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. Diagnosing and managing acute pyelonephritis is not always straightforward. In the age range of 5-65 years, it typically presents in the context of a symptomatic (eg, dysuria, frequency, urgency, gross hematuria, suprapubic pain) urinary tract infection (UTI) with classic upper urinary tract symptoms (eg, flank pain, back pain) with or without systemic symptoms (eg, fever, chills, abdominal pain, nausea, vomiting) and signs (eg, fever, costovertebral angle tenderness) with or without leukocytosis. However, it can present with nonspecific symptoms. A number of studies using immunochemical markers have shown that many women, who initially present with lower tract symptoms, actually have pyelonephritis. This group of young women is often identified when short-course therapy for uncomplicated cystitis fails. In the extremes of age, the presentation may be so atypical that pyelonephritis is not in the differential diagnosis. In the infant, the presentation may be feeding difficulty or fever. In the elderly, the presentation may be mental status change or fever. Acute pyelonephritis is complex, and there is no consistent set of signs and symptoms that are both sensitive and specific for the diagnosis; therefore, clinicians must maintain a high index of suspicion. In contrast to the plethora of data available for the treatment of lower UTI, less substantial data are available regarding the appropriate antibiotic choice or duration of therapy for acute pyelonephritis, but useful recommendations can be made. An additional cause for concern is the growing antimicrobial resistance to accepted standards of treatment. The current emphasis on cost effectiveness and the advent of newer antibiotics have led clinicians to reevaluate the benefit of hospitalization to treat patients with acute pyelonephritis; however, if the patient is managed as an outpatient, he or she should have close follow-up care. The first follow-up visit should occur in 1-2 days, depending on the clinician's estimation of the severity of the infection. Any deterioration or unsatisfactory improvement warrants admission for intravenous antibiotics and evaluation for any complications. Most cases of uncomplicated pyelonephritis in young women can be managed successfully on an outpatient basis. Pathophysiology: Acute pyelonephritis results from bacterial invasion of the renal parenchyma. In all age groups, episodes of bacteriuria occur commonly, but most are asymptomatic (ABU) and do not lead to infection. Infection is influenced by bacterial factors and host factors. Most bacterial data are derived from research with Escherichia coli, which accounts for 70-90% of uncomplicated UTIs and 21-54% of complicated UTIs. A subset of E coli, the uropathogenic E coli (UPEC), also termed extraintestinal pathogenic E coli (ExPEC), accounts for most clinical isolates from UTIs. UPEC derives commonly from the phylogenetic groups B2 and D, which express distinctive O, K, and H antigens. UPEC genes encode several postulated virulence factors (VFs), including adhesins, protectins, siderophores, and toxins, as well as having the metabolic advantage of synthesizing essential substances. Adhesins have specific regions that attach to cell receptor epitopes in a lock-and- key fashion. Mannose-sensitive adhesins (usually type 1 fimbriae) are present on essentially all E coli. They contribute to colonization (eg, bladder, gut, mouth, vagina) and possibly pathogenesis of infection; however, they also attach to polymorphonuclear leukocytes (PMN), leading to bacterial clearance. Mannose- resistant adhesins permit the bacteria to attach to epithelial cells, thereby resisting the cleansing action of urine flow and bladder emptying. They also allow the bacteria to remain in close proximity to the epithelial cell, enhancing the activity of other VFs. The P fimbriae family of adhesins are epidemiologically associated with prostatitis, pyelonephritis (70-90% of strains), and sepsis. This same family of adhesins in associated with less than 20% of ABU strains. The AFA/Dr family is associated with diarrhea, UTI, and particularly pyelonephritis in pregnancy. The S/F1C family is associated with neonatal meningitis and UTI. Siderophores are involved iron uptake, an essential element for bacteria, and possibly adhesion. Protectins include lipopolysaccharide (LPS) coatings (resist phagocytosis), Tra T and Iss (both resist action of complement), and Omp T (cleave host defense proteins, such as immunoglobulins). Toxins, including alpha hemolysin, cytotoxic necrotizing factor-1, cytolethal distending toxin, and secreted autotransporter toxin, affect various host cell functions; LPS shed from a membrane or released by bacterial lysis leads to cytokine release. No single VF is sufficient or necessary to promote pathogenesis. It seems that a multiple VFs are necessary to ensure pathogenesis, although adhesins play an important role. Bacterial strains producing ABU may provide, in some instances (controversial), a measure of protection against symptomatic infections from UPEC and other organisms; but, it may also cause increased morbidity and mortality. Once bacteriuria is established, these strains appear to stop producing adhesins, allowing them to survive and persist without producing an inflammatory