Acute Pyelonephritis 

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. (See Epidemiology.)

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. (See Presentation, Workup, Treatment, and Medication.)

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. (See Presentation and Workup.)

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; however, useful recommendations can be made. An additional cause for concern is the growing antimicrobial resistance to accepted standards of treatment. (See Treatment and Medication.)

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 (IV) antibiotics and evaluation for any complications. Most cases of uncomplicated pyelonephritis in young women can be managed successfully on an outpatient basis. (See Treatment and Medication.)

Complications occur more often in patients with diabetes mellitus, chronic renal disease, sickle cell disease, renal transplant (particularly the first 3 mo), acquired immunodeficiency syndrome (AIDS), and other immunocompromised states. (See Prognosis.)

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. (See DDx.)

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. The presentation is similar to that of 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 IV antibiotics. The mortality rate is 20%.

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. Computed tomography (CT) scanning is the study of choice to help localize the gas to the proper organ.

Treatment involves IV antibiotics and relief of any outlet obstruction. This condition is not as serious as emphysematous formation or emphysematous pyelitis, which also can occur in acute pyelonephritis.

Other complications

Additional complications of pyelonephritis include the following:

• Acute renal failure
• Chronic renal damage leading to hypertension and renal failure
• Sepsis syndromes
• Renal papillary necrosis
• Xanthogranulomatous pyelonephritis
• Abscess transformation - This may include renal cortical abscess, renal corticomedullary abscess, or perinephric abscess
• Emphysematous formation (gas in tissues) - Should this occur, recognizing it is critical; treatment may include nephrectomy

Acute pyelonephritis usually occurs secondary to bacteria ascending from the lower urinary tract. Hematogenous spread to the kidney can occur, with acute pyelonephritis resulting from bacterial invasion of the renal parenchyma.

Episodes of bacteriuria commonly occur in all age groups; most of these episodes, however, consist of asymptomatic bacteriuria (ABU) and do not lead to infection. Infection is influenced by bacterial factors and host factors.^[1]

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 complicated UTI is defined as a UTI in the presence of at least 1 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.

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, and have the metabolic advantage of synthesizing essential substances.

No single VF is sufficient or necessary to promote pathogenesis. It seems that multiple VFs are necessary to ensure pathogenesis, although adhesins play an important role.

Adhesins

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

Siderophores are involved iron uptake, an essential element for bacteria, and possibly adhesion.

Protectins

Protectins include the following:

• Lipopolysaccharide (LPS) coatings - Resist phagocytosis
• Tra T and Iss - Resist the action of the complement
• Omp T - Cleaves host defense proteins, such as immunoglobulins

Toxins

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.

Asymptomatic bacteriuria

Although the idea is controversial, bacterial strains producing ABU may provide, in some instances, a measure of protection against symptomatic infections from UPEC and other organisms.

Once bacteriuria is established, ABU strains appear to stop producing adhesins, allowing them to survive and persist without producing an inflammatory reaction. The frequency of ABU is as follows:

• Preschool girls - Less than 2%
• Pregnant women - 2-9.5%
• Women aged 65-80 years - 18-43%
• Men aged 65-80 years - 1.5-15.3%
• Women older than 80 years - 18-43%
• 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 (Open Table in a new window)

Organisms

As noted above, UPEC accounts for most infections in uncomplicated pyelonephritis and a significant portion of 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. (See Table 2, below.)

Table 2. Bacterial Etiology of Urinary Tract Infections¹ (Open Table in a new window)

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.

Response to infection

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.

Complicated urinary tract infection

When a UTI or pyelonephritis becomes complicated (complicated UTI), host defenses are compromised, thereby increasing the likelihood of infection. 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 factors, such that the efficacy of antibiotics is reduced (see Table 3, below). These factors can be more specifically described as, but are not limited to, the following:

• Obstruction (congenital or acquired)
• Stents
• Vesicoureteral reflux
• Incomplete bladder emptying - May be medication related (eg, anticholinergics)
• Use of spermicide - The 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 - 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
• Prostatitis - Bacterial prostatitis (acute or chronic) produces bacteriuria, while nonbacterial prostatitis and pelviperineal pain syndrome (prostadynia) do not
• Immunodeficiency (congenital or acquired)
• Unusual organisms - Eg, Mycoplasma or Pseudomonas
• Urea-splitting organisms - Usually Proteus, but sometimes E coli, Klebsiella, Pseudomonas, or Staphylococcus
• Medullary scars
• Pregnancy

Although there are many instances in which more than 1 factor is involved, in any given episode of acute pyelonephritis, the presence of any 1 of these factors should raise the clinician’s index of suspicion.

