Antimicrobial Selection

Oral antimicrobial agents for treatment of acute uncomplicated cystitis are listed in Table 10–16. TMP and TMP-SMX are effective and inexpensive agents for empirical therapy, resulting in bacteriologic cure (i.e., eradication of the pathogen from the urine) within 7 days after the start of treatment in approximately 94% of women (Warren et al, 1999). They are recommended in areas where the prevalence of resistance to these drugs among E. coli strains causing cystitis is less than 20% (Warren et al, 1999). The probability of resistant strains can be predicted in part from the history of recent antimicrobial usage. Women who have taken TMP-SMX recently are approximately 16 times as likely to be infected with an isolate resistant to this agent compared with women who have not taken the antimicrobial agent recently. In addition, those who have taken any other antimicrobial agent are more than twice as likely to be infected with a resistant isolate (Brown et al, 2002). With a 30% rate of resistance to TMP-SMX, the bacteriologic eradication rate is predicted to be 80% and the clinical cure rate is predicted to be 85% (Gupta et al, 2001). When used alone, TMP is as efficacious as TMP-SMX and is associated with fewer side effects, presumably because of the absence of the sulfa component (Harbord and Gruneberg, 1981). It can be prescribed to patients who are allergic to sulfa. However, TMP can cause hypersensitivity and rashes that may be erroneously attributed to sulfa (Alonso et al, 1992).

Table 10–16 Treatment Regimens for Acute Cystitis

Nitrofurantoin has maintained an excellent level of activity over 4 decades and is well tolerated, but it is more expensive than TMP-SMX and it is considerably less active against aerobic gram-negative rods other than E. coli. Furthermore, it is usually prescribed for 7 days and may cause gastrointestinal upset. It is not associated with plasmid-mediated resistance, however, so it is an excellent choice for patients with recent exposure to most other antimicrobial agents. The high in-vitro resistance to ampicillin and sulfonamide and the high cost of amoxicillin/clavulanate and the cephalosporins limit their usefulness.

The fluoroquinolones offer excellent activity and are well tolerated. Resistance to the fluoroquinolones remains below 5% in most places (Fihn et al, 1988); however, it is increasing in certain areas. Twice-daily and once-daily extended-release fluoroquinolones are equally effective (Henry et al, 2002). Their use for uncomplicated cystitis should be limited to patients with allergy to TMP-SMX, to patients with previous exposure to antimicrobial agents causing bacterial resistance, and to areas where the prevalence of resistance to TMP or TMP-SMX is 20% or greater (Warren et al, 1999; Hooton et al, 2004).

The effects of an antimicrobial agent on the vaginal flora are also important in recurrence of bacteriuria (Fihn et al, 1988). The concentrations of TMP and the fluoroquinolones that have been studied in vaginal secretions are high, eradicating E. coli but minimally altering normal anaerobic and microaerophilic vaginal flora (Hooton and Stamm, 1991). Single-dose regimens using these drugs are less effective than multiple-day regimens in this regard (Fihn et al, 1988), which probably explains why there are more early recurrent infections after single-dose therapy with these drugs. Nitrofurantoin and β-lactam drugs are generally not effective in eliminating E. coli from the vagina.

Duration of Therapy

Three-day therapy is the preferred regimen for uncomplicated cystitis in women (Norrby, 1990; Warren et al, 1999). In an excellent review of more than 300 separate clinical trials of single-dose, 3-day, or 7-day treatment with TMP, TMP-SMX, fluoroquinolones, and β-lactam antimicrobial therapies, it was concluded that, irrespective of the antimicrobial used, 3-day therapy is more effective than single-dose therapy. Three-day therapy with TMP-SMX, TMP, amoxicillin, or cloxacillin has been associated with cure rates similar to longer courses of therapy and an incidence of adverse effects about as low as that seen with single-dose therapy and lower than seen with longer courses of therapy (Charlton et al, 1976; Kunin, 1985; McCue, 1986; Warren et al, 1999). Because 7-day therapy often causes more adverse effects, it is recommended only for women with symptoms of 1 week or more, men, and individuals with possible complicating factors. Other options include nitrofurantoin, perhaps as 7-day therapy, and fosfomycin single-dose therapy; each of these requires further study. β-Lactams as a group are less effective in treatment of cystitis than TMP, TMP-SMX, and the fluoroquinolones.

Seven-day therapy is the preferred regimen in uncomplicated cystitis in men.

Cost of Therapy

The cost of treating a UTI involves not only the initial evaluation and cost of the drug but also what occurs subsequently. The most important prediction of high cost-effectiveness is high efficacy against the most common urinary pathogen, E. coli. The lower the effectiveness against this bacterium, the greater the number of revisits, cases of progression to pyelonephritis, and follow-up costs. Antimicrobial cost is a poor prediction of cost-effectiveness, as illustrated by the finding that the most expensive and least expensive drugs, the fluoroquinolones and TMP-SMX, are approximately equally cost-effective (Rosenberg, 1999). Both of these drugs are more cost-effective than nitrofurantoin and amoxicillin.

Urea-Splitting Bacteria That Cause Struvite Renal Stones

The infection that ultimately leads to an infection stone commonly begins inconspicuously as inadequately treated cystitis. Most patients with P. mirabilis cystitis do not form struvite stones. But struvite stones form in those patients who have a protracted infection with P. mirabilis, an infection that is often asymptomatic or minimally symptomatic. P. mirabilis causes intense alkalinization of the urine with precipitation of calcium, magnesium, ammonium, and phosphate salts and the subsequent formation of branched struvite renal stones. Bacteriuria in most of these patients with struvite stones recurs almost immediately on stopping antimicrobial therapy, usually within 5 to 7 days. The bacteriologic consequences are substantial because the bacteria persist inside these struvite stones even when the urine shows no growth. Indeed, struvite infection stones, together with the occasional oxalate or apatite stone that becomes secondarily colonized, constitute the major cause of bacterial persistence in women in the absence of azotemia.

Underlying urinary tract abnormalities are not a prerequisite for this type of infection. However, patients with indwelling catheters, urinary diversions, or other urinary tract abnormalities are particularly susceptible to these infections. Urea-splitting organisms, such as P. mirabilis, cause infection stones that are relatively radiolucent. If such a stone is suspected, plain film tomograms or CT scans without contrast medium enhancement should be obtained (Greenberg et al, 1982). Medical management with continued suppressive antimicrobial therapy and acidification temporarily relieves symptoms and retards deterioration of renal function in some patients. Complete removal of the calculus is generally required for bacteriologic cure and to prevent renal damage due to obstruction (Silverman and Stamey, 1983). Percutaneous nephrolithotomy and extracorporeal shockwave lithotripsy are now the preferred treatment for most renal and upper ureteral calculi.

When extracorporeal shockwave lithotripsy is used to fragment infection stones, the patient should be maintained on appropriate antimicrobial therapy until the fragments pass. Occasionally, long-term antimicrobial therapy can result in eradication of bacteriuria even if some fragments persist after lithotripsy, presumably because the shockwaves have rendered the entrapped bacteria more susceptible to antimicrobial therapy (Michaels et al, 1988). If percutaneous or open surgery is used, all the residual particles of struvite stones must be removed at surgery to prevent recurrent bacteriuria from bacterial persistence in the calculus. Rocha and Santos (1969) have shown that soaking these stones in iodine and alcohol for 6 hours will not kill the bacteria within the interior of the stone. The importance of recognizing this fact is twofold: (1) The bacteria cannot be killed by antimicrobial therapy, even though the urine may show no growth for months or even years (Shortliffe et al, 1984), and (2) any fragments left behind at the time of surgical removal leave residual bacteria within the interstices of the stone; these bacteria ensure recurrence of the staghorn calculus with its attendant morbidity.

If fragments remain after surgery, a small, multiholed polyethylene catheter should be left for postoperative irrigation with Renacidin or Suby G solution (Silverman and Stamey, 1983). Follow-up radiographs are essential to ensure that all the stone fragments are removed, and cultures must demonstrate that the urease-splitting bacteria are eradicated.

Most of the other congenital or acquired abnormalities listed in Table 10–6 require surgical removal for eradication of the source of bacterial persistence. Chronic bacterial prostatitis is treated initially with long-term antimicrobial therapy and, in select cases, by radical transurethral resection (Mears, 1978).

In patients in whom the focus of infection cannot be eradicated, long-term, low-dose antimicrobial suppression is necessary to prevent symptoms of infection. The antimicrobial drugs used for low-dose prophylaxis will also be effective for bacterial suppression if the persistent strain is susceptible. These include nitrofurantoin, TMP-SMX, cephalexin, and the fluoroquinolones.