reaction. The frequency of ABU in preschool girls is less than 2%; in pregnant women, 2- 9.5%; in women aged 65-80 years, 18-43%; in men aged 65-80 years, 1.5- 15.3%; in women older than 80 years, 18-43%; and in men older than 80 years, 5.4-21%. There is considerable morbidity associated with ABU in pregnancy, renal transplantation, and genitourinary surgery UPEC account for most infections in uncomplicated pyelonephritis and a significant portion to most infections in complicated pyelonephritis. Other microorganisms commonly isolated are Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus mirabilis, enterococci, Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter species. This is the same spectrum of organisms cultured with UTIs. In 10-15% of symptomatic UTI cases, bacteria are not cultured using routine methods, although they typically respond to antibiotic therapy. In some UTI cases, using selective media, Gardnerella vaginalis, Mycoplasma hominis, and Ureaplasma urealyticum have been cultured. These UTI data cannot be extended to acute pyelonephritis, but they do illustrate the difficulties in isolating the causative organism. Evidence suggests that the pathogenesis of pyelonephritis takes a 2-step path. First, UPEC attaches to the epithelium and triggers an inflammatory response involving at least 2 receptors, glycosphingolipid (GSL) and TOLL-like receptor 4 (TLR4). In the mouse model, GSL is the primary receptor and TLR4 is recruited and is an important receptor for the release of chemokines. When TLR4 is genetically absent, an asymptomatic carrier state develops in the infected mice. Second, as a result of the inflammatory response, chemokines, such as interleukin-8 (IL-8), chemotactic for PMNs, are released and attach to the neutrophil-activating chemokine receptor 1 (CXCR1), allowing PMNs to cross the epithelial barrier into the urine. In children prone to pyelonephritis, for example, CXCR1 expression has been shown to be significantly lower than in control subjects. Several other host factors mitigate against symptomatic UTI. Phagocytosis of bacteria in urine is maximized at pH 6.5-7.5 and osmolality of 485 mosM; values deviating from these values lead to significantly reduced or absent phagocytosis. Other important factors are the flushing action of urine flow in the ureter and bladder, the inhibiting of attachment of type 1 fimbriae E coli to uroepithelial cells by tubular cell–secreted Tamm-Horsfall protein, and the inhibiting of attachment by some surface mucopolysaccharides on the uroepithelial cells. When a UTI or pyelonephritis becomes complicated (complicated UTI), host defenses are compromised, thereby increasing the likelihood of infection. The definition of a complicated UTI is an infection of the urinary tract involving urinary tract structural abnormalities, urinary tract functional abnormalities, metabolic abnormalities predisposing to UTIs, unusual pathogens, recent antibiotic use, recent urinary tract instrumentation, or a combination of these such that the efficacy of antibiotics is reduced. These abnormalities include but are not limited to obstruction (congenital or acquired), stents, vesicoureteral reflux, incomplete bladder emptying, use of spermicide, diabetes mellitus, atrophic vaginal mucosa, prostatitis, immunodeficiency (congenital or acquired), unusual organisms (eg, Mycoplasma, Pseudomonas), urea-splitting organisms (eg, Proteus, sometimes E coli, Klebsiella, Pseudomonas, Staphylococcus), medullary scars, and pregnancy. Obstruction is the most important factor. It negates the flushing effect of urine flow; allows urine to pool (urinary stasis), providing bacteria a medium in which to multiply; and changes intrarenal blood flow, affecting neutrophil delivery. Intrinsic obstruction occurs with bladder outlet obstruction, cystocele, fungus ball, papillary necrosis, stricture, and urinary stone. The probability of stone passage decreases while the probability of obstruction increases with increasing size of the stone. Nonetheless, stones as small as 2 mm have resulted in obstruction, while 8 mm stones have occasionally passed spontaneously. Extrinsic obstruction occurs with chronic constipation (particularly in children), prostatic swelling/mass (eg, hypertrophy, infection, cancer), and retroperitoneal mass. Incomplete bladder emptying may be medication related (eg, anticholinergics). Spermicide nonoxynol-9 inhibits the growth of lactobacilli, which produce hydrogen peroxide. Frequent sexual intercourse causes local mechanical trauma to the urethra in both partners. Diabetes mellitus produces autonomic bladder neuropathy, glucosuria, leukocyte dysfunction, microangiopathy, and nephrosclerosis; additionally, it leads to recurrent bladder instrumentation secondary to the neuropathy. Atrophic vaginal mucosa in postmenopausal women predisposes to the colonization of urinary tract pathogens and UTIs due to the higher pH (5.5 vs 3.8) and the absence of lactobacilli. Bacterial prostatitis (acute or chronic) produces bacteriuria, while nonbacterial prostatitis and pelviperineal pain syndrome (prostadynia) do not. Pseudomonas aeruginosa has several mechanisms that promote adherence, including alginate, other membrane proteins, pili, and surface-associated exoenzyme S urea-splitting organisms produce urease, which hydrolyzes urea (urea-splitting), yielding ammonia, bicarbonate, and carbonate, leading to a more alkaline urine, allowing crystal formation (staghorn calculus) from the supersaturation of carbonate apatite and struvite. Staghorn calculi continue to grow in size, leading to infection, obstruction, or both. Complications of obstruction with superimposed infection include hydronephrosis, pyonephrosis, urosepsis, and xanthogranulomatous pyelonephritis (XGP). Additionally, the organisms can sequester in the struvite stones protected from the host's immune system. Proteus species are the most common urea-splitting organisms; however, E coli, Klebsiella, Pseudomonas, and Staphylococcus can produce urease; therefore, they sometimes are also involved in staghorn calculus formation. Pregnancy (hormonal and mechanical changes) predisposes a woman to upper urinary traction infections. Hydroureter of pregnancy, secondary to both hormonal and mechanical factors, is manifested as dilatation of the renal pelvis and ureters (left > right) with the ureters containing up to 200 mL urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis. Complicated UTI can result from one or more diverse factors. Although there are many instances when more than one factor is involved, in any given episode of acute pyelonephritis, the presence of any one of these factors, as described above, should raise the clinician's index of suspicion. Occult upper urinary tract infections (pyelonephritis) occur in 15-50% (or more) of all UTIs, based on several studies on localization of organisms within the urinary tract. If the host is healthy, particularly young, premenopausal women, without any of the complicating factors listed above, then the occult pyelonephritis can be considered an uncomplicated infection. However, if the host is male, elderly, or a child, or if the host has had symptoms for more than 7 days, then the infection should be considered complicated until proven otherwise. Acute pyelonephritis usually occurs secondary to bacteria ascending from the lower urinary tract. Hematogenous spread to the kidney can occur. Sources for gram-positive organisms, such as Staphylococcus, are intravenous drug abuse and endocarditis. Hematogenous spread to the kidney by gram-negative organisms appears less likely based on the observation that experimental pyelonephritis is difficult to reproduce by intravenous introduction of gram- negative bacilli, unless an underlying problem, such as an obstruction, exists. Little or no evidence supports lymphatic spread of uropathogens to the kidney. Frequency: In the US: There are at least 250,000 cases of diagnosed pyelonephritis in the United States annually (1995 estimate) with 192,000 admissions (1997 National Inpatient Sample database). Lower UTIs predispose to pyelonephritis. From 1988-1994, there were an estimated 12.7 million UTIs annually in women according to the National Health and Nutrition Examination Survey III. In men, the estimated incidence for the same period was 2 million UTIs. Several studies suggest that 15-50% of these infections are occult pyelonephritis, but these infections may be considered uncomplicated if the host is healthy, outside the extremes of age, and without any complicating factors. If complicating factors are present (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 urinary tract infections. In children 2 years and younger, the most common symptoms of UTI are failure to thrive, feeding difficulty, fever, and vomiting. In children, up to 25% of patients with UTI and no signs or symptoms of pyelonephritis do have bacteria demonstrable in the upper tract. Mortality/Morbidity: Pyelonephritis causes considerable morbidity, but these data can only be extrapolated from the morbidity data for acute lower UTIs. Specifically, acute cystitis in women produces approximately 6.1 days with symptoms, 2.4 days of restricted activity, 1.2 days that the patient is unable to work or attend class, and 0.4 days bed-ridden. Uncomplicated pyelonephritis is not a fatal disease in the antibiotic era. Pyelonephritis becomes a potentially fatal disease when secondary conditions develop, such as emphysematous pyelonephritis (20-80% mortality rate), perinephric abscess (20-50% mortality rate), or one of the sepsis syndromes (>25% overall mortality rate). The genitourinary (GU) system is the source of severe sepsis in 9.1% of all cases annually (approximately 750,000). The mortality for these GU-related cases is 16.1%. Overall severe sepsis mortality significantly increases with chronic renal disease (36.7%), acute renal dysfunction (38.2%), and age older than 64 years (25-42% with progressively increasing age to >85 y). In the age range of 0-4 years, the mortality is 5%; for ages 5-50 years, it is less than 3%. Severe sepsis, in general, treated with early goal-directed therapy has been shown to reduce in-hospital mortality from 46.5% to 30.5% (see Treatment). Rarely, acute pyelonephritis can cause acute renal failure (ARF) in children, healthy adults, and pregnant women. When this occurs, characteristically, there is a slower recovery compared to other causes of ARF. In most instances, other factors are thought to contribute to the ARF, that is, medications, hypovolemia, obstruction, or sepsis. In women, mortality is increased in those older than 65 years; it is also