Pyelonephritis, Chronic

Pyelonephritis

Pyelonephritis (PN) – is non-specific infectious inflammatory process with primary localization in kidney’s pelvis and calyces, further involvement of interstitial tissue leading to nephrosclerosis

Classification (due to WCD – 10)

 Acute pyelonephritis noncomplicated and complicated

Chronic pyelonephritis noncomplicated and complicated; phase of activation and remission; degrees of activity I, II, III.

Pyelonephritis, Acute

Background: Acute pyelonephritis is a potentially organ- and/or life-threatening infection that characteristically causes some scarring of the kidney with each infection and may lead to significant damage to the kidney (any given episode), kidney failure, abscess formation (eg, nephric, perinephric), sepsis, or sepsis syndrome/shock/multiorgan system failure. More than 250,000 cases occur in the United States each year (1995 estimate), and approximately 200,000 patients require hospitalization (1997 data). Wide variation exists in the clinical presentation, severity, options, and disposition of acute pyelonephritis.

Diagnosing and managing acute pyelonephritis is not always straightforward. In the age range of 5-65 years, it typically presents in the context of a symptomatic (eg, dysuria, frequency, urgency, gross hematuria, suprapubic pain) urinary tract infection (UTI) with classic upper urinary tract symptoms (eg, flank pain, back pain) with or without systemic symptoms (eg, fever, chills, abdominal pain, nausea, vomiting) and signs (eg, fever, costovertebral angle tenderness) with or without leukocytosis. However, it can present with nonspecific symptoms.

A number of studies using immunochemical markers have shown that many women, who initially present with lower tract symptoms, actually have pyelonephritis. This group of young women is often identified when short-course therapy for uncomplicated cystitis fails. In the extremes of age, the presentation may be so atypical that pyelonephritis is not in the differential diagnosis. In the infant, the presentation may be feeding difficulty or fever. In the elderly, the presentation may be mental status change or fever. Acute pyelonephritis is complex, and there is no consistent set of signs and symptoms that are both sensitive and specific for the diagnosis; therefore, clinicians must maintain a high index of suspicion.

In contrast to the plethora of data available for the treatment of lower UTI, less substantial data are available regarding the appropriate antibiotic choice or duration of therapy for acute pyelonephritis, but useful recommendations can be made. An additional cause for concern is the growing antimicrobial resistance to accepted standards of treatment. The current emphasis on cost effectiveness and the advent of newer antibiotics have led clinicians to reevaluate the benefit of hospitalization to treat patients with acute pyelonephritis; however, if the patient is managed as an outpatient, he or she should have close follow-up care. The first follow-up visit should occur in 1-2 days, depending on the clinician’s estimation of the severity of the infection. Any deterioration or unsatisfactory improvement warrants admission for intravenous antibiotics and evaluation for any complications. Most cases of uncomplicated pyelonephritis in young women can be managed successfully on an outpatient basis.

Pathophysiology: Acute pyelonephritis results from bacterial invasion of the renal parenchyma. In all age groups, episodes of bacteriuria occur commonly, but most are asymptomatic (ABU) and do not lead to infection. Infection is influenced by bacterial factors and host factors.

Most bacterial data are derived from research with Escherichia coli, which accounts for 70-90% of uncomplicated UTIs and 21-54% of complicated UTIs. A subset of E coli, the uropathogenic E coli (UPEC), also termed extraintestinal pathogenic E coli (ExPEC), accounts for most clinical isolates from UTIs. UPEC derives commonly from the phylogenetic groups B2 and D, which express distinctive O, K, and H antigens. UPEC genes encode several postulated virulence factors (VFs), including adhesins, protectins, siderophores, and toxins, as well as having the metabolic advantage of synthesizing essential substances.

Adhesins have specific regions that attach to cell receptor epitopes in a lock-and-key fashion. Mannose-sensitive adhesins (usually type 1 fimbriae) are present on essentially all E coli. They contribute to colonization (eg, bladder, gut, mouth, vagina) and possibly pathogenesis of infection; however, they also attach to polymorphonuclear leukocytes (PMN), leading to bacterial clearance. Mannose-resistant adhesins permit the bacteria to attach to epithelial cells, thereby resisting the cleansing action of urine flow and bladder emptying. They also allow the bacteria to remain in close proximity to the epithelial cell, enhancing the activity of other VFs.

The P fimbriae family of adhesins are epidemiologically associated with prostatitis, pyelonephritis (70-90% of strains), and sepsis. This same family of adhesins in associated with less than 20% of ABU strains. The AFA/Dr family is associated with diarrhea, UTI, and particularly pyelonephritis in pregnancy. The S/F1C family is associated with neonatal meningitis and UTI. Siderophores are involved iron uptake, an essential element for bacteria, and possibly adhesion.Protectins include lipopolysaccharide (LPS) coatings (resist phagocytosis), Tra T and Iss (both resist action of complement), and Omp T (cleave host defense proteins, such as immunoglobulins).

Toxins, including alpha hemolysin, cytotoxic necrotizing factor-1, cytolethal distending toxin, and secreted autotransporter toxin, affect various host cell functions; LPS shed from a membrane or released by bacterial lysis leads to cytokine release. No single VF is sufficient or necessary to promote pathogenesis. It seems that a multiple VFs are necessary to ensure pathogenesis, although adhesins play an important role.

Bacterial strains producing ABU may provide, in some instances (controversial), a measure of protection against symptomatic infections from UPEC and other organisms; but, it may also cause increased morbidity and mortality. Once bacteriuria is established, these strains appear to stop producing adhesins, allowing them to survive and persist without producing an inflammatory reaction. The frequency of ABU in preschool girls is less than 2%; in pregnant women, 2-9.5%; in women aged 65-80 years, 18-43%; in men aged 65-80 years, 1.5-15.3%; in women older than 80 years, 18-43%; and in men older than 80 years, 5.4-21%. There is considerable morbidity associated with ABU in pregnancy, renal transplantation, and genitourinary surgery (see Table 1).

Table 1. Asymptomatic Bacteriuria: Incidence, Morbidity, Screening, and Treatment¹

As noted above, UPEC account for most infections in uncomplicated pyelonephritis and a significant portion to most infections in complicated pyelonephritis. Other microorganisms commonly isolated are Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus mirabilis, enterococci, Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter species. This is the same spectrum of organisms cultured with UTIs. In 10-15% of symptomatic UTI cases, bacteria are not cultured using routine methods, although they typically respond to antibiotic therapy. In some UTI cases, using selective media, Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum have been cultured. These UTI data cannot be extended to acute pyelonephritis, but they do illustrate the difficulties in isolating the causative organism.

Evidence suggests that the pathogenesis of pyelonephritis takes a 2-step path. First, UPEC attaches to the epithelium and triggers an inflammatory response involving at least 2 receptors, glycosphingolipid (GSL) and TOLL-like receptor 4 (TLR4). In the mouse model, GSL is the primary receptor and TLR4 is recruited and is an important receptor for the release of chemokines. When TLR4 is genetically absent, an asymptomatic carrier state develops in the infected mice. Second, as a result of the inflammatory response, chemokines, such as interleukin-8 (IL-8), chemotactic for PMNs, are released and attach to the neutrophil-activating chemokine receptor 1 (CXCR1), allowing PMNs to cross the epithelial barrier into the urine. In children prone to pyelonephritis, for example, CXCR1 expression has been shown to be significantly lower than in control subjects.

Several other host factors mitigate against symptomatic UTI. Phagocytosis of bacteria in urine is maximized at pH 6.5-7.5 and osmolality of 485 mosM; values deviating from these values lead to significantly reduced or absent phagocytosis. Other important factors are the flushing action of urine flow in the ureter and bladder, the inhibiting of attachment of type 1 fimbriae E coli to uroepithelial cells by tubular cell–secreted Tamm-Horsfall protein, and the inhibiting of attachment by some surface mucopolysaccharides on the uroepithelial cells.

When a UTI or pyelonephritis becomes complicated (complicated UTI), host defenses are compromised, thereby increasing the likelihood of infection. The definition of a complicated UTI is an infection of the urinary tract involving urinary tract structural abnormalities, urinary tract functional abnormalities, metabolic abnormalities predisposing to UTIs, unusual pathogens, recent antibiotic use, recent urinary tract instrumentation, or a combination of these such that the efficacy of antibiotics is reduced. These abnormalities include but are not limited to obstruction (congenital or acquired), stents, vesicoureteral reflux, incomplete bladder emptying, use of spermicide, diabetes mellitus, atrophic vaginal mucosa, prostatitis, immunodeficiency (congenital or acquired), unusual organisms (eg, Mycoplasma, Pseudomonas), urea-splitting organisms (eg, Proteus, sometimes E coli, Klebsiella, Pseudomonas, Staphylococcus), medullary scars, and pregnancy.

Obstruction is the most important factor. It negates the flushing effect of urine flow; allows urine to pool (urinary stasis), providing bacteria a medium in which to multiply; and changes intrarenal blood flow, affecting neutrophil delivery. Intrinsic obstruction occurs with bladder outlet obstruction, cystocele, fungus ball, papillary necrosis, stricture, and urinary stone. The probability of stone passage decreases while the probability of obstruction increases with increasing size of the stone. Nonetheless, stones as small as 2 mm have resulted in obstruction, while 8 mm stones have occasionally passed spontaneously. Extrinsic obstruction occurs with chronic constipation (particularly in children), prostatic swelling/mass (eg, hypertrophy, infection, cancer), and retroperitoneal mass.

Incomplete bladder emptying may be medication related (eg, anticholinergics). Spermicide nonoxynol-9 inhibits the growth of lactobacilli, which produce hydrogen peroxide. Frequent sexual intercourse causes local mechanical trauma to the urethra in both partners. Diabetes mellitus produces autonomic bladder neuropathy, glucosuria, leukocyte dysfunction, microangiopathy, and nephrosclerosis; additionally, it leads to recurrent bladder instrumentation secondary to the neuropathy. Atrophic vaginal mucosa in postmenopausal women predisposes to the colonization of urinary tract pathogens and UTIs due to the higher pH (5.5 vs 3.8) and the absence of lactobacilli. Bacterial prostatitis (acute or chronic) produces bacteriuria, while nonbacterial prostatitis and pelviperineal pain syndrome (prostadynia) do not.

Pseudomonas aeruginosa has several mechanisms that promote adherence, including alginate, other membrane proteins, pili, and surface-associated exoenzyme S urea-splitting organisms produce urease, which hydrolyzes urea (urea-splitting), yielding ammonia, bicarbonate, and carbonate, leading to a more alkaline urine, allowing crystal formation (staghorn calculus) from the supersaturation of carbonate apatite and struvite. Staghorn calculi continue to grow in size, leading to infection, obstruction, or both.

Complications of obstruction with superimposed infection include hydronephrosis, pyonephrosis, urosepsis, and xanthogranulomatous pyelonephritis (XGP). Additionally, the organisms can sequester in the struvite stones protected from the host’s immune system. Proteus species are the most common urea-splitting organisms; however, E coli, Klebsiella, Pseudomonas, and Staphylococcus can produce urease; therefore, they sometimes are also involved in staghorn calculus formation.

