are unlikely to pass without surgical intervention. With MET,
stones 5-8 mm in size often pass, especially if located in the distal ureter. The larger the
stone, the lower the possibility of spontaneous passage (and thus the greater the possibility
that surgery will be required), although many other factors determine what happens with a
particular stone.

Indications and contraindications

The primary indications for surgical treatment include pain, infection, and obstruction.
Infection combined with urinary tract obstruction is an extremely dangerous situation, with
significant risk of urosepsis and death, and must be treated emergently in virtually all cases.
Additionally, certain occupational and health-related reasons exist.

General contraindications to definitive stone manipulation include the following:

Active, untreated UTI

Uncorrected bleeding diathesis

Pregnancy (a relative, but not absolute, contraindication)

Dietary Measures
In almost all patients in whom stones form, an increase in fluid intake and, therefore, an
increase in urine output is recommended. This is likely the single most important aspect of
stone prophylaxis. Patients with recurrent nephrolithiasis traditionally have been instructed to
drink 8 glasses of fluid daily to maintain adequate hydration and decrease chance of urinary
supersaturation with stone-forming salts. The goal is a total urine volume in 24 hours in
excess of 2 liters.

As a rule, dietary calcium should be restricted to 600-800 mg/d in patients with dietresponsive hypercalciuria who form calcium stones. This is roughly equivalent to a single
high-calcium or dairy meal per day.

Prevention of Nephrolithiasis
The most common causes of kidney stones are hypercalciuria, hyperuricosuria,
hyperoxaluria, hypocitraturia, and low urinary volume. Each of these major factors can be
measured easily with a 24-hour urine sample using one of several commercial laboratory
packages now available. Kidney stone preventive therapy consists of dietary adjustments,
nutritional supplements, medications, or combinations of these.
Strongly encourage patients who have a stone at a young age (ie, < 25 y), multiple
recurrences, a solitary functioning kidney, or a history of prior kidney stone surgery to obtain
a 24-hour urine collection for stone prevention analysis, especially if they are motivated to
comply with a long-term stone prevention program. These 24-hour urine collection kits can
be obtained from a number of commercial medical laboratories.

Long-Term Monitoring
Patients who do not meet admission criteria may be discharged from the ED in anticipation
that the stone will pass spontaneously at home. Arrangements should be made for follow-up
with a urologist in 2-3 days. Patients should be told to return immediately for fever,
uncontrolled pain, or vomiting. Patients should be discharged with a urine strainer and
encouraged to submit any recovered calculi to a urologist for chemical analysis.

UTI female

Practice Essentials
Urinary tract infections (UTIs) are common in females, accounting for over 6 million patient
visits to physicians per year in the United States. Cystitis (bladder infection) represents the
majority of these infections (see the image below). Related terms include pyelonephritis,
which refers to upper urinary tract infection; bacteriuria, which describes bacteria in the
urine; and candiduria, which describes yeast in the urine.

Signs and symptoms

Symptoms and signs of UTI in the adult are as follows:

Dysuria

Urinary urgency and frequency

A sensation of bladder fullness or lower abdominal discomfort

Suprapubic tenderness

Flank pain and costovertebral angle tenderness (may be present in cystitis but suggest
upper UTI)

Bloody urine

Fevers, chills, and malaise (may be noted in patients with cystitis, but more frequently
associated with upper UTI)

See Clinical Presentation for more detail.

Diagnosis
Diagnostic studies for UTI consist of dipstick, urinalysis, and culture. No imaging studies are
indicated in the routine evaluation of cystitis.
Current emphasis in the diagnosis of UTI rests with the detection of pyuria, as follows:

A positive leukocyte esterase dipstick test suffices in most instances

In females with clinical findings suggestive of UTI, urine microscopy may be
indicated even if the leukocyte esterase dipstick test is negative

Pyuria is most accurately measured by counting leukocytes in unspun fresh urine

using a hemocytometer chamber; more than 10 white blood cells (WBCs)/mL is
abnormal

Other findings are as follows:

Microscopic hematuria is found in about half of cystitis cases

Low-grade proteinuria is common

A positive nitrate test is highly specific for UTI, but it occurs in only 25% of patients
with UTI

Urine culture remains the criterion standard for the diagnosis of UTI. Consider obtaining
urine cultures in patients with probable cystitis if any of the following is present:

Immunosuppression
Recent urinary tract instrumentation

Recent exposure to antibiotics

Recurrent infection

Advanced age

Definitions of UTI in women, based on culture results in clean-catch urine specimens, are as
follows:

Cystitis: More than 1000 colony-forming units (CFU)/mL

Pyelonephritis: More than 10,000 CFU/mL

Asymptomatic bacteriuria: In a female, more than 100,000 CFU/mL in an

asymptomatic individual

Any amount of uropathogen grown in culture from a suprapubic aspirate should be

considered evidence of a UTI.
See Workup for more detail.

Management
Oral therapy with an empirically chosen antibiotic that is effective against gram-negative
aerobic coliform bacteria (eg, Escherichia coli) is the principal treatment intervention in
patients with cystitis. The first-choice agents for treatment of uncomplicated acute cystitis in
women include the following:

Nitrofurantoin monohydrate/macrocrystals
Trimethoprim-sulfamethoxazole (TMP-SMX)

Fosfomycin

Considerations in antibiotic selection are as follows:

Empiric antibiotic selection is determined in part by local resistance patterns

Beta-lactam antibiotics (eg, amoxicillin-clavulanate, cefdinir, cefaclor, cefpodoximeproxetil) may be used when other recommended agents cannot be used[1, 2]

Fosfomycin and nitrofurantoin monohydrate/macrocrystals should be avoided in

patients with possible early pyelonephritis[1]

Clinicians may wish to limit use of TMP-SMX, to reduce the emergence of resistant
organisms

Fluoroquinolones are typically reserved for complicated cystitis

Duration of antibiotic treatment for acute, uncomplicated cystitis in women who are not
pregnant is as follows:

TMP-SMX is given for 3 days

Fosfomycin is given in a single dose

Nitrofurantoin monohydrate/macrocrystals is given for 5-7 days

Beta-lactam agents are given for 37-days

For cystitis in older women or infection caused by Staphylococcus saprophyticus, 7

days of therapy is suggested

The vast majority of women with UTI present on an ambulatory basis and can be treated as
outpatients. Hospital admission may be indicated for some patients with complicated UTI.
Complicating factors include the following:

Structural abnormalities (eg, calculi, tract anomalies, indwelling catheter, obstruction)

Metabolic disease (eg, diabetes, renal insufficiency)

Impaired host defenses (eg, HIV infection, current chemotherapy, underlying active
cancer)

Background
Urinary tract infections (UTIs) are common in females, and cystitis (bladder infection)
represents the majority of these infections. Related terms include pyelonephritis, which refers
to upper urinary tract infection; bacteriuria, which describes bacteria in the urine; and
candiduria, which describes yeast in the urine. Very ill patients may be referred to as having
urosepsis.
UTI is defined as significant bacteriuria in the setting of symptoms of cystitis or
pyelonephritis. These infections account for a significant number of emergency department
(ED) visits,[3] and 20% of women develop at least one UTI. (See Epidemiology.)
Escherichia coli causes the majority of uncomplicated cystitis cases. Among the pathogens
responsible for the remainder are Staphylococcus saprophyticus, Proteus mirabilis, Klebsiella
pneumonia e, or Enterococcus faecalis. (See Etiology.)

Pathophysiology
The urinary tract is normally sterile. Cystitis represents bladder mucosal invasion, most often
by enteric coliform bacteria (eg, Escherichia coli) that inhabit the periurethral vaginal
introitus and ascend into the bladder via the urethra.
In recurrent E coli UTIs, peak colonization rates of the periurethral area 2-3 days prior to the
development of the symptoms of acute cystitis range from 46-90%. During this same period,
asymptomatic bacteriuria rates increase from 7% to 70%.[6]
Because sexual intercourse may promote this migration, cystitis is common in otherwise
healthy young women. Generally, urine is a good culture medium. Factors unfavorable to
bacterial growth include a low pH (5.5 or less), a high concentration of urea, and the presence
of organic acids derived from a diet that includes fruits and protein. Organic acids enhance
acidification of the urine.
If the defense mechanisms of the lower urinary tract fail, upper tract or kidney involvement
occurs and is termed pyelonephritis. Host defenses at this level include local leukocyte
phagocytosis and renal production of antibodies that kill bacteria in the presence of
complement. In general, there are 3 main mechanisms responsible for UTIs:

