Urinary Tract Infection, Pyelonephritis, and Reflux Nephropathy

Brenner and Rector's The Kidney, 8th ed.

CHAPTER 34. Urinary Tract Infection, Pyelonephritis, and Reflux Nephropathy

Nina E. Tolkoff-Rubin Ramzi S. Cotran^[*] Robert H. Rubin
* Deceased.

		Problems in Definition, 1203
		Bacteriology of Urinary Tract Infection, 1203
		General Considerations: The Urine Culture and Urinalysis, 1203
		Etiologic Agents, 1204
		Pathogenesis, 1205
		Hematogenous Infection, 1205
		Ascending Infection, 1205
		Vesicoureteral Reflux, 1207
		Bacterial Virulence Factors Influencing Infection, 1210
		Host Factors Influencing Infection, 1212
		Pathology, 1214
		Acute Pyelonephritis, 1214
		Chronic Pyelonephritis and Reflux Nephropathy, 1214
		Natural History of Bacteriuria and Pyelonephritis, 1217
		Frequency and Epidemiology of Urinary Tract Infection, 1217
		Clinical Impact of Urinary Tract Infection, 1219
		Clinical Presentations, 1220
		Acute Urinary Tract Infection, 1220
		Chronic Pyelonephritis and Reflux Nephropathy, 1221
		Natural History of Vesicoureteral Reflux and Reflux Nephropathy, 1222
		Diagnostic Evaluation, 1223
		History and Physical Examination, 1223
		Urine Tests, 1223
		Radiologic and Urologic Evaluations, 1224
		Treatment, 1224
		General Principles of Antimicrobial Therapy, 1224
		Specific Recommendations, 1224
		Special Forms of Pyelonephritis, 1230
		Renal Tuberculosis, 1230
		Xanthogranulomatous Pyelonephritis, 1231
		Malakoplakia, 1231

Urinary tract infection (UTI) is the most common of all bacterial infections, affecting humans throughout their life span. UTI occurs in all populations, from the neonate to the geriatric patient, but it has a particular impact on females of all ages (especially during pregnancy), males at the two extremes of life, kidney transplant recipients, and anyone with functional or structural abnormalities of the urinary tract. Not only is UTI common, but the range of possible clinical syndromes it can produce is exceptionally broad, including pyelonephritis with gram-negative sepsis, asymptomatic bacteriuria, and even so-called symptomatic abacteriuria.

PROBLEMS IN DEFINITION

The term acute pyelonephritis defines a disorder characterized by bacterial or fungal invasion of the kidney, causing acute interstitial inflammation and tubular cell necrosis. The term chronic pyelonephritis applies to findings of pelvicaliceal inflammation, fibrosis, and deformity of the kidney on histopathologic examination of the kidney. Using these simple definitions, the following correlations have been made^{[1] [2]}:

	1.	In most patients with chronic pyelonephritis, bacterial infection of the urinary tract is superimposed on an anatomic urinary tract anomaly—urinary obstruction or, most commonly, vesicoureteral reflux (VUR).
	2.	UTI in the absence of obstruc-tion or VUR is an uncommon cause of significant chronic pyelonephritis.
	3.	In contrast, chronic tubulointerstitial disease without pyelocaliceal involvement can be caused by a host of factors, including toxins, metabolic disorders, vascular diseases, and autoimmune disorders.

The term reflux nephropathy categorizes the renal scarring associated with VUR.^[2]

BACTERIOLOGY OF URINARY TRACT INFECTION

General Considerations: The Urine Culture and Urinalysis

The evaluation of the results of a quantitative urine culture and urinalysis is the cornerstone of the approach to patients with possible UTI. However, great difficulty is frequently encountered in obtaining a spontaneously voided urine specimen that is uncontaminated by the normal flora of the distal urethra, vagina, or skin. Therefore, certain guidelines are necessary for evaluating the results of urine cultures.