Low-Dose Continuous Prophylaxis

Self-Start Intermittent Therapy

With self-start intermittent therapy, the patient is given a dip slide device to culture the urine and is instructed to perform a urine culture when symptoms of UTI occur (Schaeffer and Stuppy, 1999; Blom et al, 2002). The patient is also provided a 3-day course of empirical, full-dose antimicrobial therapy to be started immediately after performing the culture. It is important that the antimicrobial agent selected for self-start therapy have a broad spectrum of activity and achieve high urinary levels to minimize development of resistant mutants. In addition, there should be minimal or no side effects on the bowel flora. Fluoroquinolones are ideal for self-start therapy because they have a spectrum of activity broader than any of the other oral agents and are superior to many parenteral antimicrobials, including aminoglycosides. Nitrofurantoin and TMP-SMX are acceptable alternatives, although they are somewhat less effective. Antimicrobial agents such as tetracycline, ampicillin, SMX, and cephalexin in full doses should be avoided because they can give rise to resistant bacteria (Wong et al, 1985).

The culture is brought to the office as soon as possible. If the culture is positive and the patient is asymptomatic, a culture is performed 7 to 10 days after therapy to determine efficacy. In most cases, the therapy is limited to two inexpensive dip slide cultures and a short course of antimicrobial therapy. If the patient has symptoms that do not respond to initial antimicrobial therapy, a repeat culture and susceptibility testing of the initial culture specimen are performed and therapy adjusted accordingly. If symptoms of infection are not associated with positive cultures, urologic evaluation should be performed to rule out other causes of irritative bladder symptoms, including carcinoma in situ, interstitial cystitis, and neurogenic bladder dysfunction. The authors’ experience with this technique has been very favorable, and is particularly attractive to patients who have less frequent infections and are willing to play an active role in their diagnosis and management.

Postintercourse Prophylaxis

Antimicrobial management through postintercourse prophylaxis is based on research establishing that sexual intercourse can be an important risk factor for acute cystitis in women (Nicolle et al, 1982). Diaphragm users have a significantly greater risk of UTI than do women who use other contraceptive methods (Fihn et al, 1985). Postintercourse therapy with antimicrobial agents, such as nitrofurantoin, cephalexin, TMP-SMX, or a fluoroquinolone taken as a single dose, will effectively reduce the incidence of reinfection (Pfau et al, 1983; Melekos et al, 1997).

Other Strategies

Cranberry juice contains proanthocyanidins that block adherence of pathogens to uroepithelial cells in vitro (Foo et al, 2000). Randomized trials in low-risk patients show that 200 to 750 mL daily of cranberry or lingonberry juice or cranberry-concentrate tablets reduce the risk of symptomatic, recurrent infection by 12% to 20% (Avorn et al, 1994; Kontiokari et al, 2001; Stothers, 2002; McMurdo et al, 2009). However, the actual cranberry content of juices and tablets varies substantially; therefore their efficacy is not predictable (Consumer Reports, 2001; Klein, 2002). Furthermore, other trials of cranberry products show no benefit and there is no evidence that they are effective for treatment of UTIs (Jepson et al, 2001; Raz et al, 2004).

Other factors, such as hygiene, frequency and timing of voiding, wiping patterns, use of hot tubs, and type of undergarments, have not been shown to predispose women to recurrent infection and there is no rationale for giving women specific instructions regarding them.

Clinical Presentation

The clinical spectrum ranges from gram-negative sepsis to cystitis with mild flank pain (Stamm and Hooton, 1993). The classic presentation is an abrupt onset of chills, fever (100° F or greater), and unilateral or bilateral flank or costovertebral angle pain and/or tenderness. These so-called upper tract signs are often accompanied by dysuria, increased urinary frequency, and urgency.

Although some authors regard loin pain and fever in combination with significant bacteriuria as diagnostic of acute pyelonephritis, it is clear from localization studies using ureteral catheterization (Stamey and Pfau, 1963) or the bladder washout technique (Fairley et al, 1967) that clinical symptoms correlate poorly with the site of infection (Stamey et al, 1965; Eykyn et al, 1972; Fairley, 1972; Smeets and Gower, 1973).

In a large study of 201 women and 12 men with recurrent UTIs, Busch and Huland (1984) showed that fever and flank pain are no more diagnostic of pyelonephritis than they are of cystitis. Of patients with flank pain and/or fever, over 50% had lower tract bacteriuria. Conversely, patients with bladder symptoms or no symptoms frequently had upper tract bacteriuria. Approximately 75% of patients give a history of previous lower UTIs.

On physical examination there often is tenderness to deep palpation in the costovertebral angle. Variations of this clinical presentation have been recognized. Acute pyelonephritis may also simulate gastrointestinal tract abnormalities with abdominal pain, nausea, vomiting, and diarrhea. Asymptomatic progression of acute pyelonephritis to chronic pyelonephritis, particularly in compromised hosts, may occur in the absence of overt symptoms. Acute renal failure may be present in the rare case (Richet and Mayaud, 1978; Olsson et al, 1980).

Laboratory Diagnosis

The patient may have leukocytosis with predominance of neutrophils. Urinalysis usually reveals numerous WBCs, often in clumps, and bacterial rods or chains of cocci. Leukocytes exhibiting brownian motion in the cytoplasm (glitter cells) may be present if the urine is hypotonic, but they are not in themselves diagnostic of pyelonephritis. The presence of large amounts of granular or leukocyte casts in the urinary sediment is suggestive of acute pyelonephritis. A specific type of urinary cast characterized by the presence of bacteria in its matrix has been demonstrated in the urine of patients who have had acute pyelonephritis (Fig. 10–18) (Lindner et al, 1980). Bacteria in the casts were not easily distinguished by simple brightfield microscopy without special staining of the sediment. Staining of the sediment with a basic dye such as dilute toluidine blue or KOVA stain (I.C.L. Scientific, Fountain Valley, CA) demonstrated the bacteria in casts without difficulty. Blood tests may show leukocytosis with a predominance of neutrophils, increased erythrocyte sedimentation rate, elevated C-reactive protein levels, and elevated creatinine levels if renal failure is present. In addition, creatinine clearance may be decreased. Blood cultures may be positive.

Figure 10–18 Brightfield micrograph of a mixed bacterial leukocyte cast from patient with acute pyelonephritis. Only the bacteria and the nucleus of a leukocyte stain strongly. Many bacteria are clearly demonstrated by through-focusing (toluidine blue O, ×640).

(From Lindner LE, Jones RN, Haber MH. A specific urinary cast in acute pyelonephritis. Am J Clin Pathol 1980;73:809–11.)

Bacteriology

Urine cultures are positive, but about 20% of patients have urine cultures with fewer than 10⁵ cfu/mL and, therefore, negative results on Gram staining of the urine (Rubin et al, 1992).

E. coli, which constitutes a unique subgroup that possesses special virulence factors, accounts for 80% of cases. If vesicoureteral reflux is absent, a patient bearing the P blood group phenotype may have special susceptibility to recurrent pyelonephritis caused by E. coli that have P pili and bind to the P blood group antigen receptors (Lomberg et al, 1983). Bacterial K antigens and endotoxins also may contribute to pathogenicity (Kaijser et al, 1977). Many cases of community-acquired pyelonephritis are caused by a limited number of multiple-antimicrobial–resistant clonal groups (Manges et al, 2004).

More resistant species, such as Proteus, Klebsiella, Pseudomonas, Serratia, Enterobacter, or Citrobacter should be suspected in patients who have recurrent UTIs, are hospitalized, or have indwelling catheters, as well as in those who required recent urinary tract instrumentation. Except for E. faecalis, S. epidermidis, and S. aureus, gram-positive bacteria rarely cause pyelonephritis.

Blood cultures are positive in about 25% of cases of uncomplicated pyelonephritis in women, and the majority replicate the urine culture and do not influence decisions regarding therapy. Therefore blood cultures should not be routinely obtained for the evaluation of uncomplicated pyelonephritis in women. However, they should be performed in men and women with systemic toxicity or in those requiring hospitalization or with risk factors such as pregnancy (Velasco et al, 2003).

Renal Ultrasonography and Computed Tomography

These studies are commonly used to evaluate patients initially for complicated UTIs or factors or to reevaluate patients who do not respond after 72 hours of therapy (see later). Ultrasonography (Fig. 10–19) and CT show renal enlargement, hypoechoic or attenuated parenchyma, and a compressed collecting system. They also may delineate focal bacterial nephritis and obstruction. When parenchymal destruction becomes pronounced, a more disorganized parenchyma and abscess formation associated with complicated renal and perirenal infections may be identified (Soulen et al, 1989).

Figure 10–19 Acute pyelonephritis. Ultrasound image of the right kidney demonstrates renal enlargement, hypoechoic parenchyma, and compressed central collecting complex (arrows).

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott William & Wilkins; 2002. p. 211–72.)

Differential Diagnosis

Acute appendicitis, diverticulitis, and pancreatitis can cause a similar degree of pain, but the location of the pain often is different. Results of the urine examination are usually normal. Herpes zoster can cause superficial pain in the region of the kidney but is not associated with symptoms of UTI; the diagnosis will be apparent when shingles appear.