increased with septic shock, bedridden status, and immunosuppression. Morbidity (prolonged hospital stay) is increased with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter. In men, mortality is increased in those older than 65 years; it is also increased with septic shock, bedridden status, and recent use of antibiotics (within 1 mo). Morbidity (prolonged hospital stay) is increased in those older than 65 years and also with a change in initial treatment, diabetes mellitus, and long-term indwelling catheter. In children, renal scarring can be detected in 6-15% after a febrile UTI. Of these patients, almost all males and some females have demonstrable renal scarring and a globally small kidney with smooth renal outlines in infancy, usually associated with VUR, and is thought to be congenital. Most females do not have demonstrable scarring on initial imaging in infancy, but they subsequently develop it. Patients with scarring are at risk for hypertension and renal insufficiency. Factors that increase this risk are delay in treatment of UTIs/pyelonephritis, recurrent UTIs, urinary obstruction, and VUR. Acute pyelonephritis (single episode; first UTI ever in one half of cases) in an adult woman leads to renal scarring in 46%, as demonstrated by Tc99m-labeled dimercaptosuccinic acid scanning 10 years later. Subsequent UTIs do not appear to affect the risk of future scarring. Acute pyelonephritis during pregnancy leads to acute renal dysfunction (creatinine, 1.2) in 2% of cases (20-25% in the past), acute renal failure in 0.03% of cases, acute respiratory distress syndrome (bilateral chest x-ray infiltrates and hypoxemia without pulmonary hypertension) in 1-8% of cases, low birth weight (<2500 g) in 7% of cases, preterm delivery (<37 wk gestation) in 5% of cases (6- 50% in the past), recurrence prior to delivery in 18-20% of cases, and sepsis (positive blood cultures) in 17% of cases. Renal scarring has been demonstrated to be 4 times more likely after pyelonephritis in pregnant women than in nonpregnant women. Acute renal transplant pyelonephritis occurring in the first 3 months after transplant has a significant association with graft loss (>40%) by 96 months as compared to all renal transplant cases with or without the occurrence of pyelonephritis at any time after the transplant up to 96 months (25-30%). Race: No racial predilection of pyelonephritis has been demonstrated. Sex: Pyelonephritis is significantly more common in females than in males. This 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 and Mortality for a discussion regarding the role of age in pyelonephritis. History: Patients may present with minimal or severe symptoms. Symptoms usually develop over hours or over the course of a day. Infrequently, symptoms develop over days and may even be present for a few weeks before a patient presents for evaluation. Symptoms of lower UTI may or may not be present to varying degrees. o Internal dysuria usually refers to the urinary tract. External dysuria most commonly refers to the vagina. o Symptoms may include urinary frequency, hesitancy, lower abdominal pain, and urgency. o Gross hematuria (hemorrhagic cystitis) is present in 30-40% of female cases, most often young adults. It may occur in males but is unusual and a more serious cause must be considered. o The description of suprapubic symptoms varies and may include discomfort, heaviness, pain, or pressure. Symptoms of acute pyelonephritis may be present to varying degrees. o Severity of pain may be mild, moderate, or severe. Flank pain may be unilateral or sometimes bilateral. Discomfort or pain may be present in the back (lower or middle) and/or the suprapubic area. Upper abdominal pain is unusual, and radiation of pain to the groin is suggestive of a ureteral stone. o Fever is not always present. When present, it is not unusual for the temperature to exceed 103¡ãF (39.4¡ãC). o The patient may demonstrate rigor, and chills may be present in the absence of demonstrated fever. o Malaise and weakness may also be present. o Gastrointestinal symptoms vary. Anorexia is common. Nausea and vomiting vary in frequency and intensity from absent to severe. Diarrhea occurs infrequently. Physical: Vital signs o There may or may not be a fever. The temperature may be greater than 103¡ãF (39.4¡ãC), or it may be subnormal in patients with associated sepsis. o Tachycardia may or may not be present, depending on associated fever, dehydration, and sepsis. o Blood pressure is usually within the reference range, unless the patient has underlying hypertension; in cases of underlying hypertension, the pressure may be elevated above the patient's baseline. A systolic blood pressure less than 90 mm Hg suggests shock secondary to sepsis or perinephric abscess. Appearance o The patient's appearance is variable. Most commonly, the patient is uncomfortable or appears ill. o Patients usually do not have a toxic appearance unless an underlying problem, such as sepsis, perinephric abscess, or significant dehydration, is present. Abdominal examination o Suprapubic tenderness usually ranges from mild to moderate without rebound. Abdominal tenderness other than in the suprapubic area suggests another diagnosis. Usually, abdominal rebound, rigidity, or guarding is not found. o Bowel sounds are often normoactive. o Flank or