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 shortcourse 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 managedsuccessfullyonan outpatient basis. Recent studies In a retrospective study of 206 elderly patients hospitalized for acute pyelonephritis, Kofteridis et al 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 longerlasting 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. The authors concluded that acute pyelonephritis is linked to bacteremia, long hospital stays, and mortality in persons with diabetes.1

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.2 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. Mannosesensitive 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 Open table in new window

Clinical Condition

Frequency (%) Female Male

Morbidity and Mortality

Screening Recommend ed

Treatme nt With Antibioti c Benefici al2 No

Comments

Infants (= 36 Months) Preschool School Children and Adolescents

0.4-1.8

0.5-2.5

None

No

0.8-1.3 1.1-1.8

0.5 ~0

None

No

No No No evidence of scar or renal failure progression, if untreated. Abx given for any indication in girls leads to increased symptomatic UTI¶s in posttreatment period. No benefits to treatment have been identified.

May persist No for years without adverse outcome. Increased incidence of symptomatic UTI¶s3 in girls in absence of treatment.

Premenopaus 0.8-5.2 al and Nonpregnant Women

-

More frequent UTI¶s and subsequent ABU. No other associated long-term adverse outcome. Prior UTI or lower socioeconomic status associated with higher frequency of ABU. 20 ± 30% untreated ABU progress to acute pyelonephriti

No

No

Pregnant Women

2-9.54

-

Yes At least 1 urine culture, preferably 2 consecutive, at end 1st trimester5

Yes Treatmen t of ABU reduces frequency of AP to 2 ± 3%

After treatment of ABU, periodic followup urine cultures recommended, e.g. once per month. 1 ± 2% women with negative initial urine culture develop ABU and experience AP later in

s (AP), usually at end of 2nd or early 3rd trimester. ABU associated with intrauterine growth retardation and neonatal death. AP is associated with prematurity. Young Men Ages 50 ± 65 Years 2.8-8.6 ~0 0.6-1.5 None None demonstrate d. Studies limited. 76% episodes ABU resolve spontaneous ly. See Ages 50 ± 65 Years. See Ages 50 ± 65 Years. Associated with urinary/bowe l incontinence and dementia. No decreased mortality in US studies. No indication of adverse outcome in women. Glucose No No No No

pregnancy.

Co-morbid conditions increase incidence of ABU and UTI.

Ages 65 ± 80 Years Ages > 80 Years Institutionaliz ed

5.8-16

1.5-15.3

No

No

See Ages 50 ± 65 Years. See Ages 50 ± 65 Years. ABU treatment does not decrease survival, symptomatic UTI frequency, or genitourinary symptoms.

18-43

5.4-21

No

No

25-53

19-37

No

No

Diabetes Mellitus

7.9-17.7

1.5-2.2

No

No

Most data in women. Increase frequency probably

control not impaired.

secondary to autonomic neuropathy of bladder. No No Intermittent urinary catheterization (men & women) and sphincterotomy with condom catheter producing a low pressure bladder, significantly reduces morbidity/mortal ity from UTI¶s. Current practice is to administer prophylactic Abx in perioperative period and to continue them long-term and to shorten the period of an indwelling catheter; this practice has reduced the morbidity to the point that there is no association of ABU and graft loss. Organ donors should be screened and treated in advance for ABU. Women have a higher frequency than men.

Spinal Cord Injury with Bladder Impairment

70-100

See Women

AP, urosepsis, renal failure. See comments.

Renal Transplant

41 1st Mo6 21 2nd Mo .01 > 3 Mo

See Women

AP, sepsis, graft loss. 11% grafts develop persistent ABU and go on to develop urological complication s.

Yes Immediate post-op period and up to 6 mos

Yes For up to 6 mos.

Short Term Catheter

2 ± 7 for each day catheter in place

See Women and Commen

Symptomatic UTI in 26% women by 14 days post catheter

No. unless patient has other risk factor

Possibilit y beneficial in women with ABU

ts

removal.

48 hours after removal of catheter No No Treatment of ABU does not decrease frequency of fever and usually leads to development of resistant strains.