Management

Initial Management

Infection in patients with acute pyelonephritis can be subdivided into (1) uncomplicated infection that does not warrant hospitalization, (2) uncomplicated infection in patients with normal urinary tracts who are ill enough to warrant hospitalization for parenteral therapy, and (3) complicated infection associated with hospitalization, catheterization, urologic surgery, or urinary tract abnormalities (Fig. 10–20).

Figure 10–20 Management of acute pyelonephritis.

It is critical to determine whether the patient has an uncomplicated or complicated UTI because significant abnormalities have been found in 16% of patients with acute pyelonephritis (Shen and Brown, 2004). In patients with presumed uncomplicated pyelonephritis that will be managed as outpatients, initial radiologic evaluation can usually be deferred. However, if there is any reason to suspect a problem or if the patient will not have reasonable access to imaging if there should be no change in condition, we prefer renal ultrasound evaluation to rule out stones or obstruction. In patients with known or suspected complicated pyelonephritis, CT provides excellent assessment of the status of the urinary tract and the severity and extent of the infection.

For patients who will be managed as outpatients, single-drug oral therapy with a fluoroquinolone is more effective than TMP-SMX for patients with domiciliary infections (Talan et al, 2000). Many physicians administer a single parenteral dose of an antimicrobial agent (ceftriaxone, gentamicin, or a fluoroquinolone) before initiating oral therapy (Israel et al, 1991; Pinson et al, 1994). If a gram-positive organism is suspected, amoxicillin or amoxicillin/clavulanic acid is recommended (Warren et al, 1999).

If a patient has an uncomplicated infection but is sufficiently ill to require hospitalization (high fever, high WBC count, vomiting, dehydration, evidence of sepsis), has complicated pyelonephritis, or fails to improve during the initial outpatient treatment period, a parenteral fluoroquinolone, an aminoglycoside with or without ampicillin, or an extended-spectrum cephalosporin with or without an aminoglycoside is recommended (Warren et al, 1999) (Table 10–23). If gram-positive cocci are causative, ampicillin/sulbactam with or without an aminoglycoside is recommended.

Table 10–23 Treatment Regimens for Acute Complicated and Uncomplicated Pyelonephritis in Women

Hospitalization, initially with complete bed rest, intravenous fluids, and antipyretics, is required.

An obstructed kidney has difficulty concentrating and excreting antimicrobial agents. Any substantial obstruction must be relieved expediently by the safest and simplest means.

A Gram stain of the urine sediment is helpful to guide the selection of the initial empirical antimicrobial therapy. In all cases, antimicrobial therapy should be active against potential uropathogens and achieve antimicrobial levels in renal tissue as well as urine.

Unfavorable Response to Therapy

When the response to therapy is slow or the urine continues to show infection, an immediate reevaluation is mandatory. Urine and blood cultures must be repeated and appropriate alterations in antimicrobial therapy made on the basis of susceptibility testing. CT is indicated to attempt to identify unsuspected obstructive uropathy, urolithiasis, or underlying anatomic abnormalities that may have predisposed the patient to infection, prevented a rapid therapeutic response, or caused complications of the infectious process, such as renal or perinephric abscess. In patients with fever lasting longer than 72 hours, CT is most helpful for ruling out obstruction and identifying renal and perirenal infections (Soulen et al, 1989). Radionuclide imaging may be useful to demonstrate functional changes associated with acute pyelonephritis (decrease in renal blood flow, delay in peak function, and delay in excretion of the radionuclide) (Fischman and Roberts, 1982) and cortical defects associated with vesicoureteral reflux.

Follow-Up

Repeat urine cultures should be performed on the fifth to the seventh day of therapy and 10 to 14 days after discontinuing antimicrobial therapy to ensure that the urinary tract remains free of infections. Between 10% and 30% of individuals with acute pyelonephritis relapse after a 14-day course of therapy. Patients who experience relapse usually are cured by a second 14-day course of therapy, but occasionally a 6-week course is necessary (Tolkoff-Rubin et al, 1984; Johnson and Stamm, 1987).

Depending on the clinical presentation and response and initial urologic evaluation, some patients may require additional evaluation (e.g., voiding cystourethrogram, cystoscopy, bacterial localization studies) and correction of an underlying abnormality of the urinary tract. Raz and colleagues (2003) evaluated the long-term impact of acute pyelonephritis in women. Scanning with ^99mTc-dimercaptosuccinic acid (^99mTc-DMSA) 10 to 20 years after acute pyelonephritis revealed scars in approximately 50% of the patients but changes in renal function were minimal and not associated with renal scarring.

Clinical Presentation

The clinical presentation of patients with acute bacterial nephritis is similar to that of patients with acute pyelonephritis but usually is more severe. About half of the patients are diabetic, and sepsis is common. Generally, leukocytosis and UTI resulting from gram-negative organisms are found; more than 50% of the patients are bacteremic (Wicks and Thornbury, 1979).

Radiologic Findings

The diagnosis must be made by radiologic examination. The mass has slightly less nephrographic density than the surrounding normal renal parenchyma.

Ultrasonography and CT establish the diagnosis. On ultrasonography the lesion is typically poorly marginated and relatively sonolucent with occasional low-amplitude echoes that disrupt the cortical medullary junction (Corriere and Sandler, 1982) (Fig. 10–21A). Enhancement with a contrast agent is necessary with CT studies because the lesion is difficult to visualize on the unenhanced study (see Fig. 10–21B). Wedge-shaped areas of decreased enhancement are seen. No definite wall is evident, and frank liquefaction is absent. Conversely, abscesses tend to have liquid centers, are usually round, and are present both before and after contrast medium enhancement. More chronic abscesses may also show a ring-shaped area of increased enhancement surrounding the lesion (Corriere and Sandler, 1982). Gallium scanning reveals uptake that is in the region of and larger than the previously demonstrated mass (Rosenfield et al, 1979). In patients with multifocal disease the findings are similar but multiple lobes are involved.

Figure 10–21 Acute focal bacterial nephritis. A, Ultrasound image: longitudinal view of the left kidney demonstrates spleen (S) and left kidney (arrows). Note irregular midpole mass (M) of slightly higher echo texture than surrounding normal renal parenchyma. B, Contrast medium–enhanced CT scan demonstrates a wedge-shaped area of low density (arrows) in the middle portion of the left kidney. The findings resolved after antimicrobial therapy.

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 211–72.)

Management

Acute bacterial nephritis probably represents a relatively early phase of frank abscess formation. In a series of cases reported by Lee and coworkers (1980) a patient with acute focal bacterial nephritis progressed to abscess formation. Treatment includes hydration and intravenous antimicrobial agents for at least 7 days, followed by 7 days of oral antimicrobial therapy. Patients with bacterial nephritis typically respond to medical therapy, and follow-up studies will show resolution of the wedge-shaped zones of diminished attenuation. Failure to respond to antimicrobial therapy is an indication for appropriate studies to rule out obstructive uropathy, renal or perirenal abscess, renal carcinoma, or acute renal vein thrombosis. Long-term follow-up studies performed in a few patients with multifocal disease have demonstrated a decrease in renal size and focal calyceal deformities suggestive of papillary necrosis (Davidson and Talner, 1978).

Clinical Presentation

All of the documented cases of emphysematous pyelonephritis have occurred in adults (Hawes, 1983). Juvenile diabetic patients do not appear to be at risk. Women are affected more often than men.

The usual clinical presentation is severe, acute pyelonephritis, although in some instances a chronic infection precedes the acute attack. Almost all patients display the classic triad of fever, vomiting, and flank pain (Schainuck et al, 1968). Pneumaturia is absent unless the infection involves the collecting system. Results of urine cultures are invariably positive. E. coli is most commonly identified. Klebsiella and Proteus are less common.

Radiologic Findings

The diagnosis is established radiographically. Tissue gas that is distributed in the parenchyma may appear on abdominal radiographs as mottled gas shadows over the involved kidney (Fig. 10–22). This finding is often mistaken for bowel gas. A crescentic collection of gas over the upper pole of the kidney is more distinctive. As the infection progresses, gas extends to the perinephric space and retroperitoneum. This distribution of gas should not be confused with cases of emphysematous pyelitis in which air is in the collecting system of the kidney. Emphysematous pyelitis is secondary to a gas-forming bacterial UTI, often occurs in nondiabetic patients, is less serious, and usually responds to antimicrobial therapy.

Figure 10–22 Emphysematous pyelonephritis; plain film. Extensive perinephric (long arrows) and intraparenchymal (short arrows) gas secondary to acute bacterial pyelonephritis.

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott William & Wilkins; 2002. p. 211–72.)