costovertebral angle (CVA) tenderness is most commonly unilateral over the involved kidney, although bilateral discomfort may be present. Discomfort varies from absent to severe. This is usually not subtle and may be elicited with mild or moderately firm palpation. Pelvic examination o A pelvic examination should be performed. Tenderness of the cervix, uterus, and adnexa should be absent. Any positive finding suggests an additional or alternative diagnosis. o If any doubt remains as to the diagnosis, if any signs or symptoms of urethritis or vaginitis are present, or if a history of dyspareunia is present, a gynecologic cause of the symptoms should be pursued. Causes: When considering the cause of acute pyelonephritis, there are 3 considerations. First, what are the uropathogens that are typically cultured and at what frequency (see Table 2)? Second, UTIs that are complicated indicate a high risk for upper urinary tract infection or occult pyelonephritis in the absence of signs and symptoms typical of acute pyelonephritis. A complicated UTI is defined as a UTI in the presence of at least one of several factors that will reduce the efficacy of antimicrobial therapy, leading to failure of therapy (eg, progression to overt pyelonephritis, sepsis, renal failure, abscess formation, worsening clinical condition, resistant organism), relapse, or persistence of infection (see Table 3). Any patient with a complicated UTI should be referred, if possible, to a nephrologist, a urologist, an infectious disease specialist, or another physician trained to managed complicated UTIs. The patient will require ongoing management, including repeat cultures, metabolic studies, and appropriate imaging studies. The third consideration in the management of acute pyelonephritis is what organisms are involved in complicated UTIs and what are their antimicrobial sensitivities (see Table 2). 1 Table 2. Bacterial Etiology of Urinary Tract Infections Bacteria % Uncomplicated % Complicated Gram Negative E. coli 70-95 21-54 P. mirabilis 1-2 1-10 Klebsiella spp 1-2 2-17 Citrobacter spp <1 5 Enterobacter spp <1 2-10 P. aeruginosa <1 2-19 Other <1 6-20 Gram Positive Coagulase-Negative 5-102 1-4 Staphylococci Enterococci 1-2 1-23 Group B Streptococci <1 1-4 S. aureus <1 1-23 Other <1 2 1 - Adapted from Hooton, 2003 2 - S. saprophyticus Table 3. Classification of Factors in Complicated UTI1 Factors Comments Alteration of Structure / Function of the Urinary Tract Most important factor Obstruction predisposing to UTI; urine (intrinsic/extrinsic): flushing effect negated; changes bladder/renal abscesses, in renal blood flow affecting cystocele, fungus ball, delivery of neutrophils and gravid uterus, papillary antibiotics; bacterial multiple in necrosis, prostatic swelling continuous pool of urine and (benign, prostatitis, cancer), more readily infect other parts of strictures, urinary stents, kidney; gravid uterus displaces urinary stones, bladder anterosuperiorly producing urinary stasis Continuously infected; usually 2 Urinary diversion procedures or more organisms; renal calculi common secondary to Proteus spp. Foreign bodies: urinary Allow surfaces for organisms to stents urinary stones, Foley colonize and multiply; biofilms catheter, Texas catheter, (microbes on surface imbedded nephrostomy tubes in protective matrix, primarily Vesicoureteral reflux polysaccharide) Identified in 30-50% children after first UTI; 5 grades; grades 1-2 (mild reflux) resolve/improve Neurogenic bladder with time; grades 3-5 manifest with moderate to severe Fistulae dilatation of ureter, pelvis, and Diabetes 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 Yrs Males & Females; co-morbidities; Neonates and Infants increased instrumentation; aging Children immune system Nosocomial infections See Pediatric Issues See Pediatric Issues Nursing home patients Co-morbidities; more virulent Other chronically pathogens; more antibiotic institutionalized patients resistance Same as Nosocomial Same as Nosocomial Metabolic / Medication Diabetes When out of control, glucose in urine leads to greater bacterial growth; microangiopathy; Pregnancy leukocyte dysfunction; Renal impairment predisposition to papillary Sickle cell disease necrosis; acute pyelonephritis Analgesic abuse 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 Acute pyelonephritis does not Neutropenia affect graft survival, except during the first three months after Congenital transplantation immunodeficiency Duration of severe neutropenia, syndromes urinary diversion, and Acquired immunodeficiency hydronephrosis were associated syndrome with pyelonephritis in 16.7% Other transplants 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) One of most common manifestations of extra-thoracic TB; in immunocompromised host Mycobacteria spp involved M. avium, M. bovis, M. kansii Yeasts and Fungi infections occur; spread to kidney Pseudomonas aeruginosa is hematogenous; complications include renal parenchymal destruction, ureteral obstruction, contracted bladder, urethral stricture, and epididymo-orchitis Usually seen in acute leukemia Resistant bacteria with neutropenia; hematogenous Proteus spp spread Opportunistic uropathogen in 35% hospital-acquired UTI's; Corynebacterium produces adhesins (lectins) urealyticum 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 Two prior