Colonization with ascending spread

Hematogenous spread

Periurogenital spread

Etiology
E coli causes 70-95% of both upper and lower UTIs. Various organisms are responsible for
the remainder of infections, including S saprophyticus, Proteus species, Klebsiella species,
Enterococcus faecalis, other Enterobacteriaceae, and yeast. Some species are more common
in certain subgroups, such as Staphylococcus saprophyticus in young women.
The most important risk factor for bacteriuria is the presence of a catheter. [8] Eighty percent of
nosocomial UTIs are related to urethral catheterization, while 5-10% are related to
genitourinary manipulation. Catheters inoculate organisms into the bladder and promote
colonization by providing a surface for bacterial adhesion and causing mucosal irritation. For
more information on this topic, see the Medscape Reference article Catheter-Related Urinary
Tract Infection.
Sexual intercourse contributes to increased risk, as does use of a diaphragm and/or
spermicide. Routine pelvic examinations are also associated with an increased risk of a UTI
for 7 weeks post procedure.[9] Women who are elderly, are pregnant, or have preexisting
urinary tract structural abnormalities or obstruction carry a higher risk of UTI.
UTIs are the most common type of infection following renal transplantation. Susceptibility is
especially high in the first 2 months following transplantation. Triggering factors include
vesicoureteral reflux and immunosuppression. Corynebacterium urealyticum (ie, CDC group
D2) has been reported to cause encrusted pyelitis and cystitis in these patients.
Calculi related to UTIs most commonly occur in women who experience recurrent UTIs with
Proteus, Pseudomonas, and Providencia species.
Candiduria is defined as more than 1000 CFU/mL of yeast from 2 cultures. Candida
albicans, which is germ tube positive, is the usual culprit. Germ tubenegative Candida
species (tropicalis, parapsilosis, glabrata, lusitaniae, krusei) are less common.
Risk factors for candiduria include diabetes mellitus, indwelling urinary catheters, and
antibiotic use. Candiduria may clear spontaneously or may result in (or from) deep fungal
infections.

Epidemiology
Age- and sex-related demographics
Uncomplicated UTIs are much more common in women than men when matched for age. A
study of Norwegian men aged 21-50 years showed an approximate incidence of 0.00060.0008 infections per person-year, compared with approximately 0.5-0.7 per person-year in
similarly aged women in the United States.
The largest group of patients with UTI is adult women. The incidence of UTI in women tends
to increase with increasing age. Several peaks above baseline correspond with specific

events, including an increase in women aged 18-30 years (associated with coitusso-called
honeymoon cystitisand pregnancy).
Rates of infection are high in postmenopausal women because of bladder or uterine prolapse
causing incomplete bladder emptying; loss of estrogen with attendant changes in vaginal flora
(notably, loss of lactobacilli), which allows periurethral colonization with gram-negative
aerobes, such as E coli; and higher likelihood of concomitant medical illness, such as
diabetes.
Of neonates, boys are slightly more likely than girls to present with UTI as part of a gramnegative sepsis syndrome. The incidence in preschool-aged children is approximately 2% and
is 10 times more common in girls. UTI occurs in 5% of school-aged girls, but it is rare in
school-aged boys.

Prognosis
Younger patients have the lowest rates of morbidity and mortality. Factors associated with an
unfavorable prognosis include the following:

Old age
General debility

Renal calculi or obstruction

Recent hospitalization

Urinary tract instrumentation or antibiotic therapy

Diabetes mellitus

Chronic nephropathy

Sickle cell anemia

Underlying cancer

Intercurrent chemotherapy

History
The classic symptoms of urinary tract infection (UTI) in the adult are primarily dysuria with
accompanying urinary urgency and frequency. A sensation of bladder fullness or lower
abdominal discomfort is often present.
Because of the referred pain pathways, even simple lower UTI may be accompanied by flank
pain and costovertebral angle tenderness. In the emergency department, however, assume that
the presence of these symptoms represents upper UTI.
Bloody urine is reported in as many as 10% of cases of UTI in otherwise healthy women; this
condition is called hemorrhagic cystitis. Fevers, chills, and malaise may be noted in patients

with cystitis, though these findings are associated more frequently with upper UTI (ie,
pyelonephritis).
A history of vaginal discharge suggests that vaginitis, cervicitis, or pelvic inflammatory
disease is responsible for symptoms of dysuria; therefore, a pelvic examination must be
performed. Important additional information includes a history of prior sexually transmitted
disease (STD) and multiple current sexual partners.

Physical Examination
The patient appears uncomfortable but not toxic. The presence of toxic fever, chills, nausea,
and vomiting suggests pyelonephritis rather than cystitis; however, immunosuppressed and
even immunocompetent patients with pyelonephritis may exhibit few, if any, of these
symptoms. In elderly women, 50% of cases of cystitis also involve the upper tracts.[13]
The clinician may appreciate signs of dehydration, such as dry mucous membranes and
tachycardia. Clammy extremities and symptomatic orthostasis suggest poor vascular tone due
to gram-negative bacteremia rather than simple cystitis.
Most adult women with simple lower UTI have suprapubic tenderness. Pelvic examination
should be performed to exclude vaginitis, cervicitis, or pelvic tenderness (eg, cervical motion
tenderness, which suggests pelvic inflammatory disease).

Acute Urethritis Versus Cystitis

The symptoms of acute urethritis overlap with those of cystitis, including acute dysuria and
urinary hesitancy. Fever may be a component of urethritis-related syndromes (eg, Reiter
syndrome, Behet syndrome) but rarely is observed in acute cystitis. Urethral discharge is
much more suggestive of urethritis, while bladder-related symptoms, such as urgency,
polyuria, and incomplete voids, are more consistent with cystitis.
The predominant complaints in acute cystitis relate to the inflamed bladder mucosa.
Constitutional symptoms, such as fever, nausea, and anorexia, are rare or mild. The
symptoms of dysuria, urgency, hesitancy, polyuria, and incomplete voids may be
accompanied by urinary incontinence, gross hematuria, and suprapubic or low back pain.
Patients may demonstrate some suprapubic tenderness to palpation.

Approach Considerations
Urinalysis
The most accurate method to measure pyuria is counting leukocytes in unspun fresh urine
using a hemocytometer chamber; greater than 10 white blood cells (WBCs)/mL is considered
abnormal. Counts determined from a wet mount of centrifuged urine are not reliable

measures of pyuria. A noncontaminated specimen is suggested by a lack of squamous

epithelial cells. Pyuria is a sensitive (80-95%) but nonspecific (50-76%) sign of UTI.
White cell casts may be observed in conditions other than infection, and they may not be
observed in all cases of pyelonephritis. If the patient has evidence of acute infection and
white cell casts are present, however, the infection likely represents pyelonephritis. A spun
sample (5 mL at 2000 revolutions per min [rpm] for 5 min) is best used for evaluation of
cellular casts.
Proteinuria is commonly observed in infections of the urinary tract, but the proteinuria
usually is low grade. More than 2 g of protein per 24 hours suggests glomerular disease.

Urine specimen collection

Urine specimens may be obtained by midstream clean catch, suprapubic aspiration, or
catheterization.
The midstream-voided technique is as accurate as catheterization if proper technique is
followed. Instruct the woman to remove her underwear and sit facing the back of the toilet.
This promotes proper positioning of the thighs.
Instruct the patient to spread the labia with one hand and cleanse from front to back with
povidone-iodine or soaped swabs with the other hand; then pass a small amount of urine into
the toilet; and finally urinate into the specimen cup. The use of a tampon may allow a proper
specimen if heavy vaginal bleeding or discharge is present.
Midstream urine specimens may become contaminated, particularly if the woman has
difficulty spreading and maintaining separation of the labia. The presence of squamous cells
and lactobacilli on urinalysis suggests contamination or colonization (see image below).
Catheterization may be needed in some women to obtain a clean specimen, although it poses
the risk of iatrogenic infection.[18]

Urine Culture
Urine culture remains the criterion standard for the diagnosis of UTI. Collected urine should
be sent for culture immediately; if not, it should be refrigerated at 4C. Two culture
techniques (dip slide, agar) are widely used and accurate.
If a Gram stain of an uncentrifuged, clean-catch, midstream urine specimen reveals the
presence of 1 bacterium per oil-immersion field, it represents 10,000 bacteria/mL of urine. A
specimen (5 mL) that has been centrifuged for 5 minutes at 2000 rpm and examined under
high power after Gram staining will identify lower numbers. In general, a Gram stain has a
sensitivity of 90% and a specificity of 88%.

Complete Blood Cell Count

A CBC is not helpful in differentiating upper from lower UTI or in making decisions
regarding admission. However, significant leukopenia in hosts who are older or
immunocompromised may be an ominous finding.

The WBC count may or may not be elevated in patients with uncomplicated UTI, but it is
usually elevated in patients with complicated UTIs. Patients with complicated UTIs may have
anemia; for example, anemia is observed in 40% of patients with perinephric abscesses.

Adjunctive Therapy
Patients with intense dysuria may obtain symptomatic relief from a bladder analgesic, such as
phenazopyridine, to be used for 1-2 days. Do not prescribe phenazopyridine if the patient has
a sulfa allergy. Avoid long-term use, as this agent may mask symptoms of therapeutic failure
or recurrence. Many authors advise stressing the intake of plenty of fluids to promote a dilute
urine flow.