Indwelling Catheter > 30 Days

100

100

AP, urosepsis, catheter obstruction, renal stones, vesicoureter al reflux, renal failure, bladder cancer (very long term) Bacteremia, sepsis

Genitourinary Surgery

20 ± 80% with ABU develop bacterem ia

See Women

Yes, to identify specific organisms and sensitivities

Yes

Use urine culture to guide therapy. Abx administered immediately prior to procedure. Comments

Clinical Condition

Frequency (%) Female Male

Morbidity and Mortality

Screening Recommend ed

Treatme nt With Antibioti c Benefici al2 No

Infants (= 36 Months) Preschool School Children and Adolescents

0.4-1.8

0.5-2.5

None

No

0.8-1.3 1.1-1.8

0.5 ~0

None

No

No No No evidence of scar or renal failure progression, if untreated. Abx given for any indication in girls leads to increased symptomatic UTI¶s in posttreatment period.

May persist No for years without adverse outcome. Increased incidence of symptomatic UTI¶s3 in girls in absence of treatment.

Premenopaus 0.8-5.2 al and Nonpregnant Women

-

More frequent UTI¶s and subsequent ABU. No other associated long-term adverse outcome. Prior UTI or lower socioeconomic status associated with higher frequency of ABU. 20 ± 30% untreated ABU progress to acute pyelonephriti s (AP), usually at end of 2nd or early 3rd trimester. ABU associated with intrauterine growth retardation and neonatal death. AP is associated with prematurity. None None demonstrate d. Studies limited. 76% episodes ABU resolve spontaneous

No

No

No benefits to treatment have been identified.

Pregnant Women

2-9.54

-

Yes At least 1 urine culture, preferably 2 consecutive, at end 1st trimester5

Yes Treatmen t of ABU reduces frequency of AP to 2 ± 3%

After treatment of ABU, periodic followup urine cultures recommended, e.g. once per month. 1 ± 2% women with negative initial urine culture develop ABU and experience AP later in pregnancy.

Young Men Ages 50 ± 65 Years

2.8-8.6

~0 0.6-1.5

No No

No No Co-morbid conditions increase incidence of ABU and UTI.

ly. Ages 65 ± 80 Years Ages > 80 Years Institutionaliz ed 5.8-16 1.5-15.3 See Ages 50 ± 65 Years. See Ages 50 ± 65 Years. Associated with urinary/bowe l incontinence and dementia. No decreased mortality in US studies. No indication of adverse outcome in women. Glucose control not impaired. No No See Ages 50 ± 65 Years. See Ages 50 ± 65 Years. ABU treatment does not decrease survival, symptomatic UTI frequency, or genitourinary symptoms.

18-43

5.4-21

No

No

25-53

19-37

No

No

Diabetes Mellitus

7.9-17.7

1.5-2.2

No

No

Most data in women. Increase frequency probably secondary to autonomic neuropathy of bladder. Intermittent urinary catheterization (men & women) and sphincterotomy with condom catheter producing a low pressure bladder, significantly reduces morbidity/mortal ity from UTI¶s. Current practice is to administer prophylactic Abx in perioperative

Spinal Cord Injury with Bladder Impairment

70-100

See Women

AP, urosepsis, renal failure. See comments.

No

No

Renal Transplant

41 1st Mo6 21 2nd Mo .01 > 3 Mo

See Women

AP, sepsis, graft loss. 11% grafts develop persistent

Yes Immediate post-op period and up to 6 mos

Yes For up to 6 mos.

ABU and go on to develop urological complication s.

period and to continue them long-term and to shorten the period of an indwelling catheter; this practice has reduced the morbidity to the point that there is no association of ABU and graft loss. Organ donors should be screened and treated in advance for ABU. No. unless patient has other risk factor Possibilit y beneficial in women with ABU 48 hours after removal of catheter No Women have a higher frequency than men.

Short Term Catheter

2 ± 7 for each day catheter in place

See Women and Commen ts

Symptomatic UTI in 26% women by 14 days post catheter removal.

Indwelling Catheter > 30 Days

100

100

AP, urosepsis, catheter obstruction, renal stones, vesicoureter al reflux, renal failure, bladder cancer (very long term) Bacteremia, sepsis

No

Treatment of ABU does not decrease frequency of fever and usually leads to development of resistant strains.

Genitourinary Surgery

20 ± 80% with ABU develop bacterem ia

See Women

Yes, to identify specific organisms and sensitivities

Yes

Use urine culture to guide therapy. Abx administered immediately prior to procedure.

1 ± Adapted from Nicolle (1997)60 and Nicolle (2003)61 2 ± Treatment of ABU with Abx does not reduce the frequency of symptomatic UTI 3 ± Abbreviations: UTI ± Urinary tract infections; Abx ± antibiotics; ABU ± asymptomatic bacteriuria; AP ± acute pyelonephritis 4 ± First trimester 5 ± Urine dipstick and microscopic analysis not efficacious for identifying ABU 6 ± First month after renal transplant 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 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 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
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 (see Pathophysiology), 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 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 (2025% in the past), acute renal failure in 0.03% of cases, acute respiratory distress syndrome (bilateral chest xray 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

y

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 (see Frequency). 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 (see Frequency).

y

Age
See Morbidity/Mortality for a discussion regarding the role of age in pyelonephritis.