episodes of typical UTI symptoms 15-50% pyelonephritis in an adult have occult pyelonephritis, as Acute renal colic demonstrated by upper tract Prior renal stones studies Gross hematuria Other Infections Other Infections Infected via hematogenous spread, reflux, surgery, cyst Infected renal cysts puncture; common complication Infected stones of cystic renal disease; can lead Bladder abscess to acute perinephric/intrarenal Hematogenous spread infection, and recurrent (endocarditis, intravenous pyelonephritis drug abuse, distant infection, See Unusual Pathogens above such as dental abscess, skin abscess, or respiratory tract Organism usually Staphylococcal infection) aureus or Streptococcus spp Notes: 1. Adapted from reviews by Hooton TM and Stamm WE (1997), Hootan (2003), Ronal and Harding (1997), and Rubenstein and Shaeffer (2003), and several articles in the Bibliography. Lab Studies: In the outpatient setting, pyelonephritis is usually suggested based on the history and physical examination and is supported by urinalysis results, which should include microscopic analysis. Other lab studies are used to evaluate for complicating conditions and to assist in determining if the patient should be admitted. Most easily diagnosed cases occur in women, both pregnant and nonpregnant. Men, patients at the extremes of age, patients harboring subclinical pyelonephritis, and patients who are hospitalized may present with an insidious onset. This section presents information relative to the perspective of pyelonephritis versus UTIs, in general. o Urinalysis Gross hematuria occurs infrequently with pyelonephritis and is more common with lower UTI (hemorrhagic cystitis). When present, the differential should include calculi, cancer, glomerulonephritis, tuberculosis, trauma, and vasculitis. Pyuria is defined as more than 5-10 WBCs per high-power field (hpf) on a specimen spun at 2000 rpm for 5 minutes. Almost all patients with pyelonephritis have significant pyuria (>20 WBCs/hpf), although the numbers may be smaller, particularly in those with subacute pyelonephritis. The dipstick leukocyte esterase test (LET) helps screen for pyuria. LET results have a sensitivity of 75-96% and a specificity of 94-98% for detecting more than 10 WBC/hpf. The nitrite production test (NPT) for bacteriuria has 92-100% sensitivity and 35-85% specificity and may be falsely negative in the presence of diuretic use, low dietary nitrate, or organisms that do not produce nitrate reductase (eg, Enterococcus, Pseudomonas, Staphylococcus). Combined, the LET-NPT has a sensitivity of 79.2% and a specificity of 81%, which is too low for it to be used as the only screening study for bacteriuria. Microscopic examination may reveal hematuria, but other causes should be considered, particularly calculi. This is especially true if the patient does not respond to therapy. White cell casts are suggestive of pyelonephritis; however, centrifuge speeds (>2000 rpm) used for urinalysis sediment preparation often fracture them and lead to their absence in the sediment. Proteinuria is expected (up to 2 g/d). When it exceeds 3 g/d, glomerulonephritis should be considered. The presence of a single bacterium in an unspun urine specimen by oil-immersion microscopic examination is equivalent to at least 105 organisms. Bacteria are identified much more easily on a stained versus an unstained specimen. o Urine culture Urine culture is indicated in any patient with pyelonephritis, whether treated in an inpatient or an outpatient setting, because of the possibility of antibiotic resistance. Specimens can be collected by clean catch, catheter, or suprapubic puncture (rarely performed or indicated). o Blood cultures Blood cultures are indicated in any patient who is being admitted or who has already been admitted. Approximately 12-20% are positive for infection. Bacteremia has not been associated with a poor outcome unless sepsis or another significant comorbidity is present. Imaging Studies: Imaging studies are rarely indicated for the diagnosis of acute pyelonephritis in the adult who presents with typical signs and symptoms. Imaging may be warranted if the presentation is atypical or confusing. It is also warranted if the patient deteriorates or does not respond to therapy, as illustrated by the following scenarios, in which the important considerations are nephrolithiasis, obstructive uropathy, and perinephric abscess: o The patient has a fever or positive blood culture results that persist for longer than 48 hours. o The patient's condition suddenly worsens. o Toxicity persists for longer than 72 hours. o The patient has a complicated UTI (see Causes). The purpose is to evaluate immediately for an organ- or life-threatening complication. Contrast-enhanced helical/spiral computed tomography scan (CECT) is the imaging study of choice when there is suspicion for the development of a complication of acute pyelonephritis, both in adults and in children. A recent study demonstrated in an experimental model that CECT, magnetic resonance imaging (MRI), and dimercaptosuccinic acid 99m-technetium (99mTc-DMSA) scintigraphy were equivalent in their sensitivity and reliability to detect acute pyelonephritis. Clinical experience is still limited with MRI in this setting, and there are the issues of cost and availability. 