Pregnancy (hormonal and mechanical changes) predisposes a woman to upper urinary traction infections. Hydroureter of pregnancy, secondary to both hormonal and mechanical factors, is manifested as dilatation of the renal pelvis and ureters (left > right) with the ureters containing up to 200 mL urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis. Complicated UTI can result from one or more diverse factors.

Although there are many instances when more than one factor is involved, in any given episode of acute pyelonephritis, the presence of any one of these factors, as described above, should raise the clinician’s index of suspicion.

Occult upper urinary tract infections (pyelonephritis) occur in 15-50% (or more) of all UTIs, based on several studies on localization of organisms within the urinary tract. If the host is healthy, particularly young, premenopausal women, without any of the complicating factors listed above, then the occult pyelonephritis can be considered an uncomplicated infection. However, if the host is male, elderly, or a child, or if the host has had symptoms for more than 7 days, then the infection should be considered complicated until proven otherwise.

Acute pyelonephritis usually occurs secondary to bacteria ascending from the lower urinary tract. Hematogenous spread to the kidney can occur. Sources for gram-positive organisms, such as Staphylococcus, are intravenous drug abuse and endocarditis. Hematogenous spread to the kidney by gram-negative organisms appears less likely based on the observation that experimental pyelonephritis is difficult to reproduce by intravenous introduction of gram-negative bacilli, unless an underlying problem, such as an obstruction, exists. Little or no evidence supports lymphatic spread of uropathogens to the kidney.

Frequency:

·                     In the US: There are at least 250,000 cases of diagnosed pyelonephritis in the United States annually (1995 estimate) with 192,000 admissions (1997 National Inpatient Sample database). Lower UTIs predispose to pyelonephritis.

From 1988-1994, there were an estimated 12.7 million UTIs annually in women according to the National Health and Nutrition Examination Survey III. In men, the estimated incidence for the same period was 2 million UTIs. Several studies suggest that 15-50% of these infections are occult pyelonephritis, but these infections may be considered uncomplicated if the host is healthy, outside the extremes of age, and without any complicating factors. If complicating factors are present, then the presence of pyelonephritis must be considered, even in the absence of typical signs and symptoms thereof.

Acute pyelonephritis develops in 20-30% of pregnant women with untreated ABU (2-9.5%), most often during the late second and early third trimesters.

The incidence of pyelonephritis in infants and children is difficult to ascertain because of the infrequency of typical symptoms, as is the case with non-upper urinary tract infections. In children 2 years and younger, the most common symptoms of UTI are failure to thrive, feeding difficulty, fever, and vomiting. In children, up to 25% of patients with UTI and no signs or symptoms of pyelonephritis do have bacteria demonstrable in the upper tract.

Mortality/Morbidity: Pyelonephritis causes considerable morbidity, but these data can only be extrapolated from the morbidity data for acute lower UTIs. Specifically, acute cystitis in women produces approximately 6.1 days with symptoms, 2.4 days of restricted activity, 1.2 days that the patient is unable to work or attend class, and 0.4 days bed-ridden.

Uncomplicated pyelonephritis is not a fatal disease in the antibiotic era. Pyelonephritis becomes a potentially fatal disease when secondary conditions develop, such as emphysematous pyelonephritis (20-80% mortality rate), perinephric abscess (20-50% mortality rate), or one of the sepsis syndromes (>25% overall mortality rate). The genitourinary (GU) system is the source of severe sepsis in 9.1% of all cases annually (approximately 750,000). The mortality for these GU-related cases is 16.1%. Overall severe sepsis mortality significantly increases with chronic renal disease (36.7%), acute renal dysfunction (38.2%), and age older than 64 years (25-42% with progressively increasing age to >85 y). In the age range of 0-4 years, the mortality is 5%; for ages 5-50 years, it is less than 3%. Severe sepsis, in general, treated with early goal-directed therapy has been shown to reduce in-hospital mortality from 46.5% to 30.5% (see Treatment).

Rarely, acute pyelonephritis can cause acute renal failure (ARF) in children, healthy adults, and pregnant women. When this occurs, characteristically, there is a slower recovery compared to other causes of ARF. In most instances, other factors are thought to contribute to the ARF, that is, medications, hypovolemia, obstruction, or sepsis.

In women, mortality is increased in those older than 65 years; it is also increased with septic shock, bedridden status, and immunosuppression. Morbidity (prolonged hospital stay) is increased with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter.

In men, mortality is increased in those older than 65 years; it is also increased with septic shock, bedridden status, and recent use of antibiotics (within 1 mo). Morbidity (prolonged hospital stay) is increased in those older than 65 years and also with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter.

In children, renal scarring can be detected in 6-15% after a febrile UTI. Of these patients, almost all males and some females have demonstrable renal scarring and a globally small kidney with smooth renal outlines in infancy, usually associated with VUR, and is thought to be congenital. Most females do not have demonstrable scarring on initial imaging in infancy, but they subsequently develop it. Patients with scarring are at risk for hypertension and renal insufficiency. Factors that increase this risk are delay in treatment of UTIs/pyelonephritis, recurrent UTIs, urinary obstruction, and VUR.

Acute pyelonephritis (single episode; first UTI ever in one half of cases) in an adult woman leads to renal scarring in 46%, as demonstrated by Tc99m-labeled dimercaptosuccinic acid scanning 10 years later. Subsequent UTIs do not appear to affect the risk of future scarring.

Acute pyelonephritis during pregnancy leads to acute renal dysfunction (creatinine, 1.2) in 2% of cases (20-25% in the past), acute renal failure in 0.03% of cases, acute respiratory distress syndrome (bilateral chest x-ray infiltrates and hypoxemia without pulmonary hypertension) in 1-8% of cases, low birth weight (<2500 g) in 7% of cases, preterm delivery (<37 wk gestation) in 5% of cases (6-50% in the past), recurrence prior to delivery in 18-20% of cases, and sepsis (positive blood cultures) in 17% of cases. Renal scarring has been demonstrated to be 4 times more likely after pyelonephritis in pregnant women than in nonpregnant women.

Acute renal transplant pyelonephritis occurring in the first 3 months after transplant has a significant association with graft loss (>40%) by 96 months as compared to all renal transplant cases with or without the occurrence of pyelonephritis at any time after the transplant up to 96 months (25-30%).

Race: No racial predilection of pyelonephritis has been demonstrated.

Sex:

·                     Pyelonephritis is significantly more common in females than in males. This separatioarrows considerably with increasing age, especially in patients aged 65 years and older. Quantitative information regarding bacteriuria and UTI reflects this observation about pyelonephritis

·                     revalence rate of bacteriuria in young nonpregnant women is 1-3%. The prevalence rate in adult men is less than or equal to 0.1%. After age 65 years, the prevalence rates for women and men are 20% and 10%, respectively. Approximately 10-30% of women develop a symptomatic UTI at some point in their lives

History:

·                     Patients may present with minimal or severe symptoms. Symptoms usually develop over hours or over the course of a day. Infrequently, symptoms develop over days and may even be present for a few weeks before a patient presents for evaluation.

·                     Symptoms of lower UTI may or may not be present to varying degrees.

o         Internal dysuria usually refers to the urinary tract. External dysuria most commonly refers to the vagina.

o         Symptoms may include urinary frequency, hesitancy, lower abdominal pain, and urgency.

o         Gross hematuria (hemorrhagic cystitis) is present in 30-40% of female cases, most often young adults. It may occur in males but is unusual and a more serious cause must be considered.

o         The description of suprapubic symptoms varies and may include discomfort, heaviness, pain, or pressure.

·                     Symptoms of acute pyelonephritis may be present to varying degrees.

o         Severity of pain may be mild, moderate, or severe. Flank pain may be unilateral or sometimes bilateral. Discomfort or pain may be present in the back (lower or middle) and/or the suprapubic area. Upper abdominal pain is unusual, and radiation of pain to the groin is suggestive of a ureteral stone.

o         Fever is not always present. When present, it is not unusual for the temperature to exceed 103،مF (39.4،مC).

o         The patient may demonstrate rigor, and chills may be present in the absence of demonstrated fever.

o         Malaise and weakness may also be present.

o         Gastrointestinal symptoms vary. Anorexia is common. Nausea and vomiting vary in frequency and intensity from absent to severe. Diarrhea occurs infrequently.

Physical:

·                     Vital signs

o         There may or may not be a fever. The temperature may be greater than 103،مF (39.4،مC), or it may be subnormal in patients with associated sepsis.

o         Tachycardia may or may not be present, depending on associated fever, dehydration, and sepsis.

o         Blood pressure is usually within the reference range, unless the patient has underlying hypertension; in cases of underlying hypertension, the pressure may be elevated above the patient’s baseline. A systolic blood pressure less than 90 mm Hg suggests shock secondary to sepsis or perinephric abscess.

·                     Appearance

o         The patient’s appearance is variable. Most commonly, the patient is uncomfortable or appears ill.

o         Patients usually do not have a toxic appearance unless an underlying problem, such as sepsis, perinephric abscess, or significant dehydration, is present.

·                     Abdominal examination

o         Suprapubic tenderness usually ranges from mild to moderate without rebound. Abdominal tenderness other than in the suprapubic area suggests another diagnosis. Usually, abdominal rebound, rigidity, or guarding is not found.

o         Bowel sounds are often normoactive.

o         Flank or costovertebral angle (CVA) tenderness is most commonly unilateral over the involved kidney, although bilateral discomfort may be present. Discomfort varies from absent to severe. This is usually not subtle and may be elicited with mild or moderately firm palpation.

·                     Pelvic examination

o         A pelvic examination should be performed. Tenderness of the cervix, uterus, and adnexa should be absent. Any positive finding suggests an additional or alternative diagnosis.

o         If any doubt remains as to the diagnosis, if any signs or symptoms of urethritis or vaginitis are present, or if a history of dyspareunia is present, a gynecologic cause of the symptoms should be pursued.

Causes: When considering the cause of acute pyelonephritis, there are 3 considerations.

First, what are the uropathogens that are typically cultured and at what frequency (see Table 2)?

Second, UTIs that are complicated indicate a high risk for upper urinary tract infection or occult pyelonephritis in the absence of signs and symptoms typical of acute pyelonephritis. A complicated UTI is defined as a UTI in the presence of at least one of several factors that will reduce the efficacy of antimicrobial therapy, leading to failure of therapy (eg, progression to overt pyelonephritis, sepsis, renal failure, abscess formation, worsening clinical condition, resistant organism), relapse, or persistence of infection (see Table 3). Any patient with a complicated UTI should be referred, if possible, to a nephrologist, a urologist, an infectious disease specialist, or another physician trained to managed complicated UTIs. The patient will require ongoing management, including repeat cultures, metabolic studies, and appropriate imaging studies.

The third consideration in the management of acute pyelonephritis is what organisms are involved in complicated UTIs and what are their antimicrobial sensitivities (see Table 2).

Table 2. Bacterial Etiology of Urinary Tract Infections ¹

Table 3. Classification of Factors in Complicated UTI

Lab Studies:

·                     In the outpatient setting, pyelonephritis is usually suggested based on the history and physical examination and is supported by urinalysis results, which should include microscopic analysis. Other lab studies are used to evaluate for complicating conditions and to assist in determining if the patient should be admitted.