Clinical
History
y
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.

y

o o o

Internal dysuria usually refers to the urinary tract. External dysuria most commonly refers to the vagina. Symptoms may include urinary frequency, hesitancy, lower abdominal pain, and urgency. 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. The description of suprapubic symptoms varies and may include discomfort, heaviness, pain, or pressure.

o y

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 o o o

Fever is not always present. When present, it is not unusual for the temperature to exceed 103°F (39.4°C). The patient may demonstrate rigor, and chills may be present in the absence of demonstrated fever. Malaise and weakness may also be present. Gastrointestinal symptoms vary. Anorexia is common. Nausea and vomiting vary in frequency and intensity from absent to severe. Diarrhea occurs infrequently.

Physical
y
Vital signs

o o o

There may or may not be a fever. The temperature may be greater than 103°F (39.4°C), or it may be subnormal in patients with associated sepsis. Tachycardia may or may not be present, depending on associated fever, dehydration, and sepsis. 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.

y

Appearance

o o y

The patient's appearance is variable. Most commonly, the patient is uncomfortable or appears ill. 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. Bowel sounds are often normoactive. 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.

o o

y

Pelvic examination

o 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. 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. The first consideration is what uropathogens are typically cultured and at what frequency (see Table 2). Second, UTIs that are complicated indicate a high risk for upper UTI 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 Infections1 Open table in new window

Bacteria Gram Negative E. coli P. mirabilis Klebsiella spp Citrobacter spp Enterobacter spp P. aeruginosa Other Gram Positive

% Uncomplicated % Complicated

70-95 1-2 1-2 <1 <1 <1 <1

21-54 1-10 2-17 5 2-10 2-19 6-20

Coagulase-Negative Staphylococci 5-102 Enterococci Group B Streptococci S. aureus Other Bacteria Gram Negative E. coli P. mirabilis Klebsiella spp Citrobacter spp Enterobacter spp 70-95 1-2 1-2 <1 <1 1-2 <1 <1 <1

1-4 1-23 1-4 1-23 2

% Uncomplicated % Complicated

21-54 1-10 2-17 5 2-10

P. aeruginosa Other Gram Positive

<1 <1

2-19 6-20

Coagulase-Negative Staphylococci 5-102 Enterococci Group B Streptococci S. aureus Other 1-2 <1 <1 <1

1-4 1-23 1-4 1-23 2

1 - Adapted from Hooton (2003)35 2 -S. saprophyticus

Table 3. Classification of Factors in Complicated UTI1 Open table in new window

Bacteria Gram Negative E. coli P. mirabilis Klebsiella spp Citrobacter spp Enterobacter spp P. aeruginosa Other Gram Positive

% Uncomplicated % Complicated

70-95 1-2 1-2 <1 <1 <1 <1

21-54 1-10 2-17 5 2-10 2-19 6-20

Coagulase-Negative Staphylococci 5-102 Enterococci Group B Streptococci S. aureus Other Bacteria Gram Negative E. coli P. mirabilis Klebsiella spp Citrobacter spp Enterobacter spp P. aeruginosa Other Gram Positive Coagulase-Negative Staphylococci 5-102 Enterococci Group B Streptococci S. aureus Other 1-2 <1 <1 <1 70-95 1-2 1-2 <1 <1 <1 <1 1-2 <1 <1 <1

1-4 1-23 1-4 1-23 2

% Uncomplicated % Complicated

21-54 1-10 2-17 5 2-10 2-19 6-20

1-4 1-23 1-4 1-23 2

1 - Adapted from Hooton (2003)35 2 -S. saprophyticus

Table 4. Classification of Factors in Complicated UTI1

Open table in new window

Factors Alteration of Structure / Function of the Urinary Tract Obstruction (intrinsic/extrinsic): bladder/renal abscesses, cystocele, fungus ball, gravid uterus, papillary necrosis, prostatic swelling (benign, prostatitis, cancer), strictures, urinary stents, urinary stones Urinary diversion procedures Foreign bodies: urinary stents urinary stones, Foley catheter, Texas catheter, nephrostomy tubes Vesicoureteral reflux Neurogenic bladder Fistulae Diabetes