99mTc-DMSA scintigraphy is used more often in children to image the urinary tract to lessen radiation exposure. Imaging early in the presentation of acute pyelonephritis may be more useful than previously thought. In one recent study, 16% of cases admitted for acute pyelonephritis were found to have new and clinically significant abnormalities on renal imaging with ultrasound (US) or computed tomography (CT) at the time of admission. Independent of this observation, there are certain patients who warrant imaging at the time of admission, including those with AIDS, poorly controlled diabetes, an organ transplant (particularly renal), another immunocompromised state, sepsis syndrome, or septic shock, because of the increased risk of a complication. The following studies have been used in the diagnosis of acute pyelonephritis: o As mentioned above, CECT is the imaging study of choice in adults. It is more sensitive than ultrasound and intravenous pyelogram (25% sensitivity), and it can more readily identify alterations in renal parenchymal perfusion, alterations in contrast excretion, perinephric fluid, and nonrenal disease. o Noncontrast helical/spiral CT findings may be normal in acute pyelonephritis with mild parenchymal involvement, but the findings are usually positive when the involvement is moderated or severe. It is the standard study for demonstrating gas-forming infections, hemorrhage, inflammatory masses, and obstruction. It also has 97% accuracy in identifying renal stones. o US can sometimes detect acute pyelonephritis, but a negative study does not exclude the possibility. Power Doppler US is superior to color Doppler US in the detection of pyelonephritis but remains inferior to CECT. It is useful in screening for urinary obstruction in children admitted for febrile illnesses. It can help differentiate solid and cystic structures, detect hydronephrosis and stones, and measure blood flow. o 99mTc-DMSA scintigraphy is almost as sensitive clinically as CECT in detecting focal renal abnormalities during acute pyelonephritis in adults. 99mTc-DMSA scintigraphy is not used much in adults because the focal abnormalities are not specific; rather, they are consistent with abscess, cyst, infarct, pyelonephritis, or tumor. Additionally, it is much less available in the acute setting than CECT. In children, it is the preferred study to lessen radiation exposure from CT scans. It is excellent for helping detect inflammation, scarring, and the distribution of renal function between kidneys. DMSA is a radiotracer that localizes to the renal cortex. o Experience with MRI in evaluating acute pyelonephritis is limited but growing. It is a suitable alternative in the patient with iodinated- dye allergy. It can evaluate the genitourinary system prenatally, renal infection/masses/vasculature, and urinary obstruction, using gadolinium-enhanced MRI, a nonnephrotoxic dye study. CT urography and MR urography are evolving modalities that allow evaluation of the renal parenchyma and urothelium, according to one comprehensive study. Currently used in the evaluation of hematuria, these modalities will become more applicable to the study of other urological problems. Imaging may be required to make the diagnosis in infants and children in whom pyelonephritis presents insidiously. Imaging studies in conjunction with urological procedures, including cystoscopy and excretory urography, may be used during a follow-up examination to evaluate for urinary tract abnormalities that can predispose the patient to infection. Patients with complicated UTIs should be considered for follow-up imaging to assess the urinary tract. Procedures: Urine specimens obtained for examination and culture should approximate the urine contained in the bladder as closely as possible. The 3 procedures for collecting such a urine specimen are clean catch, urethral catheterization, and suprapubic needle aspiration. o Clean catch When properly collected, a clean-catch specimen adequately reflects the microbiology of the urine in the bladder. This technique can be performed by ambulatory females aged 6 years and older who do not have any limiting physical handicap. The presence of a large number of epithelial cells after microscopic examination suggests that the specimen is not a true clean catch and is rendered unreliable for culture because of contamination with vaginal contents. Importantly, the patient should wash only the area where urine is passed, wash front to back, hold the cup by the outside, and keep the labia spread while collecting the urine. This is to ensure that the urine goes into the cup without touching the labia. This technique can also be performed by ambulatory males aged 6 years and older who do not have any limiting physical handicap. Specimens are usually reliable. Importantly, the patient should clean the head of the penis, retract the foreskin (in uncircumcised males), maintain a good stream, and hold the cup by the outside. In the presence of epispadias or hypospadias, care must be taken to maintain a good stream while collecting the specimen. o Urethral catheterization This engenders a small risk of introducing bacteria into the sterile bladder environment. Several indications justify this risk when a urine culture is necessary, including (1) inability or difficulty voiding urine even with hydration, (2) marked