Diet
Hydration to accentuate unidirectional clearance of bacteriuria is recommended, especially if
an obstruction was relieved recently. Drinking cranberry juice (10 oz/day) or taking cranberry
tablets may offer some benefit in reducing recurrent UTI and does not appear to be harmful.
[34, 35]

Cranberries contain type A proanthocyanidins. This compound and its urinary metabolites
interfere with the adhesiveness of uropathogenic bacteria to the bladder epithelium. [36] Their
effect is not as significant as antibiotics, but they do not induce bacterial resistance. Because
of their variable intestinal absorption, it is difficult to design a valid study comparing them
head-to-head with antimicrobials.[34]

Prevention and Long-Term Monitoring

Sexually active women may attempt voiding immediately after intercourse to lessen the risk
of coitus-related introduction of bacteria into the bladder. Some authors recommend large
urinary flow volumes as a measure that will reduce the risk of UTI.
Prophylactic regimens for women with frequent recurrent UTIs include postcoital or
continuous antibiotics. Women with fewer than 3 UTIs per year may benefit from selfinitiated antibiotic therapy.

UTI MALE

Practice Essentials
Urinary tract infections (UTIs) are rare in adult males younger than 50 years but increase in
incidence thereafter. Causes of adult male UTIs include prostatitis, epididymitis, orchitis,
pyelonephritis, cystitis, urethritis, and urinary catheters. Owing to the normal male urinary
tracts many natural defenses to infection, many experts consider UTIs in males, by
definition, to be complicated (ie, more likely to be associated with anatomic abnormalities,
requiring surgical intervention to prevent sequelae).

Signs and symptoms

Dysuria is the most frequent chief complaint in men with UTI. The combination of dysuria,
urinary frequency, and urinary urgency is about 75% predictive for UTI, whereas the acute
onset of hesitancy, urinary dribbling, and slow stream is only about 33% predictive for UTI.
Relevant clinical history includes the following:

Previous UTI(s)
Nocturia, gross hematuria, any changes in the color and/or consistency of the urine

Prostatic enlargement

Urinary tract abnormalities: Personally and within the family

Comorbid conditions (eg, diabetes )

Human immunodeficiency virus (HIV) status

Immunosuppressive treatments for other conditions (eg, prednisone)

Any previous surgeries or instrumentation involving the urinary tract

See Clinical Presentation for more detail.

Diagnosis
Perform a thorough physical examination in males presenting with genitourinary complaints.
Focus particularly on the patients vital signs, kidneys, bladder, prostate, and external
genitalia.
Examination findings may include the following:

Fever
Tachycardia

Flank pain/costovertebral angle tenderness

Abdominal tenderness in the suprapubic area

Scrotal hematoma, hydrocele, masses, or tenderness

Penile meatal discharge

Prostatic tenderness

Inguinal adenopathy

Laboratory testing
The workup of male UTI is dependent on the suspected diagnosis.
Routine laboratory studies include urine studies, such as urinalysis, Gram staining, and urine
culture. The threshold for establishing true UTI includes finding 2-5 or more white blood
cells (WBCs) or 15 bacteria per high-power field (HPF) in a centrifuged urine sediment.

Note that a positive nitrite test is poorly sensitive but highly specific for UTI; false-positives
are uncommon. Proteinuria is commonly observed in UTIs, but it is usually low grade. More
than 2g of protein per 24 hours suggests glomerular disease.
Imaging studies
Consider imaging and urologic intervention in patients with the following:

History of kidney stones, especially struvite stones: Potential for urosepsis

Diabetes: Susceptibility to emphysematous pyelonephritis and may require immediate
nephrectomy; diabetic patients may also develop obstruction from necrotic renal
papillae that are sloughed into the collecting system and obstruct the ureter

Polycystic kidneys: Prone to abscess formation

Tuberculosis: Prone to developing ureteral strictures, fungus balls, and stones

If concomitant obstructive uropathy is suspected, this is an emergent condition that requires

prompt intervention, including the following imaging studies of the urinary system:

Ultrasonography
Contrasted computed tomography (CT) scanning or helical CT scanning (currently
preferred by most experts)

Intravenous pyelography (IVP) has been replaced by CT scanning techniques and

ultrasonography because of its substantial radiation and the necessity of using
radiographic dye

See Workup for more detail.

Management
In general, all male UTIs are considered complicated. Consider the potential for renal
involvement when planning treatment strategies.
Inpatient management is recommended for patients with the following features:

Appear toxic
Have obstructive uropathy or stones

Unable to tolerate oral hydration

Have significant comorbid conditions

Unable to care for self at home

Initial inpatient treatment includes the following:

Intravenous (IV) antimicrobial therapy with a third-generation cephalosporin (eg,

ceftriaxone, ceftazidime), a fluoroquinolone (eg, ciprofloxacin, levofloxacin,

ofloxacin, norfloxacin), or an aminoglycoside (eg, gentamicin, tobramycin) (beware

ototoxicity)
Antipyretics

Analgesics

IV fluid resuscitation: To restore appropriate circulatory volume and promote

adequate urinary flow

Other medications used in the management of male UTIsor etiologic conditions such as
prostatitis; epididymitis; pyelonephritis; or cystitis/urethritisinclude the following:

Antibiotics such as trimethoprim, trimethoprim-sulfamethoxazole, ampicillin,

amoxicillin, ertapenem, erythromycin, vancomycin, doxycycline, aztreonam,
nitrofurantoin, rifampin
Urinary analgesics such as phenazopyridine

Broaden the antimicrobial coverage and add an antipseudomonal agent in patients with risk
factors associated with an unfavorable prognosis (eg, old age, debility, renal calculi, recent
hospitalization or instrumentation, diabetes, sickle cell anemia, underlying carcinoma, or
intercurrent cancer chemotherapy).
Surgery
Surgical intervention may be required in the patients with the following conditions:

Prostatitis involving bladder neck obstruction, prostatic or bladder calculi, or recurrent

prostatitis with the same bacteria[1]
Emphysematous pyelonephritis (ie, emergent nephrectomy)

Epididymitis involving spermatic cord torsion

See Treatment and Medication for more detail.

Complications
Complications of acute bacterial prostatitis include bacteremia, septic shock, prostatic
abscess, epididymitis, seminal vesiculitis, and pyelonephritis. Suspect a prostate abscess if
fever does not resolve within 48 hours; if confirmed, add anaerobic coverage and arrange for
drainage. (See Prognosis.)

Acute and chronic prostatitis

Acute prostatitis is caused by an acute infection of the entire prostate gland, resulting in fever
and localized pain. Microscopically, neutrophilic infiltrates, diffuse edema, and
microabscesses may be seen, which may coalesce into larger collections.
Chronic prostatitis may be caused by inflammatory or noninflammatory diseases. This
condition may arise via dysfunctional voiding, intraprostatic reflux, chronic exposure to
microorganisms, autoimmune mechanisms, irritative urinary metabolites, and as a variant of

neuropathic pain. Chronic bacterial prostatitis often produces few or no symptoms related to
the prostate, but it is probably the most common cause of relapsing UTI in men.

Epididymitis
Epididymitis is a clinical syndrome caused by infection or inflammation of the epididymis.
This condition is the most common cause of acute scrotum in adult male populations. Longterm complications include abscesses, infarction, recurrence, chronic pain, and infertility

Orchitis
Because of the widespread use of mumps vaccination, orchitis is no longer a common
infection in the United States. Orchitis is one of the few genitourinary infections to result
from a viral pathogen.
Mumps orchitis occurs in 18% of postpubertal boys infected with the mumps virus. Other
viruses that can cause the disease include coxsackie B, mononucleosis, and varicella. Unlike
the majority of genitourinary infections, viral particles are spread to the testicle by the
hematogenous route. Granulomatous orchitis is rare and results from hematogenous
dissemination of tuberculosis, fungi, and actinomycosis.

Pyelonephritis
Pyelonephritis is an infection of the renal parenchyma. Infection usually occurs in a
retrograde, ascending fashion from the bladder, but it may occur hematogenously. The
ureteral orifice becomes edematous and loses its one-way valve function during infection.
Retrograde flow of bacteria into the upper urinary tracts and into the renal parenchyma results
in clinical symptoms.

Bacterial cystitis
Bacterial cystitis without concomitant infection in other portions of the genitourinary tract is
believed to be a rare event in males. The abrupt onset of irritative voiding symptoms (eg,
frequency, urgency, nocturia, dysuria) and suprapubic pain are clinically diagnostic.
Most cases of bacterial cystitis occur by an ascending mechanism. Bacterial cystitis in the
male is uncommon in the absence of anatomic abnormality, defect in bladder emptying
mechanism, or urethral catheterization (eg, poor bladder emptying from prostatic obstruction
or dysfunctional voiding). Elevated postvoid residuals allow bacteria to multiply to critical
levels. High voiding pressures and poor bladder compliance diminish the natural uroepithelial
resistance to infection.