Ultrasonography usually demonstrates strong focal echoes suggesting the presence of intraparenchymal gas (Brenbridge et al, 1979; Conrad et al, 1979). CT is the imaging procedure of choice in defining the extent of the emphysematous process and guiding management (Figs. 10-23 and 10-24). An absence of fluid in CT images or the presence of streaky or mottled gas with or without bubbly and loculated gas appears to be associated with rapid destruction of renal parenchyma and a 50% to 60% mortality rate (Wan et al, 1996; Best et al, 1999). The presence of renal or perirenal fluid, the presence of bubbly or loculated gas or gas in the collecting system, and the absence of streaky or mottled gas patterns is associated with a less than 20% mortality rate. Obstruction is demonstrated in approximately 25% of the cases. A nuclear renal scan should be performed to assess the degree of renal function impairment in the involved kidney and the status of the contralateral kidney.

Figure 10–23 Type I emphysematous pyelonephritis with complete renal destruction in a 49-year-old woman. A, CT scan of the right kidney shows complete destruction with gas (arrowheads) extending beyond the renal fascia. B, CT scan with a modified lung window display shows the characteristic streaky gas in the completely destroyed kidney. The patient died on arrival in the emergency department.

(A and B, From Wan YL, Lee TY, Bullard MJ, Tsai CC. Acute gas-producing bacterial renal infection: correlation between imaging findings and clinical outcome. Radiology 1996;198:433–8.)

Figure 10–24 Type II emphysematous pyelonephritis in a 57-year-old woman. A, Radiograph shows crescent-shaped (arrowheads) and loculated (arrows) gas in the right renal area. B, CT scan obtained after administration of contrast material shows a low-attenuation area (arrowheads) in the right kidney due to acute pyelonephritis as well as a subcapsular abscess with fluid and bubbly and loculated gas. The patient survived after percutaneous drainage was performed.

(A and B, From Wan YL, Lee TY, Bullard MJ, Tsai CC. Acute gas-producing bacterial renal infection: correlation between imaging findings and clinical outcome. Radiology 1996;198:433–8.)

Management

Emphysematous pyelonephritis is a surgical emergency. Most patients are septic, and fluid resuscitation and broad-spectrum antimicrobial therapy are essential. If the kidney is functioning, medical therapy can be considered (Wan et al, 1996; Best et al, 1999). Nephrectomy is recommended for patients who do not improve after a few days of therapy (Malek and Elder, 1978). If the affected kidney is nonfunctioning and not obstructed, nephrectomy should be performed because medical treatment alone is usually lethal. If a kidney is obstructed, catheter drainage must be instituted. If the patient’s condition improves, nephrectomy may be deferred pending a complete urologic evaluation. Although there are isolated case reports of retention of renal function after medical therapy combined with relief of obstruction, most patients require nephrectomy (Hudson et al, 1986).

Clinical Presentation

The patient may present with fever, chills, abdominal or flank pain, and occasionally with weight loss and malaise. Symptoms of cystitis may occur. Occasionally these symptoms may be vague and delay diagnosis until surgical exploration or, in more severe cases, autopsy (Anderson and McAninch, 1980). A thorough history may reveal a gram-positive source of infection 1 to 8 weeks before the onset of urinary tract symptoms. The infection may have occurred in any area of the body. Multiple skin carbuncles and intravenous drug abuse introduce gram-positive organisms into the bloodstream. Other common sites are the mouth, lungs, and bladder (Lyons et al, 1972). Complicated UTIs associated with stasis, calculi, pregnancy, neurogenic bladder, and diabetes mellitus also appear to predispose the patient to abscess formation (Anderson and McAninch, 1980).

Laboratory Diagnosis

The patient typically has marked leukocytosis. The blood cultures are usually positive. Pyuria and bacteriuria may not be evident unless the abscess communicates with the collecting system. Because gram-positive organisms are most commonly blood borne, urine cultures in these cases typically show no growth or a microorganism different from that isolated from the abscess. When the abscess contains gram-negative organisms, the urine culture usually demonstrates the same organism isolated from the abscess.

Ultrasonography and CT distinguish abscess from other inflammatory renal diseases. Ultrasonography is the quickest and least expensive method to demonstrate a renal abscess. An echo-free or low-echodensity space-occupying lesion with increased transmission is found on the ultrasound image (Fig. 10–25). The margins of an abscess are indistinguishable in the acute phase, but the structure contains a few echoes and the surrounding renal parenchyma is edematous (Fiegler, 1983). Subsequently, the appearance tends to be that of a well-defined mass. The internal appearance, however, may vary from a virtually solid lucent mass to one with large numbers of low-level internal echoes (Schneider et al, 1976). The number of echoes depends on the amount of cellular debris within the abscess. The presence of air results in a strong echo with a shadow. Differentiation between an abscess and a tumor is impossible in many cases. Arteriography is used infrequently to demonstrate abscesses. The center of the mass tends to be hypervascular or avascular, with increased vascularity at the cortical margins and lack of vascular displacement and neovascularity.

Figure 10–25 Acute renal abscess. Transverse ultrasound image of the right kidney demonstrates a poorly marginated rounded focal hypoechoic mass (arrows) in the anterior portion of the kidney.

CT appears to be the diagnostic procedure of choice for renal abscesses, because it provides excellent delineation of the tissue. On CT, abscesses are characteristically well defined both before and after contrast agent enhancement. The findings depend in part on the age and severity of the abscess (Baumgarten and Baumgartner, 1997). Initially, CT shows renal enlargement and focal, rounded areas of decreased attenuation (Fig. 10–26). After several days of the onset of the infection, a thick fibrotic wall begins to form around the abscess. An echo-free or slightly echogenic mass due to the presence of necrotic debris is seen. CT of a chronic abscess shows obliteration of adjacent tissue planes, thickening of the Gerota fascia, a round or oval parenchymal mass of low attenuation, and a surrounding inflammatory wall of slightly higher attenuation that forms a ring when the scan is enhanced with contrast material (Fig. 10–27). The ring sign is caused by the increased vascularity of the abscess wall (Callen, 1979; Gerzof and Gale, 1982).

Figure 10–26 Acute renal abscess. Nonenhanced CT scan through the mid pole of the right kidney demonstrates right renal enlargement and an area of decreased attenuation (arrows). After antimicrobial therapy, a follow-up scan showed complete regression of these findings.

Figure 10–27 Chronic renal abscess. A, Enhanced CT scan shows an irregular septated low-density mass (M) extensively involving the left kidney. Note thickening of perinephric fascia (arrowheads) and extensive compression of the renal collecting system. Findings are typical of renal abscess. B, Ultrasound longitudinal image demonstrates a septated hypoechoic mass (M) occupying much of the renal parenchymal volume.

Radionuclide imaging with gallium or indium is sometimes useful in evaluating patients with renal abscesses (see earlier sections in this chapter and Chapter 4).

Management

Although the classic treatment for an abscess has been percutaneous or open incision and drainage there is good evidence that the intravenous use of antimicrobial agents and careful observation of a small abscess less than 3 cm in diameter, if begun early enough in the course of the process, may obviate surgical procedures (Hoverman et al, 1980; Levin et al, 1984; Shu et al, 2004). CT- or ultrasound-guided needle aspiration may be necessary to differentiate an abscess from a hypervascular tumor. Aspirated material should be cultured and appropriate antimicrobial therapy instituted on the basis of the findings.

The selection of empirical antimicrobial therapy is dependent on the presumed source of the infection and the resistance patterns within the hospital. When hematogenous dissemination is suspected, the pathogenic organism most frequently is penicillin-resistant Staphylococcus, and the antimicrobial of choice therefore is a penicillinase-resistant penicillin (Schiff et al, 1977). If a history of penicillin hypersensitivity is present, the recommended drug is vancomycin. Cortical abscesses that occur in the abnormal urinary tract are associated with more typical gram-negative pathogens and should be treated empirically with intravenous third-generation cephalosporins, antipseudomonal penicillins, or aminoglycosides until specific therapy can be instituted. Patients should have serial examinations with ultrasonography or CT until the abscess resolves. A clinical course contrary to this should lead to the suspicion of misdiagnosis or an uncontrolled infection with the development of perinephric abscess or infection with an organism resistant to the antimicrobial agents used in therapy.

Abscesses 3 to 5 cm in diameter and smaller abscesses in immunocompromised hosts or those that do not respond to antimicrobial therapy should be drained percutaneously (Fernandez et al, 1985; Fowler and Perkins, 1994; Siegel et al, 1996). Surgical drainage, however, currently remains the procedure of choice for most renal abscesses greater than 5 cm in diameter.

Clinical Presentation

The patient is usually very ill, with high fever, chills, flank pain, and tenderness. Occasionally, however, a patient may have only an elevated temperature and a complaint of vague gastrointestinal discomfort. A previous history of urinary tract calculi, infection, or surgery is common. Bacteriuria may not be present if the ureter is completely obstructed.