obesity or redundant labia in females, (3) ill patients who cannot reliably perform the procedure, (4) performance of a urological procedure during which a specimen can be collected, and (5) children aged 2- 6 years (unless a clinician-assisted clean-catch specimen cannot be collected). o Suprapubic needle aspiration This technique is rarely used. It is indicated when (1) another alternative is lacking, (2) the need exists to exclude contamination from other methods of collection, (3) the need exists to verify the presence of an infecting organism that is otherwise considered a contaminant, and (4) the need exists to verify infection in infants who have a positive culture result from a specimen obtained from a strap-on device. Histologic Findings: Features of acute pyelonephritis include suppurative necrosis or abscess formation within the renal substance. Features of chronic pyelonephritis (chronic interstitial nephritis) include papillary atrophy and blunting, interstitial fibrosis with inflammatory infiltrate (ie, lymphocytes, plasma cells, neutrophils [occasional]), tubules (ie, dilated with possible colloid casts, contracted with atrophy of epithelium), and concentric fibrosis about the parietal layer of the Bowman capsule. Medical Care: Supportive care o Rest o Antipyretics as needed o Oral or parenteral pain medications as needed o Oral or parenteral antiemetics as needed o Urinary tract analgesics to relieve dysuria (up to 3 d) o Intravenous or oral fluids to maintain hydration status Reasons for hospital admission o Cannot tolerate oral intake o Unstable social situation (eg, possibility of poor compliance or poor follow-up) o Unstable vital signs o Severe signs and symptoms o Pregnancy o Comorbid disorders that increase the complexity of management or the complication rate (eg, diabetes mellitus, chronic lung disease, congenital or acquired immunodeficiency syndrome) Antibiotic selection o Antibiotic selection is typically empirical, because the results of blood or urine cultures are rarely available by the time a decision must be made. o Initial selection should be guided by local antibiotic resistance patterns. Urine cultures should be checked in 48 hours to determine antibiotic efficacy. o When using an oral-only regimen, the initial dose should be administered at the time of the evaluation. o See Medication for a list of other acceptable antibiotics that are not discussed here. o The etiology of community-acquired infections is usually E coli or other Enterobacteriaceae. Infections usually involve women aged 18-50 years and, infrequently, men of the same age. Accepted outpatient regimens include the following: Administer intravenous ceftriaxone and oral fluoroquinolone to complete a 14-day course. Administer intramuscular ceftriaxone every 24 hours for 1-2 doses and oral fluoroquinolone to complete a 14-day course. Administer intravenous gentamicin (24-hour dose) and oral fluoroquinolone to complete a 14-day course. Administer an intravenous fluoroquinolone and oral fluoroquinolone to complete a 14-day course. Prescribe oral fluoroquinolone for 14 days. Prescribe amoxicillin-clavulanate potassium for 14 days. Prescribe trimethoprim-sulfamethoxazole double strength for 14 days. Use only if the organism is known to be sensitive. o Research suggests that the fluoroquinolone course can be shortened to a 7-day course, instead of the usual 14 days, in healthy, young women with uncomplicated pyelonephritis. o Some clinicians believe that initiating therapy with an intravenous or intramuscular dose of medication reduces the risk of therapeutic failure; other clinicians believe that an oral course is sufficient. Data exist to support both assertions. One prospective study supports using oral therapy alone in patients who can tolerate oral intake, lack signs of sepsis, and do not show signs of obstruction or renal suppuration on urinary tract ultrasonography findings. Another study (prospective, randomized, unblinded) in a controlled, hospital setting compared oral versus intravenous ciprofloxacin for the initial management of severe pyelonephritis. Both regimens were equally efficacious, suggesting that in the outpatient setting, it might be possible to initiate treatment with oral dosing; however, more research is needed. o If enterococci are suggested based on Gram stain results, then ampicillin or vancomycin can replace fluoroquinolone. If any doubt exists as to the diagnosis, then coverage of both Enterobacteriaceae and enterococci is acceptable. o Enterococci have a higher incidence in hospitalized and other institutionalized patients. Ampicillin or amoxicillin should be included in the regimen. If the patient is allergic to penicillin, then vancomycin should be substituted. o Admit patients who appear toxic, if they are not already hospitalized. Refer to Sepsis, Bacterial if this diagnosis is being considered. If complicated acute pyelonephritis is suggested, use one of the following regimens: Treat patients parenterally until they improve clinically. Complete the course of therapy with an oral agent selected based on culture results. Ampicillin and an aminoglycoside are appropriate. If the patient is allergic to penicillin, substitute vancomycin. Ceftriaxone is an option. Fluoroquinolone and vancomycin are options if enterococci are a consideration.