Urethritis
Urethritis has been described for thousands of years. The term gonorrhea (gonus meaning
seed, rhoia meaning flow) was coined by Galen. The urethral nonsquamous epithelium can
be penetrated by N gonorrhoeae, resulting in periurethral microabscesses. Necrotic debris is
sloughed into the urethra lumen, producing a milky penile discharge.

Urinary catheterassociated UTIs

Up to 25% of hospitalized patients have urinary catheters inserted; of these individuals, 1027% develop UTIs. In fact, UTI accounts for approximately 40% of all nosocomial
infections; 15% of these infections occur in clusters and often involve highly resistant
organisms.
The single most important risk factor for nosocomial bacteriuria and UTI is the presence of
an indwelling urethral catheter; 80% of nosocomial UTIs are associated with the use of
urethral catheters. Once the urethral catheter is in place, the daily incidence of bacteriuria is
3-10%. Because most patients who become bacteriuric do so by 30 days, that is a convenient
dividing line between short- and long-term catheterization.

Etiology
Risk factors for UTI and bacterial causes of prostatitis, epididymitis, orchitis, pyelonephritis,
cystitis, and urethritis are discussed in this section.

Risk factors
Obstruction from any cause is a major risk factor for the development of UTI, as are
instrumentation of the urinary tract, catheterization, and urologic surgery.
In males older than 50 years, prostatic hypertrophy with partial obstruction is the main
contributor to the increase in UTI. Risk factors observed more commonly in elderly or
institutionalized males include cognitive impairment, fecal or urinary incontinence, and the
use of catheters.
Catheter-associated bacteriuria risk factors include female sex, significant comorbid
conditions (especially diabetes mellitus), age older than 50 years, lack of systemic
antibiotic(s), and a serum creatinine level greater than 2mg/dL.
Risk factors for bacteremia secondary to catheter-associated UTI (CAUTI) are male sex, UTI
caused by Serratia marcescens, older age, underlying urologic disease, and an indwelling
catheter.
In young men, risk factors for acute cystitis include homosexual behavior with anal
intercourse, intercourse with a female infected or colonized with a uropathogen, lack of
circumcision, and human immunodeficiency virus (HIV) infection with CD4 counts of
200/L or less.

Prostatitis
Gram-negative uropathogens (eg, Enterobacteriaceae, such as E coli, Klebsiella, and
Pseudomonas) are acknowledged pathogens of the prostate. Probable pathogens include
Enterococcus and S aureus, and possible pathogens include coagulase-negative
Staphylococcus, Chlamydia, Ureaplasma, anaerobes, Candida, and Trichomonas.
Acknowledged nonpathogens of the prostate include diphtheroids, lactobacilli, and

Corynebacterium. Bacterial pathogens cannot be demonstrated in cases of nonbacterial

prostatitis.

Epididymitis
Chlamydia trachomatis and N gonorrhoeae are the most common pathogens in patients
younger than 35 years with UTI, whereas Enterobacteriaceae and gram-positive cocci are
frequent pathogens in older patients.

Orchitis
Orchitis is one of the few genitourinary infections resulting from viral pathogens, such as the
mumps, coxsackie B, Epstein-Barr (EBV), and varicella (VZV) viruses.

Pyelonephritis and cystitis

Bacteria responsible for pyelonephritis and cystitis in males include E coli, Klebsiella,
Enterobacter, Proteus, Pseudomonas, Serratia, Enterococcus, and Staphylococcus species.

Urethritis
N gonorrhoeae is the most common cause of urethritis in males; nongonococcal causes of
urethritis include C trachomatis (in up to 50% of cases), Ureaplasma urealyticum,
Trichomonas vaginalis, and herpes simplex virus (HSV). The role of Mycoplasma in
urethritis is controversial.

Catheter-associated bacteriuria
Short-term catheters are placed for a mean duration of 2-4 days. The usual indications are for
acute illnesses, output measurement, perioperative routine, and acute retention.
Approximately 15% of patients develop bacteriuria, usually with a single organism (E coli).
Catheter-associated bacteriuria usually resolves after the catheter is removed; however, one
third of patients may have symptoms, and bacteremia is the most serious complication.
Approximately 10-30% of patients develop a fever, and the risk of postoperative wound
infection associated with bacteriuria is increased.

Epidemiology
The incidence of UTI in men approaches that of women only in males older than 60 years; in
men aged 65 years or older, 10% have been found to have bacteriuria, as compared with 20%
of women in this age group.
Internationally, there is a similar incidence in developed countries; however, in developing
countries where men have shorter life spans, the incidence of UTI due to prostatic
hypertrophy is lower.
The incidence of true UTI in adult males younger than 50 years is low (approximately 5-8 per
year per 10,000). In this population, the symptoms of dysuria or urinary frequency are usually

due to sexually transmitted disease (STD)related infections of the urethra (eg, gonococcal
and nongonococcal urethritis) and prostate.[5]
In men older than 50 years, the incidence of UTI rises dramatically (range, 20-50%
prevalence), because of enlargement of the prostate, prostatism, debilitation, and subsequent
instrumentation of the urinary tract. The spectrum of causative agents is also somewhat
broader in these older men.

Prostatitis, epididymitis, urethritis, and orchitis

In contrast to UTI, prostatitis affects men of all ages and, from 1990-1994, accounted for
almost 2 million office visits per year in the United States. Prostatitis syndromes account for
25% of male office visits for genitourinary complaints, 8% of visits to urologists, and 1% of
visits to primary care physicians. Of these men, 5% have bacterial prostatitis, 64% have
nonbacterial prostatitis, and 31% have prostatodynia.
Epididymitis has a bimodal distribution, corresponding to different age groups and
pathogens. Most cases in men younger than 35 years are due to sexually transmitted
pathogens. Older patients are more likely to have obstructive prostatism or a history of
instrumentation or catheterization.
Gonococcal urethritis is more common in ethnic minorities, lower socioeconomic groups, and
persons living in urban centers. The risk to a male having intercourse with an infected female
is 17%. Some of these associations may be limited by confounding. The peak age for
urethritis is 20-24 years.
Mumps orchitis occurs in 18% of postpubertal boys infected with the mumps virus.

History
In men, the most frequent chief complaint related to urinary tract infection (UTI) is dysuria.
In fact, complaints of dysuria, urinary frequency, and urgency are approximately 75%
predictive for UTI, whereas the acute onset of hesitancy, urinary dribbling, and slow stream
are only approximately 33% predictive for it. Other aspects to inquire about include the
following:

Previous UTI(s)
Nocturia, gross hematuria, any changes in the color and/or consistency of the urine

Prostatic enlargement

Urinary tract abnormalities - Personally and within their families

Comorbid conditions - Eg, diabetes

Human immunodeficiency virus (HIV) status

Immunosuppressive treatments for other conditions - Eg, prednisone

Any previous surgeries or instrumentation involving the urinary tract

In a younger man, the presence of UTI is often associated with anatomic abnormality. In the
absence of this history, a detailed sexual history may implicate activities such as sex with a
new partner, sex with multiple partners, or other risk-taking behavior associated with sexually
transmitted disease (STD)-related urethritis, prostatitis, or epididymitis that may lead to UTI.

Physical Examination
Physical findings of UTI may include the following:

Fever
Tachycardia

Flank pain/costovertebral angle tenderness

Abdominal tenderness in the suprapubic area

Scrotal hematoma, hydrocele, masses, or tenderness

Meatal discharge

Prostatic tenderness

Inguinal adenopathy

Prostatitis Syndromes
These syndromes tend to occur in young and middle-aged men. Symptoms may include pain
(in the perineum, lower abdomen, testicles, or penis or with ejaculation), bladder irritation,
and, sometimes, blood in the semen.

Epididymitis and Cystitis

In early epididymitis, the epididymis is tender and indurated, but the testis itself is nontender
and soft. In hours to days, inflammation progresses to the adjacent testicle and patients may
complain of scrotal pain and swelling, as well as urinary frequency, urgency, or dysuria.
Identifying the lateral sulcus between the testicle and epididymis then becomes increasingly
difficult, and discerning testis from epididymis may be impossible.
Dysuria, frequency, urgency, and suprapubic pain usually are present in patients with cystitis.
Fever and flank pain may be present, but not usually. Note that symptoms cannot
reproducibly differentiate cystitis (lower UTI) from pyelonephritis (upper UTI).

Orchitis
The most common presentation of orchitis is in a patient in the later stages of epididymitis. In
this situation, inflammation has spread to the adjacent testicle and results in a tender, warm,

and swollen hemi-scrotal mass. Patients have the characteristic history and urinary findings
of epididymitis.
Of patients with orchitis resulting from tuberculosis, 70% have other genitourinary or
pulmonary symptoms of this disease.
Viral orchitis is notable for the symptoms of the viral syndrome. Orchitis occurs in
approximately 18% of postpubertal boys infected with the mumps virus; symptoms usually
begin within 1 week of parotitis. Up to 30% of cases are bilateral, and sterility develops in up
to 10% of cases.