Comments

Most important factor predisposing to UTI; urine flushing effect negated; changes in renal blood flow affecting delivery of neutrophils and antibiotics; bacterial multiple in continuous pool of urine and more readily infect other parts of kidney; gravid uterus displaces bladder anterosuperiorly producing urinary stasis Continuously infected; usually 2 or more organisms; renal calculi common secondary to Proteus spp. Allow surfaces for organisms to colonize and multiply; biofilms (microbes on surface imbedded in protective matrix, primarily polysaccharide) Identified in 30-50% children after first UTI; 5 grades; grades 1-2 (mild reflux) resolve/improve with time; grades 3-5 manifest with moderate to severe dilatation of ureter, pelvis, and calyces Abnormal bladder emptying; bladder over-distention; frequent instrumentation; urinary stasis; vesicoureteral reflux; host compromise secondary to chronic illness; poor personal Poor bladder emptying and urinary secondary to autonomic neuropathy; more frequent instrumentation; acute pyelonephritis may be bilateral

Special Patient Groups Age >65 years Neonates and Infants Children Nosocomial infections Nursing home patients Other chronically institutionalized patients

Males & females; co-morbidities; increased instrumentation; aging immune system See Pediatric Issues See Pediatric Issues Co-morbidities; more virulent pathogens; more antibiotic resistance Same as Nosocomial Same as Nosocomial

Metabolic / Medication Diabetes Pregnancy Renal impairment Sickle cell disease Analgesic abuse

When out of control, glucose in urine leads to greater bacterial growth; microangiopathy; leukocyte dysfunction; predisposition to papillary necrosis; acute pyelonephritis may be bilateral; associated with 75% of perinephric abscesses Elevated progesterone produces decreased ureteral peristalsis and increased bladder capacity UTI's occur commonly Predisposition to papillary necrosis

Predisposition to papillary necrosis Immunocompromise Renal transplant Neutropenia Congenital immunodeficiency syndromes Acquired immunodeficiency syndrome Other transplants

Acute pyelonephritis does not affect graft survival, except during the first three months after transplantation Duration of severe neutropenia, urinary diversion, and hydronephrosis were associated with pyelonephritis in 16.7% cases of neutropenic fever in genitourinary cancer in one study Increased UTI's with septic complications correlate with level of CD4 count Unknown whether organ transplantation other than kidney, predisposes to pyelonephritis, but may not, because of widespread use of broad-spectrum antibiotics

Special Pathogens Tuberculosis (TB) Yeasts and Fungi Pseudomonas aeruginosa Resistant bacteria Proteus spp Corynebacterium urealyticum

One of most common manifestations of extrathoracic TB; in immunocompromised host Mycobacteria spp involved M. avium, M. bovis, M. kansii infections occur; spread to kidney is hematogenous; complications include renal parenchymal destruction, ureteral obstruction, contracted bladder, urethral stricture, and epididymo-orchitis Usually seen in acute leukemia with neutropenia; hematogenous spread Opportunistic uropathogen in 35% hospital-acquired UTI's; produces adhesins (lectins) instrumental in its infectious pathogenesis; in an acute pyelonephritis mouse model, it is more efficient at increasing bacterial load and renal pathology, when involved in a biofilms; predisposes to papillary necrosis Proteus mirabilis is present in fecal flora of 25% of individuals; usually easily eradicated, but persistence leads to significant urinary alkalinization and precipitation of calcium, magnesium, ammonium, and phosphate, leading to struvite stone formation; the bacterial persist within the stone Predisposes to stone formation with organism persisting in stone

History UTI symptoms >3-7 days Two prior episodes of pyelonephritis in an adult Acute renal colic Prior renal stones Gross hematuria

In healthy, young women with typical UTI symptoms 15-50% have occult pyelonephritis, as demonstrated by upper tract studies

Other Infections Infected renal cysts Infected stones Bladder abscess Hematogenous spread (endocarditis, intravenous drug abuse, distant infection, such as dental abscess, skin abscess, or respiratory tract infection) Factors Alteration of Structure / Function of the Urinary Tract Obstruction (intrinsic/extrinsic): bladder/renal abscesses, cystocele, fungus ball, gravid uterus, papillary necrosis, prostatic swelling (benign, prostatitis, cancer), strictures, urinary stents, urinary stones Urinary diversion procedures Foreign bodies: urinary stents urinary stones, Foley catheter, Texas catheter, nephrostomy tubes Vesicoureteral reflux Neurogenic bladder Fistulae Diabetes