Table 3. Classification of Factors in Complicated UTI¹ (Open Table in a new window)

Obstruction

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.

Pseudomonas

Pseudomonas aeruginosa has several mechanisms that promote adherence, including alginate, other membrane proteins, pili, and surface-associated exoenzyme.

Urea-splitting organisms

Urea-splitting organisms produce urease, which hydrolyzes urea (urea-splitting), yielding ammonia, bicarbonate, and carbonate. This leads to a more alkaline urine, which, in turn, allows 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. 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

Pregnancy (hormonal and mechanical changes) predisposes a woman to upper UTIs. Hydroureter of pregnancy, secondary to hormonal and mechanical factors, is manifested as dilatation of the renal pelvis and ureters (left >right), with the ureters containing up to 200 mL of urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis.^[8]

Hematogenous infection

Although acute pyelonephritis usually occurs secondary to bacteria ascending from the lower urinary tract, hematogenous bacterial spread to the kidney can occur. Sources for gram-positive organisms, such as Staphylococcus, are IV 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 IV 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.

Occult upper UTIs

Occult upper UTIs (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 if the patient is a young, premenopausal woman 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.

Geriatric considerations

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

• Obstructive uropathy - Eg, urinary stones, prostatic hypertrophy, uterine prolapse, and 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

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

Occurrence in the United States

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 UTIs. In children aged 2 years or 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 demonstrable bacteria in the upper tract.

Sex-related demographics

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

The prevalence 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.

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 urologic evaluation after the first episode to rule out structural abnormalities.

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

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. 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.

Pregnant patients with pyelonephritis are at significant risk for premature labor. Timely diagnosis and management has a significant impact on the outcome. Infants and children who have had pyelonephritis should be evaluated for urinary tract abnormalities.

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

Morbidity and mortality

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 system is the source in 9.1% of the severe sepsis cases in the United States (approximately 750,000 annually). The mortality for these genitourinary-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%.

Rarely, acute pyelonephritis can cause acute renal failure in children, healthy adults, and pregnant women. When this occurs, characteristically, there is a slower recovery compared with other causes of acute renal failure. In most instances, other factors are thought to contribute to the acute renal failure, 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 a 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 a long-term, indwelling catheter.

Renal scarring

In children, renal scarring can be detected in 6-15% after a febrile UTI.^[9] 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 vesicoureteral reflux, that 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 vesicoureteral reflux.

Acute pyelonephritis (single episode; first UTI ever in one half of cases) in adult women leads to renal scarring in 46% of cases, as demonstrated by technetium-99m (^99m Tc)–labeled dimercaptosuccinic acid scanning 10 years later. Subsequent UTIs do not appear to affect the risk of future scarring.

Morbidity in pregnancy

Acute pyelonephritis during pregnancy can lead to the following morbidities:

• Acute renal dysfunction (creatinine, >1.2 mg/dL) - 2% of cases (20-25% in the past)
• Acute respiratory distress syndrome (bilateral chest radiograph infiltrates and hypoxemia without pulmonary hypertension) - 1-8% of cases
• Low birth weight (< 2500 g) - 7% of cases
• Preterm delivery (< 37 wk gestation) - 5% of cases (6-50% in the past)
• Recurrence prior to delivery - 18-20% of cases
• Sepsis (positive blood cultures) - 17% of cases

Renal scarring has been demonstrated to be 4 times more likely after pyelonephritis in pregnant women than in nonpregnant women.

Diabetes in acute pyelonephritis

A study by Kofteridis et al concluded that in persons with diabetes, acute pyelonephritis is linked to bacteremia, long hospital stays, and mortality. In a retrospective study of 206 elderly patients hospitalized for acute pyelonephritis, the investigators compared clinical and microbiologic characteristics of members of the cohort who had diabetes mellitus (88 patients) with those who did not (118 patients). The authors found that 30.7% of patients with diabetes mellitus (27 patients) had bacteremia, compared with 11% of the controls (13 patients). Moreover, patients with diabetes had longer-lasting fevers than did the controls (median, 4.5 vs 2.5 days, respectively), as well as longer hospital stays (median, 10 vs 7 days, respectively). The mortality rate in patients with diabetes was 12.5%, compared with 2.5% in the controls.^[10]

Acute renal transplant pyelonephritis

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 with all renal transplant cases with or without the occurrence of pyelonephritis at any time after the transplant up to 96 months (25-30%).

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 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 1.5L, 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.

For patient education information, see Urinary Tract Infections and Blood in the Urine.