Radiologic Findings

The ultrasonographic diagnosis of infected hydronephrosis depends on demonstration of internal echoes within the dependent portion of a dilated pyelocalyceal system. CT is nonspecific but may show thickening of the renal pelvis, stranding of the perirenal fat, and a striated nephrogram. Ultrasonography demonstrates hydronephrosis and fluid debris levels within the dilated collecting system (Corriere and Sandler, 1982) (Fig. 10–29A). The diagnosis of pyonephrosis is suggested if focal areas of decreased echogenicity are seen within the hydronephrotic parenchyma.

Figure 10–29 Pyonephrosis. A, Longitudinal ultrasound image of the right kidney demonstrates echogenic central collecting complex (C) with radiating echogenic septa (arrows) and thinned hypoechoic parenchyma. Multiple dilated calyces (o) with diffuse low-level echoes are seen. B, Antegrade pyelogram performed through a percutaneous nephrostomy catheter correlates well with the ultrasound image. Dilated pus-filled calyces are demonstrated. The renal pelvis is obliterated by chronic scarring and stone disease. The kidney did not regain function.

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 211–72.)

Management

Once the diagnosis of pyonephrosis is made, treatment is initiated with appropriate antimicrobial drugs and drainage of the infected pelvis. A ureteral catheter can be passed to drain the kidney, but if the obstruction prevents this, a percutaneous nephrostomy tube should be placed (Camunez et al, 1989) (see Fig. 10–29B). When the patient becomes hemodynamically stable, other procedures are usually needed to identify and treat the source of the obstruction.

Clinical Presentation

The onset of symptoms is typically insidious. Symptoms are present for more than 5 days in most patients with perinephric abscess compared with only about 10% of patients with pyelonephritis. The clinical presentation may be similar to that of pyelonephritis; however, more than one third of patients may be afebrile. An abdominal or flank mass can be felt in about half of the cases. Psoas abscess should be suspected if the patient has a limp and flexion and external rotation of the ipsilateral hip. Laboratory features include leukocytosis, elevated levels of serum creatinine, and pyuria in more than 75% of cases. Edelstein and McCabe (1988) showed that results of urine cultures predicted perinephric abscess isolates in only 37% of cases; a blood culture, particularly with multiple organisms, was often indicative of perinephric abscess but identified all organisms in only 42% of cases. Therefore therapy based on the results of urine and blood cultures often may be inadequate. Pyelonephritis usually responds within 4 to 5 days of appropriate antimicrobial therapy; perinephric abscess does not. Thus perinephric abscess should be suspected in a patient with UTI and abdominal or flank mass or persistent fever after 4 days of antimicrobial therapy.

CT is particularly valuable for demonstrating the primary abscess. In some cases, the abscess is confined to the perinephric space; however, extension to the flank or psoas muscle may occur (Fig. 10–30). CT is able to show with exquisite anatomic detail the route of spread of infection into the surrounding tissues (Fig. 10–31). This information may be helpful in planning the approach for surgical drainage. Ultrasonography demonstrates a diverse appearance ranging from a nearly anechoic mass displacing the kidney to an echogenic collection that tends to blend with normally echogenic fat within the Gerota fascia (Corriere and Sandler, 1982). Occasionally a retroperitoneal or subdiaphragmatic infection may spread to the paranephric fat that is outside this fascia. The clinical symptoms of insidious onset of fever, flank mass, and tenderness are indistinguishable from those associated with perinephric abscess. UTI, however, is absent. Ultrasonography and CT can usually delineate the abscess outside the Gerota fascia.

Figure 10–30 Nonenhanced CT scan through the lower pole of the right kidney (previous left nephrectomy) shows extensive perinephric abscess. Extensive abscess (A) distorts and enlarges the renal contour, infiltrates perinephric fat (straight arrows), and also extends into the psoas muscle (asterisk) and the soft tissues of the flank (curved arrow). Also note that normal renal collecting system fat has been obliterated by the process.

Figure 10–31 Perinephric abscess involving the right adrenal gland. CT scan shows large right pararenal mass (arrows) with multiple low-density areas within. At surgery, a large pararenal abscess with extensive involvement of the right adrenal was found.

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 211–72.)

Management

Although antimicrobial agents are useful to control sepsis and to prevent spread of infection, the primary treatment for perinephric abscess is drainage; reports of successful treatment by antimicrobial agents alone are unusual (Herlitz et al, 1981). A detailed analysis of 52 perinephric abscess patients by Thorley and colleagues (1974) supports this tenet. In this study, half the patients were admitted to medical services and the other half to surgical services; 65% of those admitted to medical services died, whereas 23% of those admitted to surgical services died. These mortality rates reflect differences in the population of patients. Those admitted to the medical services were usually sicker and had higher temperatures, more underlying diseases, and vaguer symptoms. More importantly, none of those admitted to medical wards had an admission diagnosis of perinephric abscess, whereas 73% of those admitted to surgical wards did. Although 71% of all the patients had eventual surgical treatment of their perinephric abscesses, the diagnostic delay of those patients admitted to medical services postponed definitive treatment and consequently caused higher mortality.

Although surgical drainage, or nephrectomy if the kidney is nonfunctioning or severely infected, is the classic treatment for perinephric abscesses, renal ultrasonography and CT make percutaneous aspiration and drainage of small perirenal collections possible (Haaga and Weinstein, 1980; Elyaderani et al, 1981; Edelstein and McCabe, 1988). Haaga and Weinstein (1980), however, consider percutaneous drainage to be contraindicated in large abscess cavities filled with thick, purulent fluid.

Gram stain identifies the pathogenesis and guides antimicrobial therapy. An aminoglycoside together with an antistaphylococcal agent, such as methicillin or oxacillin, should be started immediately. If the patient has a penicillin hypersensitivity, cephalothin or vancomycin may be used.

Once the perinephric abscess has been drained, the underlying problem must be dealt with. Some conditions such as renal cortical abscess or enteric communication require prompt attention. Nephrectomy for pyonephrosis may be performed concurrent with drainage of the perinephric abscess if the patient’s condition is good. In other instances it is best to drain the perinephric abscess first and correct the underlying problem or perform a nephrectomy when the patient’s condition has improved.

Perinephric Abscess versus Acute Pyelonephritis

It has already been emphasized that the greatest obstacle to the treatment of perinephric abscess is the delay in diagnosis. In the series of Thorley and colleagues (1974) a common misdiagnosis was acute pyelonephritis. In their review they found that two factors differentiated perinephric abscess and acute pyelonephritis: (1) most patients with uncomplicated pyelonephritis were symptomatic for less than 5 days before hospitalization, whereas most with perinephric abscesses were symptomatic for longer than 5 days; and (2) no patient with acute pyelonephritis remained febrile for longer than 4 days once appropriate antimicrobial agents were started. All patients with perinephric abscesses had a fever for at least 5 days, with a median of 7 days. Similar results were noted by Fowler and Perkins (1994).

Patients with polycystic renal disease who undergo hemodialysis may be particularly susceptible to the progression from acute UTIs to perinephric abscess. Of 445 patients undergoing chronic hemodialysis at the Regional Kidney Disease Program in Minneapolis, 5.4% had polycystic kidney disease and 33.3% of these patients developed symptomatic UTIs (Sweet and Keane, 1979). Eight (62.5%) developed perinephric abscesses, and 3 of these patients died. According to the investigators, all UTIs, even those that progressed to perinephric abscesses, were promptly treated with appropriate antimicrobial agents, and all patients in this group became afebrile and asymptomatic when the agents were stopped. Yet later, after various times, symptoms attributable to perinephric abscess developed in 8 of the patients. The mechanism of this process is not clear, but the limited bioavailability of some antimicrobial agents in cysts is variable and could contribute to the progression of renal infection.

Clinical Presentation

There are no symptoms of chronic pyelonephritis until it produces renal insufficiency, and then the symptoms are similar to those of any other form of chronic renal failure. If a patient’s chronic pyelonephritis is thought to be an end result of many episodes of acute pyelonephritis, a history of intermittent symptoms of fever, flank pain, and dysuria may be elicited. Similarly, urinary findings and the presence of renal infection correlate poorly. Bacteriuria and pyuria, the hallmarks of UTI, are not predictive of renal infection. Conversely, patients with significant renal infection may have sterile urine if the ureter draining the kidney is obstructed or the infection is outside the collecting system.

The pathologic and radiologic criteria for diagnosing renal infection may also be misleading. Asscher (1980) has tabulated eight long-term follow-up studies from the literature on kidneys of adults with UTIs. The data from these reports on 901 patients show that bacteriuria present in otherwise healthy adults for long periods may be associated with nonexistent or extremely minimal evidence of kidney damage. Conversely, patients who have chronic pyelonephritis may have negative urine cultures.