Pyelonephritis
Patients with pyelonephritis appear ill; have fever, chills, and flank pain; and may have
hypotension. Although fever is very suggestive of pyelonephritis, it has also been
demonstrated in some males with simple cystitis. Note that 30-50% of pyelonephritis cases
may be silent, without clinical symptoms.
In the older male, prostate enlargement along with delayed presentation are the primary
causes of pyelonephritis. Other historical risk factors include nephrolithiasis, neurogenic
bladder, prostatitis, or symptom duration greater than 5 days.
Classic findings with pyelonephritis include fever, chills, and flank pain/costovertebral angle
tenderness that follow the symptoms of UTI; these findings are combined with pyuria and
bacteriuria. Occasionally, the urinalysis and urine culture findings are negative, such as when
an obstruction of the upper urinary tract is present due to stone disease.

Urethritis
The incubation period of gonococcal urethritis is 2-6 days. Occasionally, 2 weeks may elapse
before symptoms such as dysuria; thick, milky discharge; and pruritus occur.
The incubation period of nongonococcal urethritis (NGU) is 2-6 weeks. The symptoms are
less severe and the discharge may be clearer than with gonococcal urethritis. Patients are
likely to have a higher level of education (ie, 90% of urethritis cases in college health
services is NGU) and fewer sexual contacts.
Because patients with urethritis have a thick, milky discharge, the underpants may be
impressively stained. Typically, patients with gonorrhea have a thicker, more copious
discharge, but significant overlap with chlamydial urethritis is not uncommon.

Dietary considerations
Keeping the patient well hydrated is important, especially if an obstruction was recently
relieved.
Drinking cranberry juice offers little benefit. Although it appears to inhibit E coli from
adhering to human uroepithelium, the amounts of bacteriostatic hippuric acid that are present
are unlikely to be clinically effective.

For complicated UTIs associated with struvite calculi, foods and vitamin supplements rich in
phosphorus and magnesium are advised. Remember that divalent cations (eg, magnesium)
can chelate oral fluoroquinolones, preventing their absorption from the gut.

Activity considerations
Bedrest and avoiding certain activities (eg, bike riding) may be beneficial in patients with
prostatitis. For patients with category IIIB (chronic, noninflammatory, abacterial) prostatitis,
bedrest for 2 weeks has been advocated. Sitting on ring cushions can be a simple way to
minimize symptoms.
In urethritis, sexual activity may be resumed when both partners have completed treatment;
barrier methods are encouraged. No one knows for certain when sexual activity may be
resumed for the other topics discussed in this article.

UTI Prevention
Preprocedure prophylaxis, condom use, and appropriate use of urinary catheters can reduce
the risk of infections and complications.[21]

GN AKUT
Background
Acute glomerulonephritis (GN) comprises a specific set of renal diseases in which an
immunologic mechanism triggers inflammation and proliferation of glomerular tissue that
can result in damage to the basement membrane, mesangium, or capillary endothelium. Acute
poststreptococcal glomerulonephritis (PSGN) is the archetype of acute GN. Acute nephritic
syndrome is the most serious and potentially devastating form of the various renal
syndromes.

Etiology
The causal factors that underlie acute GN can be broadly divided into infectious and
noninfectious groups.

Infectious
The most common infectious cause of acute GN is infection by Streptococcus species (ie,
group A, beta-hemolytic). Two types have been described, involving different serotypes:

Serotype 12 - Poststreptococcal nephritis due to an upper respiratory infection,

occurring primarily in the winter months
Serotype 49 - Poststreptococcal nephritis due to a skin infection, usually observed in
the summer and fall and more prevalent in southern regions of the United States

Nonstreptococcal postinfectious GN may also result from infection by other bacteria, viruses,
parasites, or fungi. Bacteria besides group A streptococci that can cause acute GN include
diplococci, other streptococci, staphylococci, and mycobacteria. Salmonella typhosa,
Brucella suis, Treponema pallidum, Corynebacterium bovis, and actinobacilli have also been
identified.
Cytomegalovirus (CMV), coxsackievirus, Epstein-Barr virus (EBV), hepatitis B virus
(HBV),[4] rubella, rickettsiae (as in scrub typhus), and mumps virus are accepted as viral
causes only if it can be documented that a recent group A beta-hemolytic streptococcal
infection did not occur. Acute GN has been documented as a rare complication of hepatitis A.
[5]

Noninfectious
Multisystem systemic diseases that can cause acute GN include the following:

Vasculitis (eg, granulomatosis with polyangiitis [Wegener granulomatosis]) - This

causes glomerulonephritis that combines upper and lower granulomatous nephritides).
Collagen-vascular diseases (eg, systemic lupus erythematosus [SLE]) This causes
glomerulonephritis through renal deposition of immune complexes).

Hypersensitivity vasculitis This encompasses a heterogeneous group of disorders

featuring small vessel and skin disease.

Cryoglobulinemia This causes abnormal quantities of cryoglobulin in plasma that

result in repeated episodes of widespread purpura and cutaneous ulcerations upon
crystallization.

Polyarteritis nodosa - This causes nephritis from a vasculitis involving the renal
arteries.

Henoch-Schnlein purpura This causes a generalized vasculitis resulting in

glomerulonephritis.

Goodpasture syndrome This causes circulating antibodies to type IV collagen and

often results in a rapidly progressive oliguric renal failure (weeks to months).

Primary renal diseases that can cause acute GN include the following:

Membranoproliferative glomerulonephritis (MPGN) - This is due to the expansion

and proliferation of mesangial cells as a consequence of the deposition of
complements. Type I refers to the granular deposition of C3; type II refers to an
irregular process.
Berger disease (IgG-immunoglobulin A [IgA] nephropathy) - This causes GN as a
result of diffuse mesangial deposition of IgA and IgG.
Pure mesangial proliferative GN[1]

Idiopathic rapidly progressive glomerulonephritis - This form of GN is characterized

by the presence of glomerular crescents. Three types have been distinguished: Type I
is an antiglomerular basement membrane disease, type II is mediated by immune
complexes, and type III is identified by antineutrophil cytoplasmic antibody (ANCA).

Miscellaneous noninfectious causes of acute GN include the following:

Guillain-Barr syndrome
Irradiation of Wilms tumor

Diphtheria-pertussis-tetanus (DPT) vaccine

Serum sickness

Epidermal growth factor receptor activation, [6] and possibly its inhibition by
cetuximab[7]

Epidemiology
International statistics
Worldwide, Berger disease is the most common cause of GN.
With some exceptions, the incidence of PSGN has fallen in most Western countries. PSGN
remains much more common in regions such as Africa, the Caribbean, India, Pakistan,
Malaysia, Papua New Guinea, and South America. In Port Harcourt, Nigeria, the incidence of
acute GN in children aged 3-16 years was 15.5 cases per year, with a male-to-female ratio of
1.1:1; the current incidence is not much different.[8]
Geographic and seasonal variations in the prevalence of PSGN are more marked for
pharyngeally associated GN than for cutaneously associated disease.[8, 9, 10]

Age-, sex-, and race-related demographics

Postinfectious GN can occur at any age but usually develops in children. Most cases occur in
patients aged 5-15 years; only 10% occur in patients older than 40 years. Outbreaks of PSGN
are common in children aged 6-10 years. Acute nephritis may occur at any age, including
infancy.
Acute GN predominantly affects males (2:1 male-to-female ratio). Postinfectious GN has no
predilection for any racial or ethnic group. A higher incidence (related to poor hygiene) may
be observed in some socioeconomic groups.

Prognosis
Most epidemic cases follow a course ending in complete patient recovery (as many as 100%).
The mortality of acute GN in the most commonly affected age group, pediatric patients, has
been reported at 0-7%.

Sporadic cases of acute nephritis often progress to a chronic form. This progression occurs in
as many as 30% of adult patients and 10% of pediatric patients. GN is the most common
cause of chronic renal failure (25%).
In PSGN, the long-term prognosis generally is good. More than 98% of individuals are
asymptomatic after 5 years, with chronic renal failure reported 1-3% of the time.

History
A thorough history should be obtained, focusing on the identification of an underlying
systemic disease (if any) or recent infection. Most often, the patient is a boy, aged 2-14 years,
who suddenly develops puffiness of the eyelids and facial edema in the setting of a
poststreptococcal infection. The urine is dark and scanty, and the blood pressure may be
elevated. Nonspecific symptoms include weakness, fever, abdominal pain, and malaise.
Ask the patient about the onset and duration of the illness. Symptom onset is usually abrupt.
In the setting of acute postinfectious glomerulonephritis (GN), a latent period of up to 3
weeks occurs before onset of symptoms. However, the latent period may vary; it is typically
1-2 weeks for postpharyngitis cases and 2-4 weeks for cases of postdermal infection (ie,
pyoderma). The onset of nephritis within 1-4 days of streptococcal infection suggests
preexisting renal disease.
Identify a possible etiologic agent (eg, streptococcal throat infection [pharyngitis], skin
infection [pyoderma]). Recent fever, sore throat, joint pains, hepatitis, travel, valve
replacement, and/or intravenous drug use may be causative factors. Rheumatic fever rarely
coexists with acute PSGN.
Inquire about symptoms of acute glomerulonephritis, including the following:

Hematuria - This is a universal finding, even if it is microscopic. Gross hematuria is

reported in 30% of pediatric patients, often manifesting as smoky-, coffee-, or colacolored urine.
Oliguria

Edema (peripheral or periorbital) - This is reported in approximately 85% of pediatric

patients; edema may be mild (involving only the face) to severe, bordering on a
nephrotic appearance.

