Acute pyelonefritis 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 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 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. 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. 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 (Open Table in a new window) Clinical Condition Frequency (%) Female Male Morbidity Screening Treatmen and Recommende t With Mortality d Antibioti c Beneficia l2 0.5-2.5 None No No 0.5 ~0 Comments

Infants (= 36 Months) Preschool School Children and Adolescents

0.4-1.8 0.8-1.3 1.1-1.8

Premenopausa l and Nonpregnant Women

0.8-5.2

Pregnant Women

2-9.54

None No No May persist No No No evidence of for years scar or renal without failure adverse progression, if outcome. untreated. Abx Increased given for any incidence of indication in girls symptomatic leads to increased UTIs3 in symptomatic girls in UTIs in absence of posttreatment treatment. period. More No No No benefits to frequent treatment have UTIs and been identified. subsequent ABU. No other associated long-term adverse outcome. Prior UTI or Yes Yes After treatment of lower socioTreatment ABU, periodic economic At least 1 of ABU follow-up urine status urine culture, reduces cultures associated preferably 2 frequency recommended, with higher consecutive, of AP to 2 e.g. once per

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. ~0 None Young Men 2.8-8.6 0.6-1.5 None Ages 50 65 demonstrated Years . Studies limited. 76% episodes ABU resolve spontaneousl y. 1.5-15.3 See Ages 50 Ages 65 80 5.8-16 65 Years. Years 18-43 5.4-21 See Ages 50 Ages > 80 65 Years. Years 19-37 Associated Institutionalize 25-53 with d urinary/bowe l incontinence and dementia. No decreased

at end 1st trimester5

3%

month. 1 2% women with negative initial urine culture develop ABU and experience AP later in pregnancy.

No No

No No

Co-morbid conditions increase incidence of ABU and UTI.

No No No

No No No

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

Diabetes Mellitus

7.9-17.7

mortality in US studies. 1.5-2.2 No indication of adverse outcome in women. Glucose control not impaired. See AP, Women urosepsis, renal failure. See comments.

Spinal Cord Injury with Bladder Impairment

70-100

Renal Transplant

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

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

Most data in women. Increase frequency probably 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/mortali ty from UTIs. Yes Yes Current practice is to administer Immediate For up to prophylactic Abx post-op period 6 mos. in perioperative and up to 6 period and to mos 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

No

Short Term Catheter

2 7 for See Symptomatic each day Women UTI in 26% catheter and women by 14 in place Comment days post s catheter removal.

No. unless patient has other risk factor

AP, No urosepsis, catheter obstruction, renal stones, vesicouretera l reflux, renal failure, bladder cancer (very long term) See Bacteremia, Yes, to Genitourinary 20 80% with Women sepsis identify Surgery ABU specific develop organisms and bacteremi sensitivities a Indwelling Catheter > 30 Days 1 Adapted from Nicolle (1997)[3] and Nicolle (2003)[4]

100

100

Possibilit y beneficial in women with ABU 48 hours after removal of catheter No

Women have a higher frequency than men.

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

Yes

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

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 interleukin8 (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 cellsecreted 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 hosts 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 clinicians 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 gramnegative bacilli, unless an underlying problem, such as an obstruction, exists. Little or no evidence supports lymphatic spread of uropathogens to the kidney.

Epidemiology
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 (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 18% 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 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).

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