Radiologic Findings

The diagnosis of chronic pyelonephritis can be made with the greatest confidence on the basis of pyelographic findings. The essential features are asymmetry and irregularity of the kidney outlines, blunting and dilation of one or more calyces, and cortical scars at the corresponding site (Fig. 10–32). In the absence of stones, obstruction, and tuberculosis, and with the single exception of analgesic nephritis with papillary necrosis (which can be readily excluded by history), chronic pyelonephritis is virtually the only disease that produces a localized scar over a deformed calyx (Stamey, 1980). In advanced pyelonephritis, calyceal distortion and irregularity together with cortical scars complete the picture. Hodson (1965a) pointed out that renal infarction, an extremely rare condition, may closely resemble pyelonephritic scars but that the renal pyramid remains with renal infarction in contradistinction to pyelonephritis.

Figure 10–32 Chronic pyelonephritis. Ten-minute excretory urogram demonstrates irregular renal outline with upper pole parenchymal atrophy. Note significant loss of renal cortical thickness over blunted and dilated calyces. Lower pole mass (M) is a simple cyst.

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 211–72.)

Pathology

In chronic pyelonephritis, the gross kidney is often diffusely contracted, scarred, and pitted. The scars are Y-shaped, flat, broad-based depressions with red-brown granular bases. The scarring is often polar with underlying calyceal blunting. The parenchyma is thin, and the corticomedullary demarcation is lost. Histologic changes are patchy. There is usually an interstitial infiltrate of lymphocytes, plasma cells, and occasional polymorphonuclear cells. Portions of the parenchyma may be replaced by fibrosis, and, although glomeruli may be preserved, periglomerular fibrosis is often seen. In some affected areas, glomeruli may be completely fibrosed and tubules atrophied. Leukocyte and hyaline casts are sometimes present in the tubules; the latter may cause resemblance to the thyroid colloid, hence the description renal thyroidization (Braude, 1973). In general, the changes are nonspecific; they also may be seen in toxic exposures, postobstructive atrophy, hematologic disorders, postirradiation nephritis, ischemic renal disease, and nephrosclerosis.

Management

Management of radiographic evidence of pyelonephritis should be directed at treating infection, if present; preventing future infections; and monitoring and preserving renal function. The treatment of existing infection must be based on careful antimicrobial susceptibility tests and selection of drugs that can achieve bactericidal concentrations in the urine and yet are not nephrotoxic. Achievement of acceptable bactericidal levels of a drug in the urine of a patient with chronic pyelonephritis may be difficult because the diminished concentrating ability of pyelonephritis may impair excretion and concentration of the antimicrobial agent. The duration of antimicrobial therapy is often prolonged to maximize the chance of cure. With patients in whom renal damage develops or progresses in the presence of UTI, the working hypothesis should be that there is an underlying renal, usually papillary, lesion or underlying urologic condition, such as obstruction or calculus, that has increased susceptibility to renal damage. Appropriate nephrologic and urologic evaluation should be undertaken to identify and, if possible, correct these abnormalities.

Pathogenesis

The primary factors involved in the pathogenesis of xanthogranulomatous pyelonephritis are nephrolithiasis, obstruction, and infection (Gregg et al, 1999). Nephrolithiasis has been noted in as many as 83% of the patients in various series; approximately half of the renal stones have been of the staghorn type (Parsons et al, 1983; Chuang et al, 1992; Nataluk et al, 1995). It has been proposed clinically and demonstrated experimentally that primary obstruction followed by infection with E. coli can lead to tissue destruction and collections of lipid material by macrophages (Povysil and Konickova, 1972). These macrophages (xanthoma cells) are distributed in sheets around parenchymal abscesses and calyces and are intermixed with lymphocytes, giant cells, and plasma cells. The bacteria appear to be of low virulence because spontaneous bacteremia has rarely been described. Other possible interrelated factors include venous occlusion and hemorrhage, abnormal lipid metabolism, lymphatic blockage, failure of antimicrobial therapy in UTI, altered immunologic competence, and renal ischemia (Friedenberg and Spjut, 1963; Mering et al, 1973; Goodman et al, 1979; McDonald, 1981; Tolia et al, 1981). The concept that xanthogranulomatous pyelonephritis is related to incomplete bacterial degradation and altered host response has received mixed support (Nielsen and Lorentzen, 1981; Khalyl-Mawad et al, 1982). Thus it appears that there is probably no single factor that is instrumental in the pathogenesis of this disease. Rather, there is an inadequate host acute inflammatory response within an obstructed, ischemic, or necrotic kidney.

Pathology

The kidney is usually massively enlarged and has a normal contour. Xanthogranulomatous pyelonephritis may be diffuse, as in approximately 80% of the patients, or segmental. In the diffuse form of the disease the entire kidney is involved, whereas in segmental xanthogranulomatous pyelonephritis only the parenchyma surrounding one or more calyces or one pole of a duplicated collecting system is involved. On sectioning, the kidney usually demonstrates nephrolithiasis and peripelvic fibrosis. The calyces are dilated and filled with purulent material, but fibrosis surrounding the pelvis usually prevents dilation. The papillae are often destroyed by papillary necrosis (Goodman et al, 1979). In advanced stages of the disease, multiple parenchymal abscesses are filled with viscous pus and lined by yellowish tissue (Fig. 10–33A). The cortex is often thin and replaced by xanthogranulomatous tissue. The capsule is often thickened, and extension of the inflammatory process into the perinephric or paranephric space is common (Goodman et al, 1979; McDonald, 1981; Gregg et al, 1999).

Figure 10–33 Xanthogranulomatous pyelonephritis. A, Gross specimen. Kidney is massively enlarged, measuring 23 × 12 cm; the normal architecture is replaced by a shaggy yellow upper pole mass corresponding to xanthogranulomatous inflammation and numerous distorted and dilated calyces. B, Microscopically, the shaggy yellow tissue is composed primarily of lipid-laden histiocytes mixed with other inflammatory cells.

(From Schaeffer AJ. Urinary tract infections. In: Gillenwater JY et al, editors. Adult and pediatric urology. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 211–72.)

On microscopic examination the yellowish nodules that line the calyces and surround the parenchymal abscesses contain dark sheets of lipid-laden macrophages (foamy histiocytes with small, dark nuclei and clear cytoplasm) intermixed with lymphocytes, giant cells, and plasma cells (see Fig. 10–33B). Xanthogranulomatous cells are not specific to xanthogranulomatous pyelonephritis but may be present anywhere inflammation or obstruction coexists. The origin of the fatty substance is disputed. Cholesterol esters that make up a part of the lipid might be derived from lysis of erythrocytes after hemorrhage (Saeed and Fine, 1963).

Clinical Presentation

Xanthogranulomatous pyelonephritis should be suspected in patients with UTIs and a unilateral enlarged nonfunctioning or poorly functioning kidney with a stone or a mass lesion indistinguishable from malignant tumor. Most patients present with flank pain (69%), fever and chills (69%), and persistent bacteriuria (46%) (Malek and Elder, 1978). Additional vague symptoms, such as malaise, may be present. On physical examination, 62% of the patients had a flank mass and 35% had previous calculi (Malek and Elder, 1978). Less commonly, hypertension, hematuria, or hepatomegaly is the presenting complaint. The medical history is often positive for UTIs and urologic instrumentation (Malek and Elder, 1978; Flynn et al, 1979; Goodman et al, 1979; Grainger et al, 1982; Yazaki et al, 1982; Petronic et al, 1989; Eastham et al, 1994; Nataluk et al, 1995). Diabetics also appear to be at greater risk of developing the disease (Eastham et al, 1994). Although it may occur at any age, the peak incidence of xanthogranulomatous pyelonephritis is in the fifth to the seventh decade. Women are more commonly affected than men. There is no predilection for either kidney.

Bacteriology and Laboratory Diagnosis

Although review of the literature shows Proteus to be the most common organism involved with xanthogranulomatous pyelonephritis (Anhalt et al, 1971; Tolia et al, 1981), E. coli is also common. The prevalence of Proteus organisms may reflect their association with stone formation and subsequent chronic obstruction and irritation. Malek and Elder (1978), in their analysis of 26 cases, found that renal tissue cultures grew bacteria in 22 of 23 cases. Anaerobes also have been cultured (Malek and Elder, 1978).

Approximately 10% of patients have mixed cultures. About one third of patients have no growth in their urine, probably because many patients have recently taken or are taking antimicrobial agents when cultures are obtained. The infecting organism may be revealed only by tissue cultures obtained during surgery. Urinalysis usually shows pus and protein. In addition, blood tests often reveal anemia and may show hepatic dysfunction in up to 50% of the patients (Malek and Elder, 1978).

Xanthogranulomatous pyelonephritis is almost always unilateral; therefore azotemia or frank renal failure is uncommon (Goodman et al, 1979; Gregg et al, 1999).