Headache - This may occur secondary to hypertension; confusion secondary to

malignant hypertension may be seen in as many as 5% of patients.

Shortness of breath or dyspnea on exertion - This may occur secondary to heart failure
or pulmonary edema; it is usually uncommon, particularly in children.

Possible flank pain secondary to stretching of the renal capsule

Physical Examination

The following description does not address all of the physical findings that can be associated
with the nonnephrotic features of an infectious process, renal disorder, or systemic disease
that causes acute GN; to do so would be beyond the scope of this article.
Patients often have a normal physical examination and blood pressure; most frequently,
however, patients present with a combination of edema, hypertension, and oliguria.
The physician should look for the following signs of fluid overload:

Periorbital and/or pedal edema

Edema and hypertension due to fluid overload (in 75% of patients)

Crackles (ie, if pulmonary edema)

Elevated jugular venous pressure

Ascites and pleural effusion (possible)

The physician should also look for the following:

Rash (as with vasculitis, Henoch-Schnlein purpura, or lupus nephritis)

Pallor

Renal angle (ie, costovertebral) fullness or tenderness, joint swelling, or tenderness

Hematuria, either macroscopic (gross) or microscopic

Abnormal neurologic examination or altered level of consciousness (from malignant

hypertension or hypertensive encephalopathy)

Arthritis

Other signs include the following:

Pharyngitis
Impetigo

Respiratory infection

Pulmonary hemorrhage

Heart murmur (possibly indicative of endocarditis)

Scarlet fever

Weight gain

Abdominal pain

Anorexia

Back pain

Oral ulcers

Complications
Progression to sclerosis is rare in the typical patient; however, in 0.5-2% of patients with
acute GN, the course progresses toward renal failure, resulting in kidney death in a short
period.
Abnormal urinalysis (ie, microhematuria) may persist for years. A marked decline in the
glomerular filtration rate (GFR) is rare.
Pulmonary edema and hypertension may develop. Generalized
hypoalbuminemia may develop secondary to severe proteinuria.

anasarca

and

A number of complications that result in relevant end-organ damage in the central nervous
system (CNS) or the cardiopulmonary system can develop in patients who present with
severe hypertension, encephalopathy, and pulmonary edema. Those complications include the
following:

Hypertensive retinopathy
Hypertensive encephalopathy

Rapidly progressive GN

Chronic renal failure

Nephrotic syndrome

Approach Considerations
Urinalysis and sediment examination are crucial in the evaluation of patients with acute
nephritic syndrome. Look for the following:

Protein
Blood

Red blood cells (RBCs)

White blood cells (WBCs)

Dysmorphic RBCs

Acanthocytes

Cellular (ie, RBC, WBC) casts

Granular casts

Oval fat bodies

In some instances, marked sterile pyuria is present. The presence of RBC casts is almost
pathognomonic of glomerulonephritis (GN). Urine electrolyte, urine sodium, and fractional
excretion of sodium (FENa) assays are needed to assess salt avidity.

Blood tests should include the following:

Complete blood count (CBC)

Blood urea nitrogen (BUN), serum creatinine, and serum electrolytes (especially
serum potassium)

Erythrocyte sedimentation rate (ESR)

Complement levels (C3, C4, CH50)

Streptozyme testing may be useful. Imaging studies are helpful in some patients, for
assessment of clinical signs suggesting extrarenal involvement or for structural evaluation of
the kidneys.

Urinalysis and 24-Hour Urine Study

The urine is dark. Its specific gravity is greater than 1.020. RBCs and RBC casts are present.
Proteinuria is observed.
The 24-hour urine protein excretion and creatinine clearance, though not indicated in the
emergency department (ED) setting, may be helpful to document the degree of renal
dysfunction and proteinuria. With this test, it is important to remember that creatinine
clearance is a steady-state measurement. Because of rapidly changing renal function, the
creatinine clearance may not reveal the true picture; therefore, it is better to wait until renal
function has stabilized before performing creatinine clearance.

Histologic Findings
Diffuse endocapillary proliferative changes are found. The most common histologic patterns
are diffuse (72.1%), focal (12.8%), and mesangial (8.1%) proliferative GN in adults. [3] In
postinfectious GN, the glomerulus is hypercellular with marked cellular infiltration (ie,
polymorphonuclear neutrophils, monocytes)

Approach Considerations
Treatment of acute poststreptococcal glomerulonephritis (PSGN) is mainly supportive,
because there is no specific therapy for renal disease. When acute glomerulonephritis (GN) is
associated with chronic infections, the underlying infections must be treated.

Diet and Activity

Sodium and fluid restriction should be advised for treatment of signs and symptoms of fluid
retention (eg, edema, pulmonary edema). Protein restriction for patients with azotemia should
be advised if there is no evidence of malnutrition.
Bed rest is recommended until signs of glomerular inflammation and circulatory congestion
subside. Prolonged inactivity is of no benefit in the patient recovery process.

GN KRONIK

Background
Nearly all forms of acute glomerulonephritis have a tendency to progress to chronic
glomerulonephritis. The condition is characterized by irreversible and progressive glomerular
and tubulointerstitial fibrosis, ultimately leading to a reduction in the glomerular filtration
rate (GFR) and retention of uremic toxins. If disease progression is not halted with therapy,
the net results are chronic kidney disease (CKD), end-stage renal disease (ESRD), and
cardiovascular disease. Chronic glomerulonephritis is the third leading cause and accounts for
about 10% of all causes of CKD.
In accordance with this definition, the NKF developed guidelines that classify the progression
of renal disease into five stages, from kidney disease with a preserved GFR to end-stage
kidney failure. This classification includes treatment strategies for each progressive level, as
follows:

Stage 1 This stage is characterized by kidney damage with a normal GFR ( 90

mL/min); the action plan consists of diagnosis and treatment, treatment of comorbid
conditions, slowing of the progressing of kidney disease, and reduction of
cardiovascular disease risks
Stage 2 This stage is characterized by kidney damage with a mild decrease in the
GFR (60-90 mL/min); the action plan is estimation of the progression of kidney
disease

Stage 3 This stage is characterized by a moderately decreased GFR (to 30-59

mL/min); the action plan consists of evaluation and treatment of complications

Stage 4 This stage is characterized by a severe decrease in the GFR (to 15-29
mL/min); the action plan is preparation for renal replacement therapy

Stage 5 This stage is characterized by kidney failure; the action plan is kidney
replacement if the patient is uremic

Pathophysiology
Reduction in nephron mass from the initial injury reduces the GFR. This reduction leads to
hypertrophy and hyperfiltration of the remaining nephrons and to the initiation of
intraglomerular hypertension. These changes occur in order to increase the GFR of the
remaining nephrons, thus minimizing the functional consequences of nephron loss. The
changes, however, are ultimately detrimental because they lead to glomerulosclerosis and
further nephron loss.

In early renal disease (stages 1-3), a substantial decline in the GFR may lead to only slight
increases in serum creatinine levels. Azotemia (ie, a rise in blood urea nitrogen [BUN] and
serum creatinine levels) is apparent when the GFR decreases to less than 60-70 mL/min. In
addition to a rise in BUN and creatinine levels, the substantial reduction in the GFR results in
the following:

Decreased production of erythropoietin, thus resulting in anemia

Decreased production of vitamin D, resulting in hypocalcemia, secondary
hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy

Reduction in acid, potassium, salt, and water excretion, resulting in acidosis,

hyperkalemia, hypertension, and edema

Platelet dysfunction, leading to increased bleeding tendencies

Etiology
Progression patterns may be summarized as follows:

Rapidly progressive glomerulonephritis or crescentic glomerulonephritis - About 90%

of patients progress to ESRD within weeks or months.
Focal segmental glomerulosclerosis: - About 80% of patients progress to ESRD in 10
years; patients with the collapsing variant (malignant focal segmental
glomerulosclerosis) have a more rapid progression; this form may be idiopathic or
related to HIV infection

Membranous nephropathy About 20-30% of patients with membranous nephropathy

progress to chronic renal failure (CRF) and ESRD in 10 years

Membranoproliferative glomerulonephritis: - About 40% of patients with

membranoproliferative glomerulonephritis progress to CRF and ESRD in 10 years [2]

IgA nephropathy About 10% of patients with IgA nephropathy progress to CRF and
ESRD in 10 years[3]

Poststreptococcal glomerulonephritis - About 1-2% of patients with poststreptococcal

glomerulonephritis progress to CRF and ESRD; older children who present with
crescentic glomerulonephritis are at greatest risk

Lupus nephritis Overall, about 20% of patients with lupus nephritis progress to CRF
and ESRD in 10 years; however, patients with certain histologic variants (eg, class
IV) may have a more rapid decline

History
The history should begin by focusing on cause-specific symptoms to determine the source of
the chronic kidney disease (CKD) if this is unknown. Recognition of such symptoms
facilitates the planning of further workup and management of the disease (if systemic).
The next step is to look for symptoms related to uremia to determine if renal replacement
therapy is needed. The following symptoms suggest uremia:

Weakness and fatigue

Loss of energy, appetite, and weight

Pruritus

Early morning nausea and vomiting

Change in taste sensation

Reversal in sleep pattern (ie, sleepiness in daytime and wakefulness at night)

Peripheral neuropathy

Seizures

Tremors

The presence of edema and hypertension suggests volume retention. Dyspnea or chest pain
that varies with position suggests fluid overload and pericarditis, respectively. Leg cramps
may suggest hypocalcemia or other electrolyte abnormalities. Weakness, lethargy, and fatigue
may be due to anemia.