Infected via hematogenous spread, reflux, surgery, cyst puncture; common complication of cystic renal disease; can lead to acute perinephric/intrarenal infection, and recurrent pyelonephritis See Unusual Pathogens above Organism usually Staphylococcus aureus or Streptococcus spp Comments

Most important factor predisposing to UTI; urine flushing effect negated; changes in renal blood flow affecting delivery of neutrophils and antibiotics; bacterial multiple in continuous pool of urine and more readily infect other parts of kidney; gravid uterus displaces bladder anterosuperiorly producing urinary stasis Continuously infected; usually 2 or more organisms; renal calculi common secondary to Proteus spp. Allow surfaces for organisms to colonize and multiply; biofilms (microbes on surface imbedded in protective matrix, primarily polysaccharide) Identified in 30-50% children after first UTI; 5 grades; grades 1-2 (mild reflux) resolve/improve with time; grades 3-5 manifest with moderate to severe dilatation of ureter, pelvis, and calyces Abnormal bladder emptying; bladder over-distention; frequent instrumentation; urinary stasis; vesicoureteral reflux; host compromise secondary to chronic illness; poor personal Poor bladder emptying and urinary secondary to autonomic neuropathy; more frequent instrumentation; acute pyelonephritis may be bilateral

Special Patient Groups Age >65 years Neonates and Infants Children Nosocomial infections Nursing home patients Other chronically institutionalized patients

Males & females; co-morbidities; increased instrumentation; aging immune system See Pediatric Issues See Pediatric Issues Co-morbidities; more virulent pathogens; more antibiotic resistance Same as Nosocomial Same as Nosocomial

Metabolic / Medication Diabetes Pregnancy

When out of control, glucose in urine leads to greater bacterial growth; microangiopathy; leukocyte

Renal impairment Sickle cell disease Analgesic abuse

dysfunction; predisposition to papillary necrosis; acute pyelonephritis may be bilateral; associated with 75% of perinephric abscesses Elevated progesterone produces decreased ureteral peristalsis and increased bladder capacity UTI's occur commonly Predisposition to papillary necrosis Predisposition to papillary necrosis

Immunocompromise Renal transplant Neutropenia Congenital immunodeficiency syndromes Acquired immunodeficiency syndrome Other transplants

Acute pyelonephritis does not affect graft survival, except during the first three months after transplantation Duration of severe neutropenia, urinary diversion, and hydronephrosis were associated with pyelonephritis in 16.7% cases of neutropenic fever in genitourinary cancer in one study Increased UTI's with septic complications correlate with level of CD4 count Unknown whether organ transplantation other than kidney, predisposes to pyelonephritis, but may not, because of widespread use of broad-spectrum antibiotics

Special Pathogens Tuberculosis (TB) Yeasts and Fungi Pseudomonas aeruginosa Resistant bacteria Proteus spp Corynebacterium urealyticum

One of most common manifestations of extrathoracic TB; in immunocompromised host Mycobacteria spp involved M. avium, M. bovis, M. kansii infections occur; spread to kidney is hematogenous; complications include renal parenchymal destruction, ureteral obstruction, contracted bladder, urethral stricture, and epididymo-orchitis Usually seen in acute leukemia with neutropenia; hematogenous spread Opportunistic uropathogen in 35% hospital-acquired UTI's; produces adhesins (lectins) instrumental in its infectious pathogenesis; in an acute pyelonephritis mouse model, it is more efficient at increasing bacterial load and renal pathology, when involved in a biofilms; predisposes to papillary necrosis Proteus mirabilis is present in fecal flora of 25% of individuals; usually easily eradicated, but persistence leads to significant urinary alkalinization and precipitation of calcium, magnesium, ammonium, and phosphate, leading to struvite stone formation; the bacterial persist within the stone Predisposes to stone formation with organism persisting in stone

History UTI symptoms >3-7 days

In healthy, young women with typical UTI symptoms

Two prior episodes of pyelonephritis in an adult Acute renal colic Prior renal stones Gross hematuria Other Infections Infected renal cysts Infected stones Bladder abscess Hematogenous spread (endocarditis, intravenous drug abuse, distant infection, such as dental abscess, skin abscess, or respiratory tract infection)

15-50% have occult pyelonephritis, as demonstrated by upper tract studies

Infected via hematogenous spread, reflux, surgery, cyst puncture; common complication of cystic renal disease; can lead to acute perinephric/intrarenal infection, and recurrent pyelonephritis See Unusual Pathogens above Organism usually Staphylococcus aureus or Streptococcus spp