CT is probably the most useful radiologic technique in evaluating patients with xanthogranulomatous pyelonephritis (Fig. 10–34). Fifty to 80 percent of patients show the classic triad of unilateral renal enlargement with little or no function and a large calculus in the renal pelvis (Elder, 1984). CT usually demonstrates a large, reniform mass with the renal pelvis tightly surrounding a central calcification but without pelvic dilatation (Solomon et al, 1983; Goldman et al, 1984; Hartman, 1985). Renal parenchyma is replaced by multiple water-density masses representing dilated calyces and abscess cavities filled with varied amounts of pus and debris. On enhanced scans the walls of these cavities demonstrate a prominent blush owing to the abundant vascularity within the granulation tissue. The cavities themselves, however, fail to enhance, whereas tumors and other inflammatory lesions usually do. The CT scan is particularly helpful in demonstrating the extent of renal involvement and may indicate whether adjacent organs or the abdominal wall are involved by xanthogranulomatous pyelonephritis (Eastham et al, 1994; Kaplan et al, 1997).

Figure 10–34 Xanthogranulomatous pyelonephritis. Enhanced CT scan shows collecting system and parenchymal calculi (straight arrows) with lower pole pyonephrosis (curved arrow) and an irregular, predominantly low-density perinephric abscess (A) extending into the soft tissues of the flank.

Ultrasonography usually demonstrates global enlargement of the kidney (Merenich and Popky, 1991). The normal renal architecture is replaced by multiple hypoechoic fluid-filled masses that correspond to debris-filled, dilated calyces or foci of parenchymal destruction (Fagerholm, 1983; Hartman et al, 1984). With focal involvement, a solid mass involving a segment of the kidney is demonstrated with an associated calculus in the collecting system or ureter. Renal cell carcinoma and other solid renal lesions must be considered in the differential diagnosis (Elder, 1984).

Radionuclide renal scanning using ^99mTc-DMSA is used to confirm and quantify the differential lack of function in the involved kidney (Gregg et al, 1999). MRI has not yet superseded CT in the evaluation of renal inflammation but it provides some advantages in delineating extrarenal extension of inflammation (Soler et al, 1997). Lesions of xanthogranulomatous pyelonephritis may appear as cystic foci of intermediate signal intensity on T1-weighted images and of hyperintensity on T2-weighted images. Arteriography shows hypervascular areas, but there may be some hypovascular areas (Malek and Elder, 1978; Van Kirk et al, 1980; Tolia et al, 1981). Therefore radiologic studies, although distinctive, often cannot be used to differentiate between xanthogranulomatous pyelonephritis and renal cell carcinoma.

Differential Diagnosis

Diagnosis of segmental xanthogranulomatous pyelonephritis without calculi may be difficult. Xanthogranulomatous pyelonephritis in association with massive pelvic dilation cannot be distinguished from pyonephrosis. When xanthogranulomatous pyelonephritis occurs within a small contracted kidney, the radiographic findings are nonspecific and nondiagnostic. Renal parenchymal malacoplakia may show renal enlargement and multiple inflammatory masses replacing the normal renal parenchyma, but calculi are usually not present. Renal lymphoma may be associated with multiple hypoechoic masses surrounding the contracted, nondilated pelvis, but lymphoma is usually clinically obvious, and renal involvement is usually bilateral and not associated with calculi (Hartman, 1985).

Management

The primary obstacle to the correct treatment of xanthogranulomatous pyelonephritis is incorrect diagnosis. Today, with CT technology, the diagnosis of xanthogranulomatous pyelonephritis is made preoperatively nearly 90% of the time (Eastham et al, 1994; Nataluk et al, 1995). Antimicrobial therapy may be necessary to stabilize the patient preoperatively, and, occasionally, long-term antimicrobial therapy will eradicate the infection and restore renal function (Mollier et al, 1995). Because the renal abnormality may be diagnosed preoperatively as a renal tumor and/or is diffuse, nephrectomy is usually performed. If localized xanthogranulomatous pyelonephritis is diagnosed preoperatively or at exploration, it is amenable to partial nephrectomy (Malek and Elder, 1978; Tolia et al, 1980; Osca et al, 1997).

The lipid-laden macrophages associated with xanthogranulomatous pyelonephritis, however, closely resemble clear cell adenocarcinoma and may be difficult to distinguish solely on the basis of frozen section. Furthermore, xanthogranulomatous pyelonephritis has been associated with renal cell carcinoma, papillary transitional cell carcinoma of the pelvis or bladder, and infiltrating squamous cell carcinoma of the pelvis (Schoborg et al, 1980; Pitts et al, 1981; Tolia et al, 1981); thus if malignant renal tumor cannot be excluded, nephrectomy should be performed. When diffuse and extensive disease into the retroperitoneum exists, removal of the kidney and perinephric fat may be needed. Under these circumstances the surgery may be difficult and may involve dissection of granulomatous tissue from the diaphragm, great vessels, and bowel (Malek and Elder, 1978; Flynn et al, 1979). It is important to remove the entire inflammatory mass because in nearly three fourths of patients xanthogranulomatous tissue is infected. If incision and drainage alone are performed rather than nephrectomy the patient may continue to suffer from protracted debilitating illness and may develop a renal cutaneous fistula; an even more difficult nephrectomy will then be necessary. In one early case-matched series of laparoscopic nephrectomies performed for xanthogranulomatous pyelonephritis it was concluded that the benefits of laparoscopic surgery do not extend to the treatment of this disease (Bercowsky et al, 1999); however, a larger review of a modern xanthogranulomatous pyelonephritis experience suggests that laparoscopic nephrectomy is a reasonable treatment approach.

Pathogenesis

The pathogenesis is unknown, but several theories are popular. In 93 patients who had cultures of urine, diseased tissue, or blood, 89.4% had coliform infections (Stanton and Maxted, 1981). Moreover, 40% of the patients in this review had an immunodeficiency syndrome, autoimmune disease, carcinoma, or another systemic disorder. This association of coliform infections and compromised health status in patients with malacoplakia is well recognized.

It is hypothesized that bacteria or bacterial fragments form the nidus for the calcium phosphate crystals that laminate the Michaelis-Gutmann bodies. Most investigations into the pathogenesis of this disease support theories that a defect in intraphagosomal bacterial digestion accounts for the unusual immunologic response that causes malacoplakia.

Pathology

The diagnosis is made by biopsy. The lesion is characterized by large histiocytes, known as von Hansemann cells, and small basophilic, extracytoplasmic, or intracytoplasmic calculospherules called Michaelis-Gutmann bodies, which are pathognomonic (Fig. 10–35). Electron microscopy has revealed intact coliform bacteria and bacterial fragments within phagolysosomes of the foamy-appearing malacoplakic histiocytes (Lewin et al, 1976; Stanton and Maxted, 1981). In their review of the subject, Stanton and Maxted (1981) and Esparza and associates (1989) emphasized that, although pathognomonic for the disease, Michaelis-Gutmann bodies may be absent in early malacoplakia and are not necessary for the diagnosis.

Figure 10–35 Renal parenchymal malacoplakia. A, Cut surface demonstrates extensive cortical and upper medullary replacement by multifocal, confluent, tumor-like masses. B, Cortical surface exhibits multiple, firm, plaquelike lesions. C, Hallmark of malacoplakia is demonstration of the Michaelis-Gutmann body (arrows), which represents incompletely destroyed bacteria surrounded by lipoprotein membrane (hematoxylin-eosin stain).

(From Hartman DS. Radiologic pathologic correlation of the infectious granulomatous diseases of the kidney: I and II. Monogr Urol 1985;6:3.)

It has been shown that macrophages in malacoplakia involving the kidney and bladder contain large amounts of immunoreactive α₁-antitrypsin (Callea et al, 1982). The amount of α₁-antitrypsin remains unchanged during the morphogenetic stages of the pathologic process. Macrophages from other pathologic processes, closely resembling malacoplakia but without Michaelis-Gutmann bodies, do not contain α₁-antitrypsin except for a few macrophages in tuberculosis and xanthogranulomatous pyelonephritis. Therefore immunohistochemical staining for α₁-antitrypsin may be a useful test for an early and accurate differential diagnosis of malacoplakia.

Clinical Presentation

Most patients are older than 50 years. The ratio of females to males with malacoplakia within the urinary tract is 4:1, but this disparity does not occur in other body tissues (Stanton and Maxted, 1981). The patients often are debilitated, are immunosuppressed, and have other chronic diseases. The symptoms of bladder malacoplakia are bladder irritability and hematuria. Cystoscopy reveals mucosal plaques or nodules. As these lesions progress they may become fungating, firm, sessile masses that cause filling defects of the bladder, ureter, or pelvis on excretory urograms. The distal ureter may become strictured or stenotic and cause subsequent renal obstruction or nonfunction (Sexton et al, 1982). A typical patient with renal parenchymal disease may have one or more radiographic masses and chronic E. coli infections. Renal parenchymal malacoplakia may be complicated by renal vein thrombosis and inferior vena cava thrombosis (McClure, 1983). When malacoplakia involves the testis, epididymo-orchitis is present. Malacoplakia of the prostate is rare, but, when it occurs, it may be confused with carcinoma clinically (Shimizu et al, 1981). Mortality can exceed 50%, and the morbidity can be substantial (Stanton and Maxted, 1981).