Physical Examination
Cause-specific physical examination findings are discussed elsewhere, in articles describing
the specific causes (see Etiology). Uremia-specific physical findings include the following:

Hypertension
Jugular venous distention (if severe volume overload is present)

Pulmonary rales (if pulmonary edema is present)

Pericardial friction rub in pericarditis

Tenderness in the epigastric region or blood in the stool (possible indicators of uremic
gastritis or enteropathy)

Decreased sensation and asterixis (indicators of advanced uremia)

Complications
The presence of the following complications generally indicates a need for urgent dialysis:

Metabolic acidosis
Pulmonary edema

Pericarditis

Uremic encephalopathy

Uremic gastrointestinal bleeding

Uremic neuropathy

Severe anemia and hypocalcemia

Hyperkalemia

Laboratory Studies
Urinalysis
The presence of dysmorphic red blood cells (RBCs), albumin, or RBC casts suggests
glomerulonephritis as the cause of renal failure. Waxy or broad casts are observed in all forms
of chronic kidney disease (CKD), including chronic glomerulonephritis. Low urine-specific
gravity indicates loss of tubular concentrating ability, an early finding in persons with CKD.
See Urinalysis.

Renal ultrasonography
Obtain a renal ultrasonogram to determine renal size, to assess for the presence of both
kidneys, and to exclude structural lesions that may be responsible for azotemia. Small
kidneys often indicate an irreversible process.

Pharmacologic Therapy
Blood pressure management
The target blood pressure for patients with proteinuria in excess of 1 g/day is less than 125/75
mm Hg; for patients with proteinuria of less than 1 g/day, the target pressure is less than
130/80 mm Hg.
Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used and are usually the
first choice for treatment of hypertension in patients with chronic kidney disease (CKD).

Diet and Activity

Protein-restricted diets (0.4-0.6 g/kg/day) are controversial but may be beneficial in slowing
the decline in the GFR and reducing hyperphosphatemia (serum phosphate > 5.5 mg/dL) in
patients with serum creatinine levels higher than 4 mg/dL. Monitor these patients for signs of
malnutrition, which may contraindicate protein restriction. Educate patients about how
potassium-rich diets help control hyperkalemia. Many dietary restrictions are no longer
necessary with the initiation of renal replacement therapy.
Encourage patients to increase their activity level as tolerated. Increased activity may aid in
blood pressure control.

NEFROPATI MEMBRANOSA

Background
Membranous nephropathy (MGN) is one of the more common forms of nephrotic syndrome
in the adult population. It can be idiopathic or secondary (30%). The two can be distinguished
by clinical, laboratory, and histological features.

Epidemiology
Biopsy reveals an underlying glomerular lesion in 25% of adults with nephrotic syndrome.
However, in patients older than 60 years, the incidence rate is 35%.
In the pediatric population, membranous nephropathy is rare but serious. Membranous
nephropathy accounts for approximately 3% of renal biopsies.
Race

The incidence of secondary forms may be influenced by the prevalence of hepatitis and
malaria in certain areas.
No increased incidence is reported in African Americans.

Sex

Membranous nephropathy has a predilection for males over females, with a male-to-female
ratio of 2:1.

Age

The peak is around the fourth and fifth decades of life.

Onset outside the usual range is more likely to be a result of secondary causes.

History

Onset is insidious.
Approximately 80% of patients describe edema.

Patients may present with nonspecific complaints of anorexia, malaise, and fatigue.

Some patients may present with asymptomatic proteinuria.

Physical

The overwhelming majority of patients have edema or generalized anasarca.

Hypertension may be present but is not characteristic of the disease in its early stages.
This is unlike most other renal diseases, which are associated with significant
hypertension.

Ascites and pericardial and pleural effusions are uncommon, unless the nephrotic
syndrome is severe.

Causes
Causes of membranous nephropathy can be idiopathic or secondary. Often, distinguishing
between idiopathic and secondary causes is not possible based on clinical evidence alone. In
secondary membranous nephropathy, such as lupus and hepatitis, concomitant mesangial or
subendothelial deposits may be present. De novo membranous glomerulopathy (DNMG) can
develop post transplant. This can be in the context of a donor-specific alloantibody (DSA)
directed against HLA DQ7.[5]

Autoimmune diseases
o Ankylosing spondylitis
o

Dermatomyositis

Graves disease

Hashimoto disease

Mixed connective-tissue disease

Rheumatoid arthritis

Sjgren syndrome

Systemic lupus erythematosus: Of patients with lupus nephritis, 10-20% have

membranous nephropathy.

Systemic sclerosis

Infectious diseases
o

Enterococcal endocarditis

Filariasis

Hepatitis B: This occurs in children in endemic areas.

Hepatitis C

Hydatid cyst

Leprosy

Malaria

Schistosomiasis

Syphilis

Malignancy: This is responsible for approximately 5-10% of cases of membranous

nephropathy, with the higher risk occurring in patients older than 60 years.

Carcinoma (solid organ)

Leukemia

Lymphoma

Melanoma

Drugs
o

Captopril

Gold

Lithium

Mercury-containing compounds

Nonsteroidal anti-inflammatory drugs (NSAIDs): They are an uncommon

cause; they are usually associated with minimal-change disease.

Penicillamine

Probenecid

Miscellaneous
o

De novo in renal allografts: The onset is delayed compared to recurrent

disease. The rate of graft loss may be as high as 50%. Recurrence is
infrequent, with rates of 3-7%. This can lead to loss of the graft. Membranous
nephropathy recurs in 5-10% of patients.

Diabetes (uncommon)

Kimura disease

Sarcoidosis

Sickle cell disease: This is uncommon. It usually produces focal segmental

glomerulosclerosis.

Systemic mastocytosis

Laboratory Studies

Urine microscopy: Urine sediment is typically nephrotic, with oval fat bodies and
fatty casts; however, in mild cases, the urinalysis may reveal proteinuria without
formed elements in the sediment.
Serum creatinine

Blood urea nitrogen

Serum albumin

Proteinuria (quantitative) with a 24-hour urine collection: A ratio of spot urine protein
to creatinine is easier to obtain, and the findings may be sufficient for screening
purposes.

Creatinine clearance

Antinuclear antibodies

Antidouble-strand DNA, if results from antinuclear antibody testing are positive

Hepatitis B serology (if positive, DNA quantitation)

Hepatitis C (if positive, RNA quantitation)

Syphilis serology

Complement levels

Cryoglobulin, particularly if hepatitis C and/or low levels of complement are found

Lipid profile

Urinary C5b-9

Urinary beta-2 microglobulin (worse prognosis with an increased level)

Malignancy workup: An exhaustive workup for malignancy is not recommended

because most cases of membranous nephropathy are not associated with cancer.
However, because some increase in the rate of occult malignancy is recognized in
patients with newly diagnosed membranous nephropathy, (1) ensure that ageappropriate health screening (eg, mammography, sigmoidoscopy) has been
performed, and (2) investigate any clues from the initial patient history and physical
examination.

Imaging Studies

Sonogram

Procedures

Renal biopsy: Definitive diagnosis is made based on findings from a renal biopsy.

Histologic Findings
Pathologic features can be observed using light microscopy, immunofluorescence
microscopy, and electron microscopy.

Light microscopy: The mesangium is normal, with no hypercellularity. All glomeruli

are involved. The capillary walls are thickened with patent capillary lumina.
Subepithelial deposits are seen; with trichrome stain, they are shown to have spikes.

Immunofluorescence microscopy: Use strong granular capillary wall staining for

immunoglobulin G (IgG), with C3 and both kappa and lambda light chains.

Medical Care
Search for an underlying cause. Successful treatment of the underlying cause may be curative
in secondary forms.

A low-salt diet is key to reducing anasarca. Protein restrictions may or may not be
useful in reducing the rate of progression of chronic renal failure.
Diuretics help control edema. Loop diuretics are used most often.