·                     Most easily diagnosed cases occur in women, both pregnant and nonpregnant. Men, patients at the extremes of age, patients harboring subclinical pyelonephritis, and patients who are hospitalized may present with an insidious onset. This section presents information relative to the perspective of pyelonephritis versus UTIs, in general.

o         Urinalysis

§           Gross hematuria occurs infrequently with pyelonephritis and is more common with lower UTI (hemorrhagic cystitis). When present, the differential should include calculi, cancer, glomerulonephritis, tuberculosis, trauma, and vasculitis.

§           Pyuria is defined as more than 5-10 WBCs per high-power field (hpf) on a specimen spun at 2000 rpm for 5 minutes. Almost all patients with pyelonephritis have significant pyuria (>20 WBCs/hpf), although the numbers may be smaller, particularly in those with subacute pyelonephritis (pictures1-2).

Picture 1 Leukocyturia

Picture 2 Leukocyte cast

§           The dipstick leukocyte esterase test (LET) helps screen for pyuria. LET results have a sensitivity of 75-96% and a specificity of 94-98% for detecting more than 10 WBC/hpf.

§           The nitrite production test (NPT) for bacteriuria has 92-100% sensitivity and 35-85% specificity and may be falsely negative in the presence of diuretic use, low dietary nitrate, or organisms that do not produce nitrate reductase (eg, Enterococcus, Pseudomonas, Staphylococcus). Combined, the LET-NPT has a sensitivity of 79.2% and a specificity of 81%, which is too low for it to be used as the only screening study for bacteriuria.

§           Microscopic examination may reveal hematuria (picture 3), but other causes should be considered, particularly calculi. This is especially true if the patient does not respond to therapy. White cell casts are suggestive of pyelonephritis; however, centrifuge speeds (>2000 rpm) used for urinalysis sediment preparation often fracture them and lead to their absence in the sediment.

Picture 3 Erythrocyteuria

§           Proteinuria is expected (up to 2 g/d). When it exceeds 3 g/d, glomerulonephritis should be considered.

§           The presence of a single bacterium in an unspun urine specimen by oil-immersion microscopic examination is equivalent to at least 105 organisms. Bacteria are identified much more easily on a stained versus an unstained specimen/ dfcteral cast are specific for PN (.(pictures 4-5).

Picture 4 Bacterial cast

Picture 5 Yeast cast

o         Urine culture

§           Urine culture is indicated in any patient with pyelonephritis, whether treated in an inpatient or an outpatient setting, because of the possibility of antibiotic resistance.

§           Specimens can be collected by clean catch, catheter, or suprapubic puncture (rarely performed or indicated).

o         Blood cultures

§           Blood cultures are indicated in any patient who is being admitted or who has already been admitted.

§           Approximately 12-20% are positive for infection. Bacteremia has not been associated with a poor outcome unless sepsis or another significant comorbidity is present.

Imaging Studies:

·                     Imaging studies are rarely indicated for the diagnosis of acute pyelonephritis in the adult who presents with typical signs and symptoms. Imaging may be warranted if the presentation is atypical or confusing. It is also warranted if the patient deteriorates or does not respond to therapy, as illustrated by the following scenarios, in which the important considerations are nephrolithiasis, obstructive uropathy, and perinephric abscess:

o         The patient has a fever or positive blood culture results that persist for longer than 48 hours.

o         The patient’s condition suddenly worsens.

o         Toxicity persists for longer than 72 hours.

o         The patient has a complicated UTI

·                     The purpose is to evaluate immediately for an organ- or life-threatening complication. Contrast-enhanced helical/spiral computed tomography scan (CECT) is the imaging study of choice when there is suspicion for the development of a complication of acute pyelonephritis, both in adults and in children. A recent study demonstrated in an experimental model that CECT, magnetic resonance imaging (MRI), and dimercaptosuccinic acid 99m-technetium (99mTc-DMSA) scintigraphy were equivalent in their sensitivity and reliability to detect acute pyelonephritis. Clinical experience is still limited with MRI in this setting, and there are the issues of cost and availability. 99mTc-DMSA scintigraphy is used more often in children to image the urinary tract to lessen radiation exposure.

·                     Imaging early in the presentation of acute pyelonephritis may be more useful than previously thought. In one recent study, 16% of cases admitted for acute pyelonephritis were found to have new and clinically significant abnormalities on renal imaging with ultrasound (US) or computed tomography (CT) at the time of admission. Independent of this observation, there are certain patients who warrant imaging at the time of admission, including those with AIDS, poorly controlled diabetes, an organ transplant (particularly renal), another immunocompromised state, sepsis syndrome, or septic shock, because of the increased risk of a complication.

·                     The following studies have been used in the diagnosis of acute pyelonephritis:

o         As mentioned above, CECT is the imaging study of choice in adults. It is more sensitive than ultrasound and intravenous pyelogram (25% sensitivity), and it can more readily identify alterations in renal parenchymal perfusion, alterations in contrast excretion, perinephric fluid, and nonrenal disease.

o         Noncontrast helical/spiral CT findings may be normal in acute pyelonephritis with mild parenchymal involvement, but the findings are usually positive when the involvement is moderated or severe. It is the standard study for demonstrating gas-forming infections, hemorrhage, inflammatory masses, and obstruction. It also has 97% accuracy in identifying renal stones.

o         US can sometimes detect acute pyelonephritis, but a negative study does not exclude the possibility. Power Doppler US is superior to color Doppler US in the detection of pyelonephritis but remains inferior to CECT. It is useful in screening for urinary obstruction in children admitted for febrile illnesses. It can help differentiate solid and cystic structures, detect hydronephrosis and stones, and measure blood flow.

o         99mTc-DMSA scintigraphy is almost as sensitive clinically as CECT in detecting focal renal abnormalities during acute pyelonephritis in adults. 99mTc-DMSA scintigraphy is not used much in adults because the focal abnormalities are not specific; rather, they are consistent with abscess, cyst, infarct, pyelonephritis, or tumor. Additionally, it is much less available in the acute setting than CECT. In children, it is the preferred study to lessen radiation exposure from CT scans. It is excellent for helping detect inflammation, scarring, and the distribution of renal function between kidneys. DMSA is a radiotracer that localizes to the renal cortex.

o         Experience with MRI in evaluating acute pyelonephritis is limited but growing. It is a suitable alternative in the patient with iodinated-dye allergy. It can evaluate the genitourinary system prenatally, renal infection/masses/vasculature, and urinary obstruction, using gadolinium-enhanced MRI, a nonnephrotoxic dye study.

·                     CT urography and MR urography are evolving modalities that allow evaluation of the renal parenchyma and urothelium, according to one comprehensive study. Currently used in the evaluation of hematuria, these modalities will become more applicable to the study of other urological problems.

·                     Imaging may be required to make the diagnosis in infants and children in whom pyelonephritis presents insidiously.

·                     Imaging studies in conjunction with urological procedures, including cystoscopy and excretory urography, may be used during a follow-up examination to evaluate for urinary tract abnormalities that can predispose the patient to infection.

·                     Patients with complicated UTIs should be considered for follow-up imaging to assess the urinary tract.

Procedures:

·                     Urine specimens obtained for examination and culture should approximate the urine contained in the bladder as closely as possible. The 3 procedures for collecting such a urine specimen are clean catch, urethral catheterization, and suprapubic needle aspiration.

o         Clean catch

§           When properly collected, a clean-catch specimen adequately reflects the microbiology of the urine in the bladder.

§           This technique can be performed by ambulatory females aged 6 years and older who do not have any limiting physical handicap. The presence of a large number of epithelial cells after microscopic examination suggests that the specimen is not a true clean catch and is rendered unreliable for culture because of contamination with vaginal contents. Importantly, the patient should wash only the area where urine is passed, wash front to back, hold the cup by the outside, and keep the labia spread while collecting the urine. This is to ensure that the urine goes into the cup without touching the labia.

§           This technique can also be performed by ambulatory males aged 6 years and older who do not have any limiting physical handicap. Specimens are usually reliable. Importantly, the patient should clean the head of the penis, retract the foreskin (in uncircumcised males), maintain a good stream, and hold the cup by the outside. In the presence of epispadias or hypospadias, care must be taken to maintain a good stream while collecting the specimen.

o         Urethral catheterization

§           This engenders a small risk of introducing bacteria into the sterile bladder environment.

§           Several indications justify this risk when a urine culture is necessary, including (1) inability or difficulty voiding urine even with hydration, (2) marked obesity or redundant labia in females, (3) ill patients who cannot reliably perform the procedure, (4) performance of a urological procedure during which a specimen can be collected, and (5) children aged 2-6 years (unless a clinician-assisted clean-catch specimen cannot be collected).

o         Suprapubic needle aspiration

§           This technique is rarely used.

§           It is indicated when (1) another alternative is lacking, (2) the need exists to exclude contamination from other methods of collection, (3) the need exists to verify the presence of an infecting organism that is otherwise considered a contaminant, and (4) the need exists to verify infection in infants who have a positive culture result from a specimen obtained from a strap-on device.

Histologic Findings: Features of acute pyelonephritis include suppurative necrosis or abscess formation within the renal substance. Features of chronic pyelonephritis (chronic interstitial nephritis) include papillary atrophy and blunting, interstitial fibrosis with inflammatory infiltrate (ie, lymphocytes, plasma cells, neutrophils [occasional]), tubules (ie, dilated with possible colloid casts, contracted with atrophy of epithelium), and concentric fibrosis about the parietal layer of the Bowman capsule.

Medical Care:

·                     Supportive care

o         Rest

o         Antipyretics as needed

o         Oral or parenteral pain medications as needed

o         Oral or parenteral antiemetics as needed

o         Urinary tract analgesics to relieve dysuria (up to 3 d)

o         Intravenous or oral fluids to maintain hydration status

·                     Reasons for hospital admission

o         Cannot tolerate oral intake

o         Unstable social situation (eg, possibility of poor compliance or poor follow-up)

o         Unstable vital signs

o         Severe signs and symptoms

o         Pregnancy

o         Comorbid disorders that increase the complexity of management or the complication rate (eg, diabetes mellitus, chronic lung disease, congenital or acquired immunodeficiency syndrome)

·                     Antibiotic selection

o         Antibiotic selection is typically empirical, because the results of blood or urine cultures are rarely available by the time a decision must be made.

o         Initial selection should be guided by local antibiotic resistance patterns. Urine cultures should be checked in 48 hours to determine antibiotic efficacy.

o         When using an oral-only regimen, the initial dose should be administered at the time of the evaluation.

o         The etiology of community-acquired infections is usually E coli or other Enterobacteriaceae. Infections usually involve women aged 18-50 years and, infrequently, men of the same age. Accepted outpatient regimens include the following:

§           Administer intravenous ceftriaxone and oral fluoroquinolone to complete a 14-day course.

§           Administer intramuscular ceftriaxone every 24 hours for 1-2 doses and oral fluoroquinolone to complete a 14-day course.

§           Administer intravenous gentamicin (24-hour dose) and oral fluoroquinolone to complete a 14-day course.

§           Administer an intravenous fluoroquinolone and oral fluoroquinolone to complete a 14-day course.

§           Prescribe oral fluoroquinolone for 14 days.

§           Prescribe amoxicillin-clavulanate potassium for 14 days.