Radiologic Findings

Multifocal malacoplakia on excretory urography typically presents as enlarged kidneys with multiple filling defects. Renal calcification, lithiasis, and hydronephrosis are absent. The multifocal nature is best appreciated by using ultrasonography, CT, or arteriography. Ultrasound examination may demonstrate renal enlargement and distortion of the central echo complex. The masses are often confluent, resulting in an overall increase in the echogenicity of the renal parenchyma (Hartman et al, 1980). On CT the foci of malacoplakia are less dense than the surrounding enhanced parenchyma (Hartman, 1985). Arteriography typically reveals a hypovascular mass without peripheral neovascularity (Cavins and Goldstein, 1977; Trillo et al, 1977).

Unifocal malacoplakia on excretory urography appears as a noncalcified mass that is indistinguishable from other inflammatory or neoplastic lesions. Ultrasonography and CT may demonstrate a solid or cystic structure, depending on the degree of internal necrosis. Angiography may demonstrate neovascularity (Trillo et al, 1977). Extension beyond the kidney, which can occur with either multifocal or uniform malacoplakia, is best demonstrated by CT.

Differential Diagnosis

The differential diagnosis includes renal cystic disease, neoplasia, and renal inflammatory disease (Hartman, 1985). Malacoplakia should be considered when one or more renal masses are observed, particularly in female patients with recurrent UTIs with E. coli, altered immune response syndromes, or cystoscopic evidence of malacoplakia or filling defects in the collecting system (Charboneau, 1980). Malacoplakia should also be suspected when these radiographic findings occur in a renal transplant patient who has persistent UTI despite appropriate antimicrobial therapy. Cystic disease generally can be excluded by careful ultrasound and CT evaluations. Renal involvement with metastatic disease or lymphomas usually occurs late in the course of the disease, which is well established. Multifocal renal cell carcinoma is most often seen in the context of von Hippel-Lindau disease with its other clinical manifestations. Patients with xanthogranulomatous pyelonephritis usually have signs and symptoms of UTI. As with malacoplakia, the involved kidney is enlarged but renal calculi and obstruction are common. Multiple renal abscesses are often associated with hematogenous dissemination resulting from cardiac disease.

Management

Management of malacoplakia should be directed at control of the UTIs, which should stabilize the disease process. This subject is well reviewed by Stanton and Maxted (1981). Although multiple long-term antimicrobial agents, including many antituberculosis agents, have been used, the sulfonamides, rifampin, doxycycline, and TMP are thought to be especially useful because of their intracellular bactericidal activity (Maderazo et al, 1979). Fluoroquinolones are taken up by macrophages directly and have also proven effective in the management of malacoplakia (Vallorosi et al, 1999). Other investigators have used ascorbic acid and cholinergic agents such as bethanechol in conjunction with antimicrobial therapy and have reported good results (Abdou et al, 1977; Zornow et al, 1979; Stanton et al, 1983). Both agents are thought to increase intracellular cyclic guanosine monophosphate levels, which have been postulated as the biologic defect causing macrophage dysfunction. Surgical intervention, however, may be necessary if the disease progresses in spite of antimicrobial treatment. Nephrectomy is usually performed for the treatment of symptomatic unilateral renal lesions.

The long-term prognosis appears to be related to the extent of the disease. When parenchymal renal malacoplakia is bilateral or occurs in the transplanted kidney, death usually occurs within 6 months (Bowers and Cathey, 1971; Deridder et al, 1977). Patients with unilateral disease usually have a long-term survival after nephrectomy.

Pathogenesis and Pathology

Echinococcosis is produced by the larval form of the tapeworm, which in its adult form resides in the intestine of the dog, the definitive host. The adult worm is 3 to 9 mm long. The ova in the feces of the dog contaminate grass and farmlands and are ingested by sheep, pigs, or humans, the intermediate hosts. Larvae hatch, penetrate venules in the wall of the duodenum, and are carried by the bloodstream to the liver. Those larvae that escape the liver are next filtered by the lungs. Approximately 3% of the organisms that escape entrapment in the liver and lungs may then enter the systemic circulation and infect the kidneys. The larvae undergo vesiculation, and the resultant hydatid cyst gradually develops at a rate of about 1 cm/yr. Thus the cyst may take 5 to 10 years to reach pathologic size.

Echinococcosis cysts of the kidney are usually single and located in the cortex (Nabizadeh et al, 1983). The wall of the hydatid cyst has three zones: a peripheral zone of fibroblasts derived from tissues of the host becomes the adventitia and may calcify; an intermediate laminated layer becomes hyalinized; and a single inner layer is composed of nucleated epithelium and is called the germinal layer. The germinal layer gives rise to brood capsules that increase in number, become vacuolated, and remain attached to the germinal membrane by a pedicle. New larvae (scoleces) develop in large numbers from the germinal layer within the brood capsule (Fig. 10–36). The hydatid cyst is also filled with fluid. When brood capsules detach, they enlarge and move freely in the fluid and are then called daughter cysts. Hydatid sand is composed of free larvae and daughter cysts.

Figure 10–36 Echinococcosis. A, Gross specimen. A cystic mass measuring 7 × 11 cm in the lower pole. Smaller daughter cysts are identified within the larger cystic mass. B, Gross specimen. Daughter cysts represent brood capsules that have detached and move freely. C, Photomicrograph. Brood capsules (B) arising from the germinal layer (G) contain viable and degenerating scoleces (S).

(From Hartman DS. Radiologic pathologic correlation of the infectious granulomatous diseases of the kidney: III and IV. Monogr Urol 1985;6:26.)

Clinical Presentation

The symptoms of echinococcosis are those of a slowly growing tumor. Most patients are asymptomatic or have a flank mass, dull pain, or hematuria (Gilsanz et al, 1980; Nabizadeh et al, 1983). Because the cyst is focal, it rarely affects renal function. Rarely, the cyst ruptures into the collecting system, and the patient may experience severe colic and passage of debris resembling grape skins in the urine (hydatiduria). The cyst may also rupture into an adjacent viscus or the peritoneal cavity. The fluid is extremely antigenic (Hartman, 1985).

Laboratory Diagnosis

If cyst rupture occurs, the definitive diagnosis can be established by identifying daughter cysts in the urine or by identifying the laminated wall of the cyst (Sparks et al, 1976). Fewer than half of the patients have eosinophilia. The most reliable diagnostic test uses partially purified hydatid arc 5 antigens in a double-diffusion test (Coltorti and Varela-Diaz, 1978). Complement fixation, HA, and the Casoni intradermal skin tests are less reliable but, when combined, are positive in about 90% of patients (Sparks et al, 1976).

Radiologic Findings

Excretory urography typically shows a thick-walled cystic mass, occasionally calcified (Buckley et al, 1985). If the cyst ruptures into the collecting system, daughter cysts may be outlined in the pelvis as an irregular mass or as multiple solitary lesions (Gilsanz et al, 1980). Occasionally, direct filling of the cyst with contrast medium occurs.

Ultrasonography and CT are useful in characterizing the mass. Ultrasonography usually demonstrates a multicystic or multiloculated mass. A sudden change in position may demonstrate bright falling echoes corresponding to hydatid sand, which can be observed during real-time evaluation of hydatid cysts (Saint Martin and Chiesa, 1984).

On CT several patterns of renal echinococcosis may be recognized. The most specific is a cystic mass with discrete, round daughter cysts and a well-defined enhancing membrane (Martorana et al, 1981). The less-specific pattern is that of a thick-walled multiloculated cystic mass (Gilsanz et al, 1980). The presence of daughter cysts within the mother cyst differentiates the lesion from a simple renal cyst and from renal abscesses, infected cysts, and necrotic neoplasm.

Both CT and ultrasonography are useful in evaluating the liver. Angiography is seldom required. Diagnostic aspiration should not be performed because of the danger of rupture and spillage of the highly antigenic cyst contents and risk of fatal anaphylaxis. Nevertheless, Baijal and coworkers (1995) described a percutaneous management of renal hydatidosis as a minimally invasive diagnostic and therapeutic option.

Management

The prognosis of echinococcosis is good but depends on the site and size of the cysts. Medical treatment with benzimidazole compounds such as mebendazole or albendazole has shown limited success with significant side effects (Nabizadeh et al, 1983).

Surgery remains the mainstay of treatment of renal echinococcosis (Poulios, 1991). The cyst should be removed without rupture to reduce the chance of seeding and recurrence. If the cyst wall is calcified, the larvae are probably dead and the risk of seeding is low, although a daughter cyst may be viable. If the cyst ruptures or cannot be removed and marsupialization is required, then the contents of the cyst initially should be aspirated and filled with a scolicidal agent such as 30% sodium chloride, 0.5% silver nitrate, 2% formalin, or 1% iodine for approximately 5 minutes to kill the germinal portion (Sparks et al, 1976; Nabizadeh et al, 1983; Shetty et al, 1992).