Question

• Discuss common causes of acute pyelonephritis, and describe the pathophysiology, clinical manifestations, evaluation, and treatment.

Answer 1

Acute pyelonephritis results from bacterial invasion of the renal parenchyma. Bacteria usually reach the kidney by ascending from the lower urinary tract.

Signs and symptoms

The classic presentation in patients with acute pyelonephritis is as follows:

Fever - This is not always present, but when it is, it is not unusual for the temperature to exceed 103°F (39.4°C)

Costovertebral angle pain - Pain may be mild, moderate, or severe; flank or costovertebral angle tenderness is most commonly unilateral over the involved kidney, although bilateral discomfort may be present

Nausea and/or vomiting - These vary in frequency and intensity, from absent to severe; anorexia is common in patients with acute pyelonephritis

Pathophysiology

Acute pyelonephritis results from bacterial invasion of the renal parenchyma. Bacteria usually reach the kidney by ascending from the lower urinary tract. In all age groups, episodes of bacteriuria occur commonly, but most are asymptomatic and do not lead to infection. The development of infection is influenced by bacterial factors and host factors. Bacteria may also reach the kidney via the bloodstream. Hematogenous sources of gram-positive organisms, such as Staphylococcus, are intravenous drug abuse and endocarditis. Experimental evidence suggests that hematogenous spread of gram-negative organisms to the kidney is less likely unless an underlying problem exists, such as an obstruction. Little or no evidence supports lymphatic spread of uropathogens to the kidney.

Most bacterial data are derived from research with Escherichia coli, which accounts for 70-90% of uncomplicated UTIs and 21-54% of complicated UTIs (ie, UTIs that are secondary to anatomic or functional abnormalities that impair urinary tract drainage; are associated with metabolic disorders; or involve unusual pathogens). 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, siderophores, protectins, and toxins, as well as having the metabolic advantage of synthesizing essential substances.

Virulence factors

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 neutrophils (PMNs), leading to bacterial clearance.

Siderophores are involved in iron uptake, an essential element for bacteria, and possibly adhesion. Protectins and their contributions to virulence include the following:

Lipopolysaccharide (LPS) coatings: resist phagocytosis

Tra T and Iss: resist action of complement

Omp T: cleave host defense proteins (eg, immunoglobulins)

Toxins, which affect various host cell functions, include the following:

Alpha-hemolysin

Cytotoxic necrotizing factor–1

Cytolethal distending toxin

Secreted autotransporter toxin

Asymptomatic bacteriuria strains

Bacterial strains that produce ABU may in some instances provide a measure of protection against symptomatic infections from UPEC and other organisms. On the other hand, ABU 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.

Pathogens

As noted above, UPEC account for most uncomplicated pyelonephritis cases and a significant portion of complicated pyelonephritis cases. The following microorganisms are also commonly isolated:

Staphylococcus saprophyticus

Klebsiella pneumoniae

Proteus mirabilis

Enterococci

S aureus

Pseudomonas aeruginosa

Enterobacter species.

Epithelial attachment and inflammatory response

Complicated infection

Complicated UTI is an infection of the urinary tract in which the efficacy of antibiotics is reduced because of the presence of one or more of the following:

Structural abnormalities of the urinary tract

Functional abnormalities of the urinary tract

Metabolic abnormalities predisposing to UTIs

Unusual pathogens

Recent antibiotic use

Recent urinary tract instrumentation

For more information on this topic, see Pathophysiology of Complicated Urinary Tract Infections.

Obstruction

Obstruction is the most important factor. It negates the flushing effect of urine flow; allows urine to pool (urinary stasis), providing bacteria a medium in which to multiply; and changes intrarenal blood flow, affecting neutrophil delivery. Obstruction may be extrinsic or intrinsic. Extrinsic obstruction occurs with chronic constipation (particularly in children), prostatic swelling/mass (eg, hypertrophy, infection, cancer), and retroperitoneal mass.

Infectious stones, urease stones, or triple-phosphate stones composed of magnesium ammonium phosphate or struvite and apatite account for 10-15% of all urinary stones. They develop secondary to the action of urea-splitting organisms and can grow rapidly and branch out (ie, staghorn calculi).

Incomplete bladder emptying may be related to medication (eg, anticholinergics). The spermicide nonoxynol-9 inhibits the growth of lactobacilli. Lactobacilli produce hydrogen peroxide, which protects the vaginal ecosystem against pathogens. Frequent sexual intercourse causes local mechanical trauma to the urethra in both partners.

Urea-splitting organisms produce urease, which hydrolyzes urea, yielding ammonia, bicarbonate, and carbonate; this leads to a more alkaline urine and allows crystal formation (staghorn calculus) from the supersaturation of carbonate apatite and struvite. Staghorn calculi continue to grow in size, leading to infection, obstruction, or both.

Pregnancy

Pregnancy produces hormonal and mechanical changes that predispose the woman to upper urinary traction infections. Hydroureter of pregnancy, secondary to both hormonal and mechanical factors, manifests as dilatation of the renal pelvis and ureters (greater on the left than on the right), with the ureters containing up to 200 mL of urine. Progesterone decreases ureteral peristalsis and increases bladder capacity. The enlarging uterus displaces the bladder, contributing to urinary stasis.