§           Prescribe trimethoprim-sulfamethoxazole double strength for 14 days. Use only if the organism is known to be sensitive.

o         Research suggests that the fluoroquinolone course can be shortened to a 7-day course, instead of the usual 14 days, in healthy, young women with uncomplicated pyelonephritis.

o         Some clinicians believe that initiating therapy with an intravenous or intramuscular dose of medication reduces the risk of therapeutic failure; other clinicians believe that an oral course is sufficient. Data exist to support both assertions. One prospective study supports using oral therapy alone in patients who can tolerate oral intake, lack signs of sepsis, and do not show signs of obstruction or renal suppuration on urinary tract ultrasonography findings. Another study (prospective, randomized, unblinded) in a controlled, hospital setting compared oral versus intravenous ciprofloxacin for the initial management of severe pyelonephritis. Both regimens were equally efficacious, suggesting that in the outpatient setting, it might be possible to initiate treatment with oral dosing; however, more research is needed.

o         If enterococci are suggested based on Gram stain results, then ampicillin or vancomycin can replace fluoroquinolone. If any doubt exists as to the diagnosis, then coverage of both Enterobacteriaceae and enterococci is acceptable.

o         Enterococci have a higher incidence in hospitalized and other institutionalized patients. Ampicillin or amoxicillin should be included in the regimen. If the patient is allergic to penicillin, then vancomycin should be substituted.

o         Admit patients who appear toxic, if they are not already hospitalized considered. If complicated acute pyelonephritis is suggested, use one of the following regimens:

§           Treat patients parenterally until they improve clinically. Complete the course of therapy with an oral agent selected based on culture results.

§           Ampicillin and an aminoglycoside are appropriate. If the patient is allergic to penicillin, substitute vancomycin.

§           Ceftriaxone is an option.

§           Fluoroquinolone and vancomycin are options if enterococci are a consideration.

Surgical Care: Surgical intervention may be emergent if it occurs during active infection, or it may be elective if it occurs after recovery from infection. Emergent surgery is performed to preserve kidney function or to save the life of the patient. Elective surgical intervention reduces or prevents future morbidity.

Elective surgery is performed to reverse conditions that predispose the kidney to recurrent infections and renal damage. These conditions include congenital anomalies, fistulae involving the urogenital tract, prostatic hypertrophy, renal calculi, and vesicoureteral reflux.

An emergent surgical condition may be indicated by a patient with fever or positive blood culture results persisting longer than 48 hours, a patient with a deteriorating condition, or a patient who appears toxic for longer than 72 hours. The etiology may not be immediately evident, but an unexpected change in the clinical picture warrants immediate evaluation for potential surgical intervention. The following is a list of conditions that are in the differential diagnosis of surgical conditions relative to patients presenting with acute pyelonephritis who do not respond to standard therapy.

·                     Renal cortical abscess (renal carbuncle)

o         This is an uncommon condition that is usually caused by the hematogenous spread of S aureus. It occurs 3 times more commonly in men than in women. Microabscesses develop in the cortex and coalesce to form a circumscribed abscess that may or may not communicate with the collecting system. This process takes days to months. Patient presentation includes fever, chills, back pain, abdominal pain, flank mass, and urinary symptoms if the collecting system is involved.

o         Blood culture results are usually negative. Diagnosis is best made using CT scan, although ultrasonography can be useful in distinguishing among an abscess, a cyst, and a tumor. Treatment includes parenteral antibiotics for 10-14 days, incision and drainage, enucleation of the carbuncle, nephrectomy, or any combination of these therapies. If parenteral antibiotic therapy is successful, oral therapy is instituted for an additional 2-4 weeks.

·                     Renal corticomedullary abscess

o         This condition is usually associated with a urinary tract abnormality such as vesicoureteral reflux or obstruction. It is commonly caused by Enterobacteriaceae.

o         The pathology represents a spectrum of disease, as follows:

§           Acute focal bacterial nephritis (eg, acute lobar nephroma, focal pyelonephritis) that affects a single renal lobe with interstitial inflammation represented by marked polymorphonuclear leukocytes

§           Acute multifocal bacterial nephritis with a similar process throughout the kidney that produces liquefaction and abscess formation

§           XGP with chronic parenchymal infection, granulomatous tissue, and perirenal fibrosis Emphysematous pyelonephritis with severe, necrotizing infection (discussed separately below)

o         Men and women are equally affected by these conditions, although XGP affects women more often than men. The presentation of the first 3 described entities includes fever, chills, abdominal pain, flank pain, nausea, vomiting, urinary symptoms (may be absent), flank mass (60%), hepatomegaly (30%), draining sinus in the flank (rare), leukocytosis, bacteriuria/pyuria (normal urine in 30%), and bacteremia (acute forms of disease).

o         CT scan is the preferred imaging method. Treatment includes parenteral antibiotics for 48 hours (usually successful), incision and drainage, and nephrectomy. If antibiotic therapy is successful, oral therapy is instituted for an additional 2 weeks.

·                     Emphysematous pyelonephritis

o         Emphysematous pyelonephritis is a severe, necrotizing form of acute multifocal bacterial nephritis with extension of the infection through the renal capsule. This leads to the presence of gas within the kidney substance and in the perinephric space. Persons with diabetes (with or without obstruction) account for 85-100% of cases, although some cases have occurred in patients who had obstruction without diabetes. Females outnumber males (2-6:1).

o         Emphysematous pyelonephritis occurs on the left side in approximately two thirds of cases. The etiology is usually Enterobacteriaceae (E coli, 60%), with some reported cases of Streptococcus species and Candida species. A triad of diabetes, obstruction, and remote or recent pyelonephritis should raise clinical suspicion. Patient presentation includes fever, chills, abdominal pain, nausea, vomiting, flank pain, flank mass (50%), crepitation (over thigh or flank), urinary symptoms, and pyuria.

o         CT scan is the preferred imaging method to use in the diagnosis and to help localize the gas pattern to the collecting system, intrarenal, or perinephric. Plain radiographs (85%) and ultrasonography can help detect renal emphysema but do not help in localization. Considerable mortality is associated with this entity. When gas is within the kidney only, the mortality rate is 60% (antibiotic therapy with surgical drainage); when gas extends to the perinephric space, the mortality rate is 80% (antibiotic therapy only); wheephrectomy is performed, the mortality rate is 20%.

·                     Perinephric abscess

o         The suppurative material of the abscess is located between the renal capsule and the surrounding renal fascia. The material is secondary to chronic or recurrent pyelonephritis, rupture or extension of a suppurative process from within the kidney, or dissemination (blood, lymph) or direct extension from other sites of infection. Although it is usually confined to the perinephric space, it may extend to the colon, flank, groin, lung (empyema, nephrobronchial fistula), paracervical area, peritoneal cavity, psoas muscle, skin surface, or subphrenic space.

o         Development is insidious. Patient presentation includes fever, chills, unilateral flank pain (70%), dysuria (40%), nausea, vomiting, weight loss (25%), flank tenderness, CVA tenderness, abdominal tenderness (60%), referred pain (ie, hip, thigh, or knee), flank or abdominal mass (<50%), pyuria (70%), sterile urine (40%), and bacteremia (40%). One third of patients are diagnosed upon admission; another third are diagnosed at autopsy. This diagnosis is not usually readily apparent; a high index of clinical awareness is necessary.

o         CT scan is the preferred diagnostic study. Ultrasound findings may be falsely negative in 36% cases. MRI may help define extension better than CT scan. The mortality rate is 20-50%, but this rate can be decreased with early recognition, surgical drainage, and antimicrobial therapy (not adequate alone). Antibiotics should include an aminoglycoside and an antistaphylococcal agent. If Pseudomonas species are considered or demonstrated, an antipseudomonal beta-lactam antibiotic should be added. For enterococci, an aminoglycoside and ampicillin are recommended. Other organisms that have been reported include tuberculosis and fungi. Nephrectomy may be necessary.

·                     Obstructing calculus

o         Obstructing calculi may pass with time, hydration, and analgesia.

o         In the presence of acute infection, they must be removed immediately using cystoscopy or open surgical procedure.

·                     Renal papillary necrosis

o         Most patients with renal papillary necrosis have diabetes. Patient presentation is similar to that for pyelonephritis.

o         The imaging study of choice is retrograde pyelography. Confirmatory evidence is histologic verification of voided medullary tissue, which may occur only at autopsy. Treatment is admission for intravenous antibiotics). If the response is not good, CT-guided drainage or surgical drainage with debridement is indicated.

·                     Xanthogranulomatous pyelonephritis

o         This rare form of pyelonephritis is almost always associated with chronic obstruction (ie, staghorn calculus [75% cases], another calculus, stricture, or tumor). In adults, the female-to-male ratio is 3:1; in children, it is 1.1:1.

o         It is a chronic infection that finally manifests acutely with fever and flank pain or tenderness, and it may be complicated by a flank mass, cutaneous fistula, septic arthritis, or hematochezia if extension has occurred beyond the renal capsule. Kidney function is absent (71%) or poor (25%) in almost all cases. Diagnosis is difficult preoperatively.

o         The imaging study of choice is CT scan. Ultrasound images may suggest the diagnosis in the presence of an enlarged kidney and a staghorn calculus.

o         The treatment of choice is nephrectomy after the patient is stabilized. Staghorn calculus: Infectious stones, urease stones, or triple-phosphate stones composed of magnesium ammonium phosphate or struvite and apatite account for 10-15% of all urinary stones. They develop secondary to the action of urea-splitting organisms) and can grow rapidly and branch out.

o         If left untreated, they will destroy the kidney and may cause the death of the patient. Complications include azotemia, hydropyonephrosis, perinephric abscess, pyelonephritis (severe or end-stage), sepsis, and XGP.

o         The treatment of choice is to remove the whole stone. Fragments left behind remain infected and will grow again.

Consultations: Consultation is indicated if the infection is complicated. Most cases of acute pyelonephritis occur in adult women and are readily managed without consultation. The following are reasons for consulting various subspecialists.

·                     A urologist may be consulted regarding patients with ureteral or urethral obstruction, urinary stones, urogenital abnormality, recurrent pyelonephritis, or for the first episode of pyelonephritis in an infant or child.

·                     A renal specialist may be consulted regarding patients with acute renal failure or advanced chronic renal failure or for neonates or infants.

·                     An infectious diseases specialist may be consulted regarding patients with an unusual or resistant pathogen, those who are immunocompromised, patients with persisting fever (>48 h) or toxicity (>72 h), or patients whose blood culture results are positive beyond 48 hours.

·                     An obstetrician may be consulted for patients who are pregnant.

Diet: A regular diet is permitted as tolerated. Special dietary considerations, such as those associated with diabetes mellitus, should be honored. Hydration status is very important.

·                     If oral intake is not tolerated, intravenous hydration is warranted. Intravenous fluids should include 1 L of 5% dextrose in saline to reverse any existing ketosis, regardless of whether ketones are detected in the urine. Additional intravenous hydration is accomplished with saline.

·                     If admission is not indicated and the patient will be monitored in an outpatient setting, hydration status should be normalized with intravenous fluids; the physician should not assume that the patient can or will accomplish this with oral hydration alone.

·                     When hydrating intravenously, exercise caution regarding conditions that might be adversely affected by improper amounts of fluid, saline, or glucose.

Activity: Rest is essential for recovery. Activity should be minimized. Patients who are treated in an outpatient setting should not return to work for 2 weeks in order to allow time for the infection to be eliminated. This time also allows the patient to recuperate physical strength. This recommendation can be tempered in special circumstances as warranted by the clinician.