NSAIDs help to decrease the proteinuria. These have been largely supplanted by
angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers
(ARBs).

ACE inhibitors decrease proteinuria and control hypertension; use ARBs for patients
intolerant of ACE inhibitors.

Hepatic 3-methylglutaryl
hypercholesterolemia.

Routine anticoagulation is controversial. However, the risk of renal vein thrombosis

and other deep vein thromboses is significant, and the clinician must be vigilant in
monitoring for signs of venous thrombosis. Once found, anticoagulation is generally
continued indefinitely. In a study of membranous nephropathy, the risk of developing
VTE (venous thromboembolism) increased 3.9-fold with a reduction in serum
albumin below the threshhold of 2.8g/dl and 5.8-fold with a serum albumin of less
than 2.2 g/dl.[6]

In hepatitis-associated membranous nephropathy, antivirals may be useful.

Treat hypertension aggressively.

Do not treat patients with asymptomatic nonnephrotic proteinuria with

immunosuppressives. Patients who are asymptomatic and nephrotic may undergo
remission, particularly if they have normal renal function and an early lesion. They
may also be observed.

Therapy with immunosuppressive agents is indicated in those patients who have the
following:

coenzyme

reductase

inhibitors

help

Increased creatinine level at presentation

Progressive disease

Severe symptomatic nephrotic syndrome

Persistent nephrotic syndrome

Thromboembolism

Persistent nephrotic syndrome, male sex, and age older than 50 years

treat

Increased IgG excretion, HLA-DR3+/B8+, white race, and elevation of urinary

excretion of complement activation products

Tubulointerstitial changes or focal sclerosis

Surgical Care
Transplantation is indicated if the patient progresses to ESRD. Some risk of recurrence in the
allograft is recognized.

Diet

Institute a low-salt diet.

Protein restrictions may or may not be useful.

Activity

Activity can be performed as tolerated.

Further Outpatient Care

Management is on an outpatient basis, with emphasis on controlling blood pressure.

Observation for signs and symptoms of renal vein thrombosis, deep vein thrombosis,
and pulmonary embolism is crucial in these patients.
Renal function, proteinuria (measured by the ratio of urinary protein to creatinine),
and electrolytes need to be monitored at regular intervals.
Additional monitoring is indicated for pharmacologic interventions.

Complications

Most complications are associated with heavy proteinuria.

Serositis is a possible complication.

Hypovolemia, with the possibility of acute renal failure, may occur in patients who
are overdiuresed. Hypovolemia exacerbates the adverse renal effects of ACE
inhibitors, ARBs, and NSAIDs.

Increased incidence of infection may be present, even in patients not receiving

immunosuppressives.

Hyperfibrinogenemia and erythrocytosis may lead to a hypercoagulable state,

particularly renal vein thrombosis. Nephrotic syndrome may also result in loss of
antithrombin III.

Lethargy and tiredness are complications.

An increased incidence of ischemic heart disease has not been proven.

Prognosis

The outcome depends on the renal function at the time of diagnosis and the amount of
proteinuria, ranging from remission without medication to ESRD.

MINIMAL CHANGE
Background
Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease, is the most
common single form of nephrotic syndrome in children. It refers to a histopathologic lesion
in the glomerulus that almost always is associated with nephrotic syndrome. It typically is a
disease of childhood, but it also can occur in adults.

Epidemiology
Frequency
In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all
cases of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%, while
in adults, MCNS accounts for 10-15% of primary nephrotic syndrome cases. The incidence
of nephrotic syndrome is 2-7 new cases annually per 100,000 children, and the prevalence is
15 cases per 100,000 children.

Race-, Sex-, and Age-related Demographics

Rates of MCD vary as follows:

Asians may be at increased risk for MCD

In children, MCD is found twice as frequently in boys than in girls; in
adults, however, the frequency is the same between the sexes

The incidence of MCD peaks in children aged 2 years, with approximately

80% being younger than 6 years at the time of diagnosis

In adults, the mean age of onset is 40 years

History
Facial edema is noted first. Edema may be preceded by an upper respiratory tract infection,
an allergic reaction to a bee sting, the use of certain drugs, or malignancies.

Malaise and easy fatigability can occur. Weight gain often is an additional feature.
The patient also may present with one or more of the following:

Hypovolemia
Hypertension

Thromboembolism

Infection

Causes
Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may
have an identifiable cause. Secondary cases may be due to any of the following:

Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon,

ampicillin/penicillin, trimethadione, mercury-containing cosmetic skin cream
Toxins - Mercury, lithium, bee stings, fire coral exposure

Infection - Infectious mononucleosis, HIV, immunization

Tumor - Hodgkin lymphoma (most commonly), carcinoma, other lymphoproliferative

diseases

Hematopoietic stem cell transplantation

Physical Examination
The blood pressure usually is normal in children [6] but may be elevated in adults. (In addition,
the plasma creatinine in adults is often slightly elevated at presentation.)
Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual
edema with horizontal lines (called Muehrcke lines) also may occur.
Hernias may be found, and the elasticity of the ears may be decreased.
Heavy proteinuria over an extended period of time leads to a state of protein depletion with
muscle wasting, thinning of the skin, and growth failure.
Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be
the first indication of an underlying nephrotic syndrome.
Children may have growth failure.

Histologic Findings

Light microscopy
In children with frequently relapsing MCD, some involuted glomeruli may be present. These
lesions are small and sclerotic but retain their podocyte and parietal epithelial cell
constituents. The presence of these glomeruli is related to the duration of the disease.
The most common tubular lesion is protein and lipid droplets in epithelial cells due to
increased reabsorption. The presence of areas of tubular atrophy and interstitial fibrosis
should raise the suspicion of FSGS.

Approach Considerations
Urinalysis findings are benign in minimal-change disease (MCD), but profound proteinuria
and oval fat bodies may be observed. In children, the critical level for diagnosis is proteinuria
of more than 40 mg/h/m2. In adults, the threshold is more than 3.5 g/d/1.73 m2.
Hypoalbuminemia is an important marker of nephrotic syndrome. The level at which edema
occurs varies, but it tends to be lower in children than in adults. Nephrotic syndrome in
children is defined by a serum albumin of less than 2.5 g/dL. Hyperlipidemia also is a feature
of a nephrotic state.
Other laboratory findings are as follows:

Renal function usually is normal except in cases of undiagnosed focal segmental

glomerulosclerosis (FSGS) or in those cases that progress to acute renal failure
Serologic workup (including antinuclear antibodies, complements, and cryoglobulins)
is normal

Hyponatremia is often observed and is in part a spurious finding secondary to the

hyperlipidemic state; it also occurs from water retention caused by hypovolemia and
antidiuretic hormone release

Elevated hemoglobin and hematocrit are consequences of plasma volume contraction

Renal sonogram results are normal in patients with MCD.

Approach Considerations
Because of the high prevalence of minimal-change disease (MCD) in children with nephrotic
syndrome, an empiric trial of corticosteroids commonly is the first step in therapy.
Corticosteroids are the treatment of choice, leading to complete remission of proteinuria in
most cases. Approximately 90% of children respond within 2 weeks to prednisone at a dose
of 2 mg/kg/day (not to exceed 80 mg/day). After the remission of proteinuria, prednisone is
continued for another 6 weeks, at lower doses.

Diet and Activity

An adequate dietary protein intake, in accordance with the recommended daily allowance
(RDA) is necessary. No evidence suggests that hepatic albumin synthesis is elevated with
protein intake that is higher than the RDA.
Dietary sodium restriction helps forestall the progression of edema and also is prudent in the
management of hypertension.
Mobilization, rather than bed rest, is indicated to avoid thromboembolic complications.

Further Outpatient Care

MCD is treated in the outpatient setting. Followup care includes the following:

Carefully monitor medication doses and adverse effects

Monitor vital signs for possible onset of hypertension

Monitor volume status

Monitor for signs of infection

Complications
The most common complications are the adverse effects of medications. Additional
complications may include peritonitis, infections, and acute renal failure. Acute renal failure
occurs because of either acute tubular necrosis or acute tubulointerstitial nephritis.
Patients with nephrotic syndrome have an increased incidence of arterial and venous
thromboemboli, particularly deep vein and renal vein thrombosis.
Hypercholesterolemia and hypertriglyceridemia can lead to accelerated atherosclerosis and
perhaps cause progressive glomerular injury.

Prognosis
Use of antibiotics and glucocorticoids and better-organized schedules of management have
substantially reduced the mortality rates associated with MCD. Deaths still occur from
disease complications.
Relapses eventually cease. Only approximately 5% of children continue to have steroidresponsive relapses when older than 18 years.
Adults have a similarly good prognosis. Survival rates of 85-90% are observed 10 years or
more after disease onset.
Chronic renal failure is extremely rare in patients who are steroid responsive. If chronic renal
failure occurs, the possibility that the pathologic lesion is different or has evolved must be
considered.