Diabetes

Diabetes mellitus produces autonomic bladder neuropathy, glucosuria, leukocyte dysfunction, microangiopathy, and nephrosclerosis; additionally, it leads to recurrent bladder instrumentation secondary to the neuropathy. Complicated UTIs in patients who have diabetes mellitus include the following:

Renal and perirenal abscess

Emphysematous pyelonephritis

Emphysematous cystitis

Fungal infections

Xanthogranulomatous pyelonephritis

Papillary necrosis

Diagnosis

In the outpatient setting, pyelonephritis is usually suggested by a patient’s history and physical examination and supported by urinalysis results. Urine specimens can be collected through the following methods:

Clean catch

Urethral catheterization

Suprapubic needle aspiration

Urinalysis can include the following:

Dipstick leukocyte esterase test (LET) - Helps to screen for pyuria

Nitrite production test (NPT) - To screen for bacteriuria

Examination for hematuria (gross and microscopic) and proteinuria

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

Imaging studies that may be used in assessing acute pyelonephritis include the following:

Computed tomography (CT) scanning -

Magnetic resonance imaging (MRI) –

Ultrasonography

Scintigraphy - To detect focal renal abnormalities

CT and MR urography - Used in the evaluation of hematuria

Inpatient Treatment

The decision regarding admission of a patient with acute pyelonephritis depends on age; host factors, such as immunocompromising chemotherapy or chronic diseases, known urinary tract structural abnormalities, renal calculi, recent hospitalization, or urinary tract instrumentation; and the patient's response to ED therapy.

Admit all patients with complicated UTI. Complicating factors include the following:

Structural abnormalities (eg, calculi, tract anomalies, indwelling catheter, obstruction)

Metabolic disease (eg, diabetes, renal insufficiency)

Impaired host defenses (eg, HIV, current chemotherapy, underlying active cancer)

Pregnancy

Admission is also indicated for patients with apparent clinically uncomplicated pyelonephritis who have any of the following:

Inability to maintain adequate oral hydration

Evidence of vasomotor instability

Unrelenting fever despite antipyretic therapy

Debilitating pain or dehydration that cannot be corrected promptly in the ED

Inadequate home care or resources to fill prescriptions or comply with the medical regimen (eg, homeless patients, adolescents, elderly patients in an acute illness setting who are at risk for clouded judgment, patients with substance abuse issues or other issues that will prevent adequate compliance)

Inpatient care includes the following:

Continue supportive care

Monitor urine and blood culture results

Monitor comorbid conditions for deterioration

Maintain hydration status with IV fluids until hydration can be maintained with oral intake

Continue IV antibiotics until defervescence and significant symptomatic improvement occur; convert to an oral regimen tailored to urine or blood culture results

In patients with acute pyelonephritis who require hospitalization, treatment begins with intravenous (IV) antibiotics. IV therapy should be given for 24-48 hours or until severe symptoms improve. A systematic review of 8 randomized, controlled trials in hospitalized patients with acute pyelonephritis found that early switching to oral antibiotic treatment appears to be as effective and safe as exclusively IV regimens.

Duration of therapy should be at least 10-14 days, inclusive of initial IV therapy. Patient circumstances may warrant more prolonged therapy.

Selection of a regimen should be based on local resistance data, and the regimen should be tailored on the basis of susceptibility results. Recommended regimens are listed in Table 3, below. However, a multinational study in 184 patients found that cefazolin is non-inferior to ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. At 72 hours, defervescence or normalization of white blood cell count had occurred in 87.0% of the cefazolin group versus 85.9% of the ceftriaxone group; in addition, no difference was observed between the two groups for length of stay or 30-day readmission for cystitis or pyelonephritis.

First-line therapy

Ciprofloxacin (Cipro) 400 mg IV q12h for 10-14d or

Levofloxacin (Levaquin) 250 mg IV q24h for 10d or

Levofloxacin (Levaquin) 750 mg IV q24h for 5d

Second-line therapy

Extended-spectrum cephalosporins or penicillins:

Ampicillin-sulbactam (Unasyn) 1.5 g IV q6h or

Piperacillin-tazobactam (Zosyn) 3.375 g IV q6h or

Ticarcillin-clavulanate (Timentin) 3.1 g IV 4-6h or

Cefotaxime (Claforan) 1-2 g IV q8h or

Ceftriaxone (Rocephin) 1 g IV q24h or

Ceftazidime (Fortaz, Tazicef) 2 g IV q8h

All of the above can be administered with or without an aminoglycoside (except in pregnant patients); see Aminoglycosides, below

Carbapenems:

Meropenem (Merrem) 500 mg IV q8h or

Ertapenem (Invanz) 1 g IV q24h or

Doripenem (Doribax) 500 mg IV q8h\

Monobactam (for patients with penicillin allergy):

Aztreonam (Azactam) 1 g IV q8-12h

Alternative therapy

Aminoglycosides (because of their potential nephrotoxicity, aminoglycoside antibiotics should be reserved for patients with serious and potentially life-threatening infections, and their dosage and blood levels should be carefully monitored to minimize the risk of nephrotoxicity):

Gentamicin 3 mg/kg/day IV/IM in 3 divided doses or 7 mg/kg/day pulsed dosing or

Tobramycin 3 mg/kg/day IV/IM in 3 divided doses or 7 mg/kg/day pulsed dosing or

Amikacin 10 mg/kg/day IV/IM in 3 divided doses or 20 mg/kg/day pulsed dosing