Several classes of drugs may be required for the management of pyelonephritis. These pharmaceuticals include antibiotics, analgesics, antipyretics, and antiemetics. Only antibiotics and urinary tract analgesics are specifically addressed. Symptomatic management using analgesics, antipyretics, and antiemetics is accomplished by oral or parenteral means according to the clinical condition of the patient.

Not all antibiotics reported to be effective in the management of acute pyelonephritis are listed in the pharmacological information below because of space limitations. Other effective antibiotics include parenteral penicillins (eg, piperacillin, piperacillin-tazobactam, ticarcillin-clavulanate), third-generation cephalosporins (eg, cefotaxime), oral fluoroquinolones (eg, enoxacin, lomefloxacin, ofloxacin), parenteral fluoroquinolones (eg, lomefloxacin), aminoglycosides (eg, amikacin), monobactams (eg, aztreonam), and carbapenems (eg, imipenem).

Drug Category: Antibiotics — Therapy should cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood or urine culture sensitivity results whenever feasible.

 

 

 

 

 

 

 

 

 

 

Drug Category: Urinary analgesics — Indicated when patient has dysuria to such an extent that it disrupts activities of daily living.

Drug Category: Antibiotics — Indicated for the outpatient management of pyelonephritis.

 

 

 

Further Inpatient Care:

·                     Continue supportive care.

·                     Monitor urine and blood culture results.

·                     Monitor comorbid conditions for deterioration.

·                     Maintain hydration status with intravenous fluids until hydration can be maintained with oral intake.

·                     Maintain intravenous antibiotics until defervescence and significant symptomatic improvement occur. Convert to an oral regimen guided by urine or blood culture results.

Further Outpatient Care:

·                     Continue supportive care by prescribing antiemetics, antipyretics, analgesics, and urinary tract analgesics as needed.

·                     Complete a 14-day course of oral antibiotics. Recent evidence suggests that when treating a young, healthy female, the course of treatment can be shortened to 7 days from 14 days, if the antibiotic being used is a fluoroquinolone. Healthy young males should complete a 14-day course.

·                     Obtain follow-up urine culture results in any patient with a complicated UTI (see Causes), a complicated course, or increased risk of infection.

·                     Urine cultures are generally not indicated in healthy, nonpregnant women with resolved symptoms.

·                     Rest is essential for recovery. Activity should be minimal. The patient should not return to work for 2 weeks in order to allow time for the infection to be eliminated and for the patient to recuperate physical strength. Temper this recommendation depending on the physical condition of the patient and the presence of comorbid conditions.

·                     If the patient is not admitted at the time of diagnosis, follow-up reevaluation is important in 1-2 days to be sure the patient is progressing properly. A good rule based on common sense is that if the managing clinician is concerned that the patient may not respond well to outpatient management but still thinks the patient deserves a trial at home, then the initial follow-up visit should take place in 24 hours. If the clinician thinks that patient will do quite well with outpatient management, the initial follow-up visit can take place in 48 hours.

·                     If the patient thinks that he or she is not progressing well or is getting worse, then the patient should be evaluated emergently for consideration for admission and intravenous antibiotics.

·                     All patients with a complicated UTI should be considered for outpatient follow-up imaging of their urinary tract to evaluate for abnormalities that predispose to further infections.

In/Out Patient Meds:

·                     Antipyretics may be beneficial.

·                     Use oral and parenteral antiemetics as needed. Early in the course of the illness, parenteral medication is ofteecessary to reduce morbidity from symptoms.

·                     Use oral and parenteral analgesics as needed. Early in the course of the illness, parenteral medication is ofteecessary to reduce morbidity from symptoms. Nonsteroidal medications and narcotics are complementary and do not assume that one is better than the other.

·                     Parenteral antibiotics are often initially administered at the time of diagnosis, regardless of whether the patient is admitted or discharged home. Continuing intravenous antibiotics for the admitted patient is essential until defervescence and improvement in the clinical condition warrants changing to oral antibiotics to complete the course. Once the patient is improved, due consideration can be given to discharge and close follow-up care in an outpatient setting.

·                     Urinary tract analgesics may be beneficial if the patient has dysuria to such an extent that it disrupts the activities of daily living.

Transfer:

·                     When patients are treated in an inpatient setting, the facility to which they are admitted should be able to provide an appropriate level of care for pyelonephritis and any comorbid conditions. If the admitting facility is unable to provide an appropriate level of care, the patient should be transferred to a facility that is able to meet that patient’s needs.

Deterrence/Prevention:

·                     Prevention of pyelonephritis involves identifying clinical situations that could lead to pyelonephritis and developing a strategy to decrease that likelihood. These strategies may include a change in contraceptive behavior, administration of prophylactic antibiotics, or early identification and treatment of UTIs. Several such strategies are elaborated below. Failure of these strategies to eliminate infection, recurrence of infection, or relapse (reinfection <14 d after completing an appropriate regimen) indicates the need to refer the patient for systematic evaluation for predispositional anatomic, functional, or structural abnormalities.

·                     Children with recurrent UTIs or urinary tract structural abnormalities require prompt evaluation of urinary tract symptoms and appropriate treatment.

·                     Premenopausal or postmenopausal women with recurrent, uncomplicated UTIs

o         In this population, recurrent UTIs may be defined as 2-2.6 UTIs per year, which occur in approximately 25% of women who develop acute uncomplicated UTIs.

o         Various behavioral and nutritional techniques have been recommended to decrease the recurrence of UTIs in young women. Daily cranberry juice intake has been suggested to be beneficial, but no conclusive evidence has been found. Behavioral techniques, such as postcoital voiding and front-to-back wiping after defecation, have been considered efficacious measures for lessening the risk of UTI; however, in a study of college-aged women, they accorded no benefit. Additionally, oral contraceptive use and tampon use were not associated with UTIs.

o         If the patient is using a diaphragm with spermicide for contraception, another method of contraception should be substituted so that spermicide-associated colonization of the vagina by uropathogens is avoided.

o         If the patient has 3 or more UTIs per year, postcoital or continuous antibiotic therapy is recommended for 6 months, followed by a reevaluation. Postcoital regimens include trimethoprim-sulfamethoxazole at 40 mg/200 mg, cephalexin at 125-250 mg, and nitrofurantoin at 50 mg (effective in pregnancy). Regimens for continuous dosing (daily or 3 times/wk) include trimethoprim-sulfamethoxazole at 40 mg/200 mg, trimethoprim at 100 mg, norfloxacin at 200 mg, nitrofurantoin at 200 mg, and cephalexin at 125-250 mg.

o         If the patient has fewer than 3 UTIs per year, patient-initiated therapy is recommended using standard regimens, such as single-dose therapy or 3-day therapy. Referral for urological evaluation is indicated if the patient is not responding, if the patient has any complicating condition, or if the patient has a relapse.

·                     Catheter-related infections or neurogenic bladder

o         Indwelling catheters have a cumulative incidence rate of bacteriuria of 3-10% per day. Two strategies for reducing bacteriuria and its sequelae are removal of the catheters as soon as possible and keeping the closed system closed. After the indwelling catheter is removed, alternative strategies for emptying the bladder that reduce but do not eliminate the risk of infection are condom catheters, intermittent catheterization (1-3% risk of bacteriuria per catheterization), intraurethral catheters, and suprapubic catheters.

o         Situations in which treatment of asymptomatic bacteriuria are indicated include culture of Serratia marcescens, clearance of an organism responsible for an infection cluster in an institution, and clearance of an organism in a high-risk patient (eg, neutropenic, posttransplantation, pregnant).

·                     Chronic bacterial prostatitis

o         This condition produces recurrent bacteriuria interspersed with prolonged periods without bacteriuria.

o         Treatment involves 2-3 months of a fluoroquinolone that has good prostate penetration. The goal of therapy is to eradicate infection from the prostate.

·                     Renal transplant recipients

o         The frequency of UTIs (35-79%) and the potential morbidity of transplant pyelonephritis are relatively high in this population.

o         Transplant recipients typically receive prophylaxis with trimethoprim-sulfamethoxazole for at least the first 6-12 months following transplantation.

o         The antibiotic chosen may be modified depending on local organism sensitivities.

Complications:

·                     Complications occur more often in patients with diabetes mellitus, chronic renal disease, sickle cell disease, renal transplant (particularly the first 3 mo), AIDS, and other immunocompromised states. Sometimes, determining if the entities listed below are occurring as a complication of pyelonephritis or presenting in the absence of pyelonephritis with signs and symptoms suggestive of pyelonephritis is difficult. The important point is to have a high index of suspicion because they are associated with markedly increased morbidity and mortality.

o         Abscess formation): This may include renal cortical abscess, renal corticomedullary abscess, or perinephric abscess.

o         Emphysematous formation (gas in tissues): This may occur), and recognizing it is critical. Treatment may include nephrectomy.

o         Emphysematous pyelitis (pneumopyonephrosis): This involves gas that is localized to the collecting system. Diabetes mellitus is present in 85-100% of patients. The left kidney is more affected than the right. Presentation is similar to pyelonephritis. On plain radiographs, the gas pattern is noted in the renal pelvis and may be seen in the ureter. The patient should be admitted and treated with intravenous antibiotics). The mortality rate is 20%.

o         Emphysematous cystitis (cystitis emphysematosa): This involves gas that is localized to the bladder secondary to a bladder infection. Gas in the bladder is more frequently related to a fistula between the bladder and the colon or vagina than to a gas-producing infection. As many as 80% of patients are diabetic. Patient presentation is similar to that for pyelonephritis. Plain radiographs may demonstrate gas in the bladder wall or lumen, an air-fluid level in the bladder, or a cobblestone appearance to the bladder wall. CT scan is the study of choice to help localize the gas to the proper organ. Treatment involves intravenous antibiotics () and relief of any outlet obstruction. This condition is not as serious as the other 2 previously described emphysematous conditions.

o         Acute renal failure

o         Chronic renal damage leading to hypertension and renal failure

Prognosis:

·                     In healthy, nonpregnant women with uncomplicated disease, the prognosis is excellent for full recovery and minimal damage to the kidney.

·                     In healthy men without any known complicating conditions, the prognosis is good for full recovery; however, urologic evaluation is recommended to rule out an underlying complicating condition.

·                     In children, the prognosis is good. Importantly, children should undergo a urological evaluation after the first episode to rule out structural abnormalities.

·                     If the patient has a known complicating condition, urological evaluation is indicated to determine the status of the complicating condition and the status of the kidney.

Patient Education:

·                     Patients must take antibiotics as directed and complete the course as prescribed. This minimizes the risk of recurrence and the development of resistant organisms.

·                     Avoidance of dehydration is important for both patient well-being and kidney function. When under stress, men drink only enough liquid to replace two thirds of the loss. When ill, individuals drink less and predispose themselves to dehydration. Unavoidable daily water loss is 1.5 L, of which approximately 500 mL is replaced by the oxidation of carbohydrates. Because patients cannot measure urine specific gravity at home, they should drink enough water or other liquid to produce light-colored urine, almost like water.

Medical/Legal Pitfalls:

·                     Any poor outcome in a patient’s illness could potentially raise a question of liability on the part of the physician managing that patient’s case. Alternatively, in many instances good medical management decisions are made in a timely fashion but the outcome is still poor. Always keep in mind that the natural history of the disease may subvert even the best medical and surgical management possible.

·                     The following are clinical issues in the management of pyelonephritis that are important considerations with the potential for liability, particularly if complications arise or the outcome is poor:

o         For patients with pyelonephritis who have an organ-threatening infection, the follow-up examination is important to be sure that the patient is progressing satisfactorily and that recovery is complete.

o         Patients with diabetes are at increased risk for complications related to pyelonephritis. Failure to diagnose these complications in a timely fashion could predispose the patient to a poor outcome.

o         Pregnant patients with pyelonephritis are at significant risk for premature labor. Timely diagnosis and management has a significant impact on the outcome.

o         Infants and children who have had pyelonephritis should be evaluated for urinary tract abnormalities.

o         Any patient with acute pyelonephritis who deteriorates suddenly or does not respond to conventional therapy may have a complication, resistant organism, or unrecognized comorbidity.

Special Concerns:

·                     Pregnancy issues

o         Physiological changes in the urinary tract predispose pregnant women to an increased risk of UTI and pyelonephritis, which may lead to preterm labor and kidney damage.

o         Hydroureter of pregnancy develops around the seventh week and progresses throughout the remainder of pregnancy; it resolves by 8 weeks postpartum. The ureters may dilate sufficiently to contain 200 mL of urine or more. In addition, the kidneys enlarge and bladder capacity may double. The left kidney is more affected than the right. The prevalence rate of bacteriuria in pregnancy is 2-25%, depending on the study criteria.

o         Symptomatic UTI (1-3% of all pregnancies) leads to premature labor in 20-50% of cases. The recommendation is that all pregnant women have a screening urine culture at 16 weeks’ gestation. If the results are negative for a UTI, no additional cultures are indicated. If the patient has a history of recurrent UTIs, further cultures and other screening techniques (eg, nitrite dipstick or urine Gram stain) may be needed to detect the development of asymptomatic bacteriuria.

o         Accepted regimens for treating asymptomatic bacteriuria include amoxicillin (250 mg tid for 3 d or 7 d; 3-g single dose), cephalexin (2- or 3-g single dose), and nitrofurantoin (200-mg single dose; 100 mg qid for 3 d or 7 d). Successfully treated bacteriuria prevents pyelonephritis.

o         Presentation of pyelonephritis is similar in pregnant and nonpregnant females. The antibiotic regimen of choice is intravenous ampicillin and gentamicin. This is followed by an oral regimen to complete a 14-day course guided by results from susceptibility studies. Obtain an additional urine culture 1-2 weeks after the completion of therapy to verify eradication of the infection, and obtain monthly urine cultures until delivery to monitor the urine for recurrent infection.

o         Postcoital therapy with cephalexin or nitrofurantoin is recommended for prophylaxis against recurrent infection.

o         If the initial infection requires a second agent for clearing the infection or a recurrent infection occurs, suppressive therapy until delivery is indicated with nitrofurantoin (50 mg or 100 mg qhs).

o         Recurrent infection or persistent bacteriuria is an indication for urological evaluation 3-6 months after delivery.

·                     Geriatric issues

o         After age 65 years, at least 20% of women and 10% of men have bacteriuria. Several factors appear to account for this level of bacterial presence in the urinary tracts of elderly persons, as follows:

§           Obstructive uropathy (eg, urinary stones, prostatic hypertrophy, uterine prolapse, cystocele)

§           Decreased bactericidal activity in prostatic secretions

§           Perineal soiling with fecal matter in women with dementia

§           Neuromuscular disease

§           Increased instrumentation of urinary tract

§           Urinary catheters

§           Reduced Tamm-Horsfall protein secretion in the urine

§           Increased uropathogens in the postmenopausal vagina and introitus

o         The single most important factor predisposing the urinary tract to infection is obstruction in any form.

o         Elderly patients may present with pyelonephritis manifesting as abnormal urine coupled with fever, mental status change, decompensation in another organ system, or generalized deterioration. Alternatively, the presentation may include previously described signs and symptoms  If sepsis is suggested, . If an underlying condition is decompensating as a result of pyelonephritis, refer to the appropriate eMedicine article for management of the condition. Management principles remain the same as outlined above. The important issue is to consider the diagnosis in any elderly patient who presents with an acute medical condition.

·                     Pediatric issues

o         The manifestation of symptomatic UTI and pyelonephritis varies in the pediatric population depending on the age of the patient. The classic signs and symptoms observed in adults are often absent in children, particularly neonates and infants. When fever is present, pyelonephritis should be in the differential diagnosis.

o         Indications for immediate urological referral during acute pyelonephritis are abnormal electrolyte values associated with acidosis, elevated blood urea nitrogen level, hypertension, a palpable bladder, and voiding difficulty (dribbling, poor stream, straining).

o         Aside from the effects of acute infection, the overriding concern is progressive renal deterioration of an already compromised kidney (hypoplastic or dysplastic) secondary to scarring from recurrent pyelonephritis with or without associated obstruction.

o         The groups at greatest risk are infants and preschool-aged children. Initial management varies with patient age and presentation.

o         Close follow-up examination, regardless of whether the patient is initially admitted, is essential to ensure recovery. Immediate reevaluation is encouraged for any recurrence of symptoms because treatment of asymptomatic bacteriuria and long-term suppressive therapy have not been found to be efficacious.

o         Urological evaluation is necessary to establish the presence of any urological abnormality. The preferred imaging study for the diagnosis of acute pyelonephritis is DMSA scintigraphy. Ultrasonography is the imaging study of choice for the diagnosis of urinary tract structural abnormalities.

o         Age-related data adapted from Harwood-Nuss and colleagues and Hansson and colleagues are presented in the following table.

Table 4. Pediatric Urinary Tract Infections

	Neonates	Infants Aged 6 Weeks to 3 Years	Children Aged 3-6 Years	Children Aged 6-11 Years
UTI Frequency, %	1	1.5-3	1.5-3	1.2
Female-to-Male Ratio	1:1.5	10:1	10:1	30:1
Route of Infection	Blood	Ascending	Ascending	Ascending
Signs and Symptoms	Failure to thrive, fever, hypothermia, irritability, jaundice, poor feeding, sepsis, vomiting	Diarrhea, failure to thrive, fever, irritability, poor feeding, strong-smelling urine, vomiting	Abdominal pain, dysuria, enuresis, fever, gross hematuria, meningismus, strong-smelling urine, urinary urgency, urinary frequency, vomiting	Dysuria, enuresis, fever,flank pain or tenderness, urinary urgency, urinary frequency
Predominant Organism	Klebsiella species	E coli	E coli, Proteus species in older boys	E coli
Management	Admit for intravenous ampicillin and gentamicin and further evaluation.	Admit for intravenous ampicillin and gentamicin and further evaluation.	Follow adult guidelines, but avoid fluoroquinolones, which are theoretically contraindicated due to potential effects on the musculoskeletal system.	Follow adult guidelines, but avoid fluoroquinolones, which are theoretically contraindicated due to potential effects on the musculoskeletal system.

 Pyelonephritis, Chronic

Background: Chronic pyelonephritis is renal injury induced by recurrent or persistent renal infection. It occurs almost exclusively in patients with major anatomic anomalies, including urinary tract obstruction, struvite calculi, renal dysplasia, or, most commonly, vesicoureteral reflux (VUR) in young children. Sometimes, this diagnosis is established based on radiologic evidence obtained during an evaluation for recurrent urinary tract infection (UTI) in young children. VUR is a congenital defect that results in incompetence of the ureterovesical valve due to a short intramural segment. The condition is present in 30-40% of young children with symptomatic UTIs and in almost all children with renal scars. VUR may also be acquired by patients with a flaccid bladder due to spinal cord injury. VUR is classified into 5 grades (I-V), according to the increasing degree of reflux.

Pathophysiology: Chronic pyelonephritis is associated with progressive renal scarring, which can lead to end-stage renal disease (ESRD), eg, reflux nephropathy. Intrarenal reflux of infected urine is suggested to induce renal injury, which heals with scar formation. In some cases, scars may form in utero in patients with renal dysplasia with perfusion defects. Infection without reflux is less likely to produce injury. Dysplasia may also be acquired from obstruction. Scars of high-pressure reflux can occur in persons of any age. In some cases, normal growth may lead to spontaneous cessation of reflux by age 6 years. Factors that may affect the pathogenesis of chronic pyelonephritis are (1) the sex of the patient and his or her sexual activity; (2) pregnancy, which may lead to progression of renal injury with loss of renal function; (3) genetic factors; (4) bacterial virulence factors; and (5) neurogenic bladder dysfunction. In cases with obstruction, the kidney may become filled with abscess cavities

Frequency:

·                     In the US: VUR may be present in 30-45% of children with UTIs. The prevalence rate of VUR in siblings of patients with chronic pyelonephritis is approximately 35%. VUR and chronic pyelonephritis are less common in black children than in white children.

Mortality/Morbidity: Conditions associated with mortality and morbidity related to chronic pyelonephritis include (1) progressive renal scarring, (2) proteinuria, (3) hypertension, (4) ESRD, (5) focal glomerulosclerosis, and (6) xanthogranulomatous pyelonephritis (XPN). XPN occurs in 8.2% of patients and in 25% of patients with pyonephrosis.

Race: Chronic pyelonephritis is less common in black children than in white children.

Sex: Chronic pyelonephritis is more common in females than in males.

Age: Chronic pyelonephritis occurs in children and adults

History:

·                     Many cases of VUR are suggested based on prenatal sonography findings.

·                     Patients with chronic pyelonephritis may report the following:

o         Fever

o         Lethargy

o         Nausea and vomiting

o         Flank pain or dysuria

·                     Some children may present with failure to thrive.

Physical:

·                     The following may be noted:

o         Hypertension

o         Failure to thrive in young children

o         Flank tenderness

Causes:

Chronic pyelonephritis is renal injury induced by recurrent or persistent renal infection. Lab Studies:

·                     Urinalysis

o         Urinalysis results may reveal pyuria.

o         Obtain a urine culture, which often isolates gram-negative bacteria such as Escherichia coli or Proteus species.

o         A negative result from urine culture does not exclude a diagnosis of chronic pyelonephritis.

o         Proteinuria may be present and is a negative prognostic factor for this disease.

·                     Serum creatinine and blood urine nitrogen levels are elevated (azotemia).

Imaging Studies:

·                     Findings from an intravenous urogram help establish the diagnosis of pyelonephritis because they reveal caliceal dilatation and blunting with cortical scars. Ureteral dilatation and reduced renal size also may be evident.

(picture 6)

Picture 6 Intravenous urogram  in pyelonephritis

·                     Voiding cystourethrogram (VCUG) findings may document the reflux of urine to the renal pelvis and ureteral dilatation in children with gross reflux.

·                     Radioisotopic scanning with technetium dimercaptosuccinic acid is more sensitive than intravenous pyelography for helping detect renal scars. This is the preferred test for many pediatric nephrologists and radiologists because it is sensitive and easy to perform.

·                     Cystoscopy images show evidence of reflux at the ureteral orifices.

·                     Renal sonography images may show calculi.

·                     CT scan is the procedure of choice to help diagnose XPN.

·                     Renal ultrasonography images may show calculi, but ultrasound is not a sensitive screening procedure for reflux nephropathy (picture 7)

 

Picture 7 Renal ultrasonography in caliculi pyelonephritis

Procedures:

·                     Cystoscopy findings show evidence of previous reflux at the ureteral orifices, even if VCUG images show no reflux because of the spontaneous cessation of reflux due to puberty.

Histologic Findings: Renal biopsy specimens show focal glomerulosclerosis in advanced reflux nephropathy, while XPN must be distinguished from renal malakoplakia based on the presence of inclusions called Michaelis-Gutmann bodies.

Medical Care:

·                     Stages I and II VUR

o         This is reflux of urine to the ureter or renal pelvis without ureteral dilatation.

o         Medical therapy with antibiotics such as amoxicillin, trimethoprim/sulfamethoxazole (Bactrim), trimethoprim alone, or nitrofurantoin is usually sufficient.

o         Continue antibiotic therapy until puberty or until reflux resolves.

o         The rule in these cases is spontaneous resolution; surgery is not indicated.

·                     Stages III and IV VUR (severe reflux)

o         Data from the Birmingham Reflux Study (international reflux study in children) show that medical and surgical therapies for reflux are equally effective.

o         Surgery for severe reflux involves reimplantation of the ureters.

o         The indications for surgery include (1) medical noncompliance with formation of new scars and (2) reflux persisting after puberty in women (should be surgically treated to prevent possible complications, eg, pyelonephritis, abortions in pregnancy).

Surgical Care:

·                     The following are indications for surgical therapy:

o         Failure to comply with medical regimen

o         Breakthrough infections occurring in patients who are compliant

o         Women of childbearing age who prefer surgical therapy

·                     Surgery entails the reimplantation of the ureters with the creation of an adequate submucosal tunnel and detrusor support.

Diet:

Progressive renal injury can be reduced by restricting dietary protein intake.

The penicillins (amoxicillin) and first-generation cephalosporins are the drugs of choice because of good activity against gram-negative rods and good oral bioavailability. In infants, the choice of antibiotics is either amoxicillin or a first-generation cephalosporin. In patients aged 3-6 months, therapy can be changed to sulfamethoxazole or nitrofurantoin. Older children and adults may be treated with trimethoprim-sulfamethoxazole (Bactrim). Once one antibiotic is chosen, frequent changes in the antibiotic regimen are discouraged to help prevent the development of resistance.

Drug Category: Antibiotics — Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

 

 

 

In/Out Patient Meds:

·                     In young children, the choice of antibiotics is either amoxicillin or a first-generation cephalosporin.

·                     In children aged 3-6 months, therapy can be changed to sulfamethoxazole or nitrofurantoin.

·                     Once an antibiotic is chosen, frequent changes in the antibiotic regimen are discouraged to help prevent the development of resistance.

Deterrence/Prevention:

·                     Diet: Progressive renal injury can be reduced by dietary protein restriction.

·                     Hypertension therapy: Aggressive blood pressure control is beneficial to slow the progression of renal failure. ACE inhibitors are particularly beneficial in this setting.

·                     Pregnancy: Careful follow-up and monitoring of renal function is beneficial. Vigorously treat a UTI or bacteriuria in a patient who is pregnant to prevent renal failure, preeclampsia, and abortions.

·                     Screening: Renal sonography is recommended for siblings of patients with VUR. If an abnormality is found, then perform a VCUG.

Complications:

·                     Proteinuria

·                     Focal glomerulosclerosis

·                     Progressive renal scarring leading to ESRD

·                     XPN (may occur in approximately 8.2% of cases)

·                     Pyonephrosis (may occur in cases of obstruction)

·                     Progressive renal scarring (reflux nephropathy)

o         The characteristic renal scars of VUR are often present at the time of initial diagnosis of chronic pyelonephritis.

o         New renal scars may develop in 3-5% of patients after the initial evaluation.

o         The progression of renal scars is inversely related to the promptness with which specific antibiotic therapy is instituted.

o         The presence of new scars often suggests the occurrence of breakthrough infections.

·                     Hypertension

o         Hypertension contributes to the accelerated loss of renal function in persons with this disease.

o         Reflux nephropathy is the most common cause of hypertension in children, occurring in 10-20% of children with VUR and renal scars.

o         The resolution of reflux does not appear to correct hypertension.

Prognosis:

·                     Although most children with chronic pyelonephritis due to VUR may experience spontaneous resolution of reflux, approximately 2% can still progress to renal failure and 5-6% can have long-term complications, including hypertension.

·                     The Birmingham Reflux Study clearly shows that medical and surgical management are equally effective in preventing subsequent renal damage.

·                     Almost all children should receive a trial of medical management.

Medical/Legal Pitfalls:

·                     Failure to continue outpatient follow-up, which is considered mandatory, because the potential for long-term renal injury can be ameliorated with appropriate therapy

Special Concerns:

·                     XPN may be confused with renal cancer.

·                     Analgesic abuse nephropathy may resemble chronic pyelonephritis.

·                     Renal tuberculosis and renal malakoplakia also may resemble chronic pyelonephritis. However, in malakoplakia, the characteristic Michaelis-Gutmann bodies may be seen

 

 

References:

A – Basic:

1.      Davidson’s Principles and practice of medicine (21^st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2.      Harrison’s principles of internal medicine (18^th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3.      The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

4.      Web -sites:

a)                  http://emedicine.medscape.com/

b)                  http://meded.ucsd.edu/clinicalmed/introduction.htm

 

B – Additional:

1.      Lawrence M. Tierney, Jr. et al: Current Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health Professions Division, 2000.

 

BIBLIOGRAPHY OGR

• Alan C, Ataus S, Tunc B: Xanthogranulomatous pyelonephritis with psoas abscess: 2 cases and review of the literature. Int Urol Nephrol 2004; 36(4): 489-93[Medline].

• Birmingham Reflux Study Group: Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: five years’ observation. Br Med J (Clin Res Ed) 1987 Jul 25; 295(6592): 237-41[Medline].

• Dillon MJ, Goonasekera CD: Reflux nephropathy. J Am Soc Nephrol 1998 Dec; 9(12): 2377-83[Medline].

• Dracon M, Lemaitre L: [Urinary tract infection in adult. Leukocyturia]. Rev Prat 2003 May 15; 53(10): 1137-42[Medline].

• Eke N, Echem RC: Chronic pyonephrosis associated with renal neovascularisation. Afr J Med Med Sci 2004 Sep; 33(3): 267-9[Medline].

• Gillenwater JL, Grayhack JT, Howards SS, eds: Adult and Pediatric Urology. 3rd ed. St. Louis, Mo: Mosby-Year Book; 1996: 320-5.

• Gonzalez Resina R, Barrero Candau R, Arguelles Salido E, et al: [Xanthogranulomatous pyelonephritis in childhood. A case report]. Actas Urol Esp 2005 Jun; 29(6): 596-8[Medline].

• Hiraoka M, Hori C, Tsukahara H, et al: Vesicoureteral reflux in male and female neonates as detected by voiding ultrasonography. Kidney Int 1999 Apr; 55(4): 1486-90[Medline].

• Kohler J, Tencer J, Thysell H, Forsberg L: Vesicoureteral reflux diagnosed in adulthood. Incidence of urinary tract infections, hypertension, proteinuria, back pain and renal calculi. Nephrol Dial Transplant 1997 Dec; 12(12): 2580-7[Medline].

• Muter E, Nath KA: Chronic tubulointerstitial nephritis. In: Jacobson HR, Striker GE, Klahr S, eds. The Principle and Practice of Nephrology. 2nd ed. St. Louis, Mo: Mosby-Year Book; 1995: 218-9.

• Noe HN: The long-term results of prospective sibling reflux screening. J Urol 1992 Nov; 148(5 Pt 2): 1739-42[Medline].

• Oosterhof GO, Delaere KP: Xanthogranulomatous pyelonephritis. A review with 2 case reports. Urol Int 1986; 41(3): 180-6[Medline].

• Saavedra Jo S, Pow-Sang Godoy M, Benavente Corrales V, et al: [Xanthogranulomatous pyelonephritis: clinical, radiological and pathologic characteristics]. Arch Esp Urol 2004 Jul-Aug; 57(6): 595-600[Medline].

• Takayasu H, Ishimaru Y, Kisaki Y: Diffuse xanthogranulomatous pyelonephritis in a patient with myotonic dystrophy and cerebral palsy. Int J Urol 2005 May; 12(5): 497-9[Medline].

• Zermann DH, Loffler U, Reichelt O: Bladder dysfunction and end stage renal disease. Int Urol Nephrol 2003; 35(1): 93-7[Medline].

• Zugor V, Amann K, Schrott KM, Schott GE: [Xanthogranulomatous pyelonephritis: presentation of an unusual case]. Aktuelle Urol 2005 Jun; 36(3): 245-8[Medline].

• Foxman B, Frerichs RR: Epidemiology of urinary tract infection: I. Diaphragm use and sexual intercourse. Am J Public Health 1985 Nov; 75(11): 1308-13[Medline].

• Foxman B, Klemstine KL, Brown PD: Acute pyelonephritis in US hospitals in 1997: hospitalization and in-hospital mortality. Ann Epidemiol 2003 Feb; 13(2): 144-50[Medline].

• Gargan RA, Hamilton-Miller JM, Brumfitt W: Effect of pH and osmolality on in vitro phagocytosis and killing by neutrophils in urine. Infect Immun 1993 Jan; 61(1): 8-12[Medline].

• Gonzalez R: Urologic disorders in infants. In: Nelson WE, Behrman RE, Kliegman RM, eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, Pa: WB Saunders; 1996: 1528-34.

• Griebling TL: Urologic diseases in America project: trends in resource use for urinary tract infections in men. J Urol 2005 Apr; 173(4): 1288-94[Medline].

• Griebling TL: Urologic diseases in America project: trends in resource use for urinary tract infections in women. J Urol 2005 Apr; 173(4): 1281-7[Medline].

• Hansson S, Martinell J, Stokland E, Jodal U: The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1997 Sep; 11(3): 499-512[Medline].

• Harjai K, Mittal R, Chhibber S, Sharma S: Contribution of Tamm-Horsfall protein to virulence of Pseudomonas aeruginosa in urinary tract infection. Microbes Infect 2005 Jan; 7(1): 132-7[Medline].

• Harwood-Nuss AL, Etheredge W, McKenna I: Urological Emergencies. In: Harwood-Nuss A, Wolfson AB, eds. The Clinical Practice of Emergency Medicine. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001: 2227-61.

• Hill JB, Sheffield JS, McIntire DD, Wendel GD Jr: Acute pyelonephritis in pregnancy. Obstet Gynecol 2005 Jan; 105(1): 18-23[Medline].

• Hoberman A, Chao HP, Keller DM, et al: Prevalence of urinary tract infection in febrile infants. J Pediatr 1993 Jul; 123(1): 17-23[Medline].

• Hooton TM, Stamm WE: Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997 Sep; 11(3): 551-81[Medline].

• Hooton TM, Scholes D, Hughes JP, et al: A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med 1996 Aug 15; 335(7): 468-74[Medline].

• Hooton TM: The current management strategies for community-acquired urinary tract infection. Infect Dis Clin North Am 2003 Jun; 17(2): 303-32[Medline].

• Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003 Jan 9; 348(2): 138-50[Medline].

• Huang JJ, Tseng CC: Emphysematous pyelonephritis: clinicoradiological classification, management, prognosis, and pathogenesis. Arch Intern Med 2000 Mar 27; 160(6): 797-805[Medline].

• Israel RS, Lowenstein SR, Marx JA, et al: Management of acute pyelonephritis in an emergency department observation unit. Ann Emerg Med 1991 Mar; 20(3): 253-7[Medline].

• Jacobson SH, Eklof O, Eriksson CG: Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. BMJ 1989 Sep 16; 299(6701): 703-6[Medline].

• Johnson JR: Microbial virulence determinants and the pathogenesis of urinary tract infection. Infect Dis Clin North Am 2003 Jun; 17(2): 261-78, viii[Medline].

• Johnson JR, Stamm WE: Urinary tract infections in women: diagnosis and treatment. Ann Intern Med 1989 Dec 1; 111(11): 906-17[Medline].

• Kaplan DM, Rosenfield AT, Smith RC: Advances in the imaging of renal infection.
  
  Helical CT

  and modern coordinated imaging. Infect Dis Clin North Am 1997 Sep; 11(3): 681-705[Medline].

• Kawashima A, LeRoy AJ: Radiologic evaluation of patients with renal infections. Infect Dis Clin North Am 2003 Jun; 17(2): 433-56[Medline].

• Kawashima A, Glockner JF, King BF: CT urography and MR urography. Radiol Clin North Am 2003 Sep; 41(5): 945-61[Medline].

• Kontiokari T, Sundqvist K, Nuutinen M, et al: Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ 2001 Jun 30; 322(7302): 1571[Medline].

• Kooman JP, Barendregt JN, van der Sande FM: Acute pyelonephritis: a cause of acute renal failure?. Neth J Med 2000 Nov; 57(5): 185-9[Medline].

• Kunin CM: The natural history of recurrent bacteriuria in schoolgirls. N Engl J Med 1970 Jun 25; 282(26): 1443-8[Medline].

• Lee B, Bhuta T, Craig J, Simpson J: Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev 2002; (1): CD003265[Medline].

• Majd M, Nussbaum Blask AR, Markle BM, et al: Acute pyelonephritis: comparison of diagnosis with 99mTc-DMSA, SPECT, spiral CT, MR imaging, and power Doppler US in an experimental pig model. Radiology 2001 Jan; 218(1): 101-8[Medline].

• Marriott HL: Water and salt depletion. Charles C. Thomas Springfield, Ill; 1950.

• Martinell J, Hansson S, Claesson I, et al: Detection of urographic scars in girls with pyelonephritis followed for 13-38 years. Pediatr Nephrol 2000 Sep; 14(10-11): 1006-10[Medline].

• Millar LK, Wing DA, Paul RH, Grimes DA: Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial. Obstet Gynecol 1995 Oct; 86(4 Pt 1): 560-4[Medline].

• Miller O, Hemphill RR: Urinary tract infection and pyelonephritis. Emerg Med Clin North Am 2001 Aug; 19(3): 655-74[Medline].

• Mittal P, Wing DA: Urinary tract infections in pregnancy. Clin Perinatol 2005 Sep; 32(3): 749-64[Medline].

• Mombelli G, Pezzoli R, Pinoja-Lutz G, et al: Oral vs intravenous ciprofloxacin in the initial empirical management of severe pyelonephritis or complicated urinary tract infections: a prospective randomized clinical trial. Arch Intern Med 1999 Jan 11; 159(1): 53-8[Medline].

• Nahar A, Akom M, Hanes D, et al: Pyelonephritis and acute renal failure. Am J Med Sci 2004 Aug; 328(2): 121-3[Medline].

• Nicolle LE: Asymptomatic bacteriuria in the elderly. Infect Dis Clin North Am 1997 Sep; 11(3): 647-62[Medline].

• Nicolle LE: Asymptomatic bacteriuria: when to screen and when to treat. Infect Dis Clin North Am 2003 Jun; 17(2): 367-94[Medline].

• Patterson JE, Andriole VT: Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 1997 Sep; 11(3): 735-50[Medline].

• Patterson LT, Strife CF: Acquired versus congenital renal scarring after childhood urinary tract infection. J Pediatr 2000 Jan; 136(1): 2-4[Medline].

• Patterson TF, Andriole VT: Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era. Infect Dis Clin North Am 1997 Sep; 11(3): 593-608[Medline].

• Pewitt EB, Schaeffer AJ: Urinary tract infection in urology, including acute and chronic prostatitis. Infect Dis Clin North Am 1997 Sep; 11(3): 623-46[Medline].

• Pfaller MA, Koontz FP: Laboratory evaluation of leukocyte esterase and nitrite tests for the detection of bacteriuria. J Clin Microbiol 1985; 21: 840-42.

• Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: ED management of acute pyelonephritis in women: a cohort study. Am J Emerg Med 1994 May; 12(3): 271-8[Medline].

• Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB: Oral antibiotic therapy for acute pyelonephritis: a methodologic review of the literature. J Gen Intern Med 1992 Sep-Oct; 7(5): 544-53[Medline].

• Pitts GC, Johnson RE, Consolazio FC: Work in the heat as affected by intake of water, salt, and glucose. Med Sci Sports Exerc 1944; 142: 253.

• Quinn FM, Dick AC, Corbally MT, et al: Xanthogranulomatous pyelonephritis in childhood. Arch Dis Child 1999 Dec; 81(6): 483-6[Medline].

• Ramakrishnan K, Scheid DC: Diagnosis and management of acute pyelonephritis in adults. Am Fam Physician 2005 Mar 1; 71(5): 933-42[Medline].

• Raz R, Stamm WE: A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993 Sep 9; 329(11): 753-6[Medline].

• Raz R, Sakran W, Chazan B, et al: Long-term follow-up of women hospitalized for acute pyelonephritis. Clin Infect Dis 2003 Oct 15; 37(8): 1014-20[Medline].

• Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001 Nov 8; 345(19): 1368-77[Medline].

• Rivers EP, McIntyre L, Morro DC, Rivers KK: Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity. CMAJ 2005 Oct 25; 173(9): 1054-65[Medline].

• Ronald AR, Harding GK: Complicated urinary tract infections. Infect Dis Clin North Am 1997 Sep; 11(3): 583-92[Medline].

• Rubenstein JN, Schaeffer AJ: Managing complicated urinary tract infections: the urologic view. Infect Dis Clin North Am 2003 Jun; 17(2): 333-51[Medline].

• Rusinek H, Kaur M, Lee VS: Renal magnetic resonance imaging. Curr Opin Nephrol Hypertens 2004 Nov; 13(6): 667-73[Medline].

• Safrin S, Siegel D, Black D: Pyelonephritis in adult women: inpatient versus outpatient therapy. Am J Med 1988 Dec; 85(6): 793-8[Medline].

• Saint S, Chenoweth CE: Biofilms and catheter-associated urinary tract infections. Infect Dis Clin North Am 2003 Jun; 17(2): 411-32[Medline].

• Schlager TA: Urinary tract infections in infants and children. Infect Dis Clin North Am 2003 Jun; 17(2): 353-65, ix[Medline].

• Scholes D, Hooton TM,
  
  Roberts PL

  , et al: Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med 2005 Jan 4; 142(1): 20-7[Medline].

• Segura JW, Preminger GM, Assimos DG, et al: Nephrolithiasis Clinical Guidelines Panel summary report on the management of staghorn calculi. The American Urological Association Nephrolithiasis Clinical Guidelines Panel. J Urol 1994 Jun; 151(6): 1648-51[Medline].

• Sheehan GJ, Harding GK, Haase DA, et al: Double-blind, randomized comparison of 24 weeks of norfloxacin and 12 weeks of norfloxacin followed by 12 weeks of placebo in the therapy of complicated urinary tract infection. Antimicrob Agents Chemother 1988 Aug; 32(8): 1292-3[Medline].

• Shen Y, Brown MA: Renal imaging in pyelonephritis. Nephrology (Carlton) 2004 Feb; 9(1): 22-5[Medline].

• Smaill F: Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev 2000; (2): CD000490[Medline].

• Smellie JM, Prescod NP, Shaw PJ, et al: Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol 1998 Nov; 12(9): 727-36[Medline].

• Sobel JD: Pathogenesis of urinary tract infection. Role of host defenses. Infect Dis Clin North Am 1997 Sep; 11(3): 531-49[Medline].

• Sobel JD, Kaye D: Urinary tract infections. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5th ed. Philadelphia. Pa: Churchill Livingstone; 2000: 773-805.

• Stamm WE, Hooton TM: Management of urinary tract infections in adults. N Engl J Med 1993 Oct 28; 329(18): 1328-34[Medline].

• Stapleton A, Stamm WE: Prevention of urinary tract infection. Infect Dis Clin North Am 1997 Sep; 11(3): 719-33[Medline].

• Stapleton A: Prevention of recurrent urinary-tract infections in women. Lancet 1999 Jan 2; 353(9146): 7-8[Medline].

• Strom BL, Collins M, West SL, et al: Sexual activity, contraceptive use, and other risk factors for symptomatic and asymptomatic bacteriuria. A case-control study. Ann Intern Med 1987 Dec; 107(6): 816-23[Medline].

• Talan DA, Stamm WE, Hooton TM, et al: Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis in women: a randomized trial. JAMA 2000 Mar 22-29; 283(12): 1583-90[Medline].

• Talner L, Vaughan M: Nonobstructive renal causes of flank pain: findings on noncontrast helical CT (CT KUB). Abdom Imaging 2003 Mar-Apr; 28(2): 210-6[Medline].

• Taskinen S, Ronnholm K: Post-pyelonephritic renal scars are not associated with vesicoureteral reflux in children. J Urol 2005 Apr; 173(4): 1345-8[Medline].

• Teichman JM, Long RD, Hulbert JC: Long-term renal fate and prognosis after staghorn calculus management. J Urol 1995 May; 153(5): 1403-7[Medline].

• Tolkoff-Rubin NE, Rubin RH: Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am 1997 Sep; 11(3): 707-17[Medline].

• Vargas AD, Bragin SD, Mendez R: Staghorn calculis: its clinical presentation, complications and management. J Urol 1982 May; 127(5): 860-2[Medline].

• Vazquez JC, Villar J: Treatments for symptomatic urinary tract infections during pregnancy. Cochrane Database Syst Rev 2000; (3): CD002256[Medline].

• Warren JW, Abrutyn E, Hebel JR, et al: Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999 Oct; 29(4): 745-58[Medline].

• Warren JW: Catheter-associated urinary tract infections. Infect Dis Clin North Am 1997 Sep; 11(3): 609-22[Medline].

• Wennerstrom M, Hansson S, Jodal U, Stokland E: Primary and acquired renal scarring in boys and girls with urinary tract infection. J Pediatr 2000 Jan; 136(1): 30-4[Medline].

• Wing DA: Pyelonephritis. Clin Obstet Gynecol 1998 Sep; 41(3): 515-26[Medline].

• Wullt B, Bergsten G, Fischer H: The host response to urinary tract infection. Infect Dis Clin North Am 2003 Jun; 17(2): 279-301[Medline].

• Yadav V, Harjai K, Kaur R: Urovirulence of Pseudomonas aeruginosa: planktonic cells vs. biofilm cells. Folia Microbiol (Praha) 2004; 49(4): 465-70[Medline].