The first clue to the importance of a positive urine culture report comes from the nature of the organism or organisms isolated on culture. In more than 95% of UTIs, the infecting organism is a gram-negative bacillus Enterococcus faecalis or, in the case of reproductive-age women who are sexually active, Staphylococcus saprophyticus ( Table 34-1 ).^[3] In contrast, the organisms that commonly colonize the distal urethra and skin of both men and women and the vagina of women—including Staphylococcus epidermidis, Corynebacteria, lactobacilli, Gardnerella vaginalis, and a variety of anaerobes—rarely cause UTI ( Table 34-2 ).^{[2] [3] [4] [5]}

TABLE 34-1 -- Bacteriologic Findings Among 250 Outpatients and 150 Inpatients with Urinary Tract Infection

Bacterial Species	Outpatients (%)	Inpatients (%)
Escherichia coli	89.2	52.7
Proteus mirabilis	3.2	12.7
Klebsiella pneumoniae
Enterococci
Enterobacter aerogenes
Pseudomonas aeruginosa
Proteus spp (excluding P. mirabilis)	2.4
	2.0
	0.8
	0.4
	0.4	9.3
	7.3
	4.0
	6.0
	3.3
Serratia marcescens	0.0	3.3
Staphylococcus epidermidis^[*]	1.6	0.7
S. aureus	0.0	0.7

Modified from Rubin RH: Infections of the urinary tract. In Dale DC, Federman DD (eds): Scientific American Medicine, sec 7, subsec 23. New York, Scientific American, 1996, pp 1–10. Copyright © [1996] Scientific American, Inc. All rights reserved.

^*	It is likely that most of the outpatient S. epidermidis strains in healthy, sexually active young women were S. saprophyticus.

TABLE 34-2 -- Common Bacterial Contaminants of Urine Cultures That Are Unlikely Causes of True Urinary Tract Infections

Staphylococcus epidermidis

Corynebacteria (diphtheroids)

Lactobacillus

Gardnerella vaginalis

Anaerobic bacteria

A more difficult problem in interpreting urine cultures is vaginal contamination because 5% to 20% of women may harbor gram-negative bacilli at this site in the absence of UTI. In these situations, further information can be gained from the number of different bacterial species identified in a particular urine specimen. In more than 95% of true UTIs, a single bacterial species is responsible for the infection. True polymicrobial UTI occurs uncommonly and is observed in very few clinical situations: when a long-term urinary catheter or another “foreign body” (e.g., calculi, necrotic tumors) is in place; when the patient has a stagnant pool of urine because of inadequate emptying of the bladder, particularly when repeated instrumentation is necessary; or when there is a fistulous communication between the urinary tract and the gastrointestinal or female genital tract. Otherwise, the isolation of two or more bacterial species on urine culture usually signifies a contaminated specimen.^{[5] [6] [7]}

The second major criterion for determining the validity of culture results is based on the quantification of the number of colony-forming units (CFUs) in the urine. Those individuals with urine cultures that reveal at least 10⁵CFU/mL (often termed significant bacteriuria) of a single uropathogen have a high probability of true infection. Unfortunately, the direct application of these quantitative criteria in clinical practice has led to significant confusion. Patients with symptoms referable to the urinary tract may have treatable bacteriuria (and the awkward designation of “true but less than significant bacteriuria”) with as few as 10²CFU/mL on quantitative culture.^{[2] [3] [7]}As a result, criteria have been established to ensure adequate sensitivity and specificity.

Women who present with symptoms of acute, uncomplicated UTI (dysuria, frequency, suprapubic discomfort) are believed to have true infection when at least 10³CFU/mL of a single species of uropathogen are found on quantitative culture (sensitivity of 80% and specificity of 90%). In patients with symptoms of acute, uncomplicated pyelonephritis (fever, rigors, flank pain, with or without dysuria or frequency), the cutoff is 10⁴CFU/mL or less (sensitivity and specificity of 95%).^{[2] [3] [6] [7]} Circumstances associated with lower densities of bacteria in the urine when the patient has true infection include the acute urethral syndrome, infection with S. saprophyticus and Candida species, prior administration of antimicrobial therapy, rapid diuresis, extreme acidification of the urine, obstruction of the urinary tract, and extraluminal infection.^{[4] [6] [7]}

Examination of the urine for leukocytes is the final validation test that can be applied in the evaluation of patients with possible UTI. When a randomly collected urine sample is examined in a hemocytometer and at least 10 leukocytes/mm³ are found, there is a high probability of clinical infection^[2]:

	1.	More than 96% of symptomatic men and women with significant bacteriuria have at least this level of pyuria; fewer than 1% of asymptomatic, nonbacteriuric individuals have this level of pyuria.
	2.	Most symptomatic women with pyuria but without significant bacteriuria have an inflammatory process, most commonly bacterial or chlamydial infection responsive to therapy. Other causes of “sterile pyuria” include interstitial cystitis, genitourinary tuberculosis, systemic mycotic infection, and contiguous infection resting on the ureter or bladder and inducing “sympathetic inflammation” in the urine.
	3.	One situation in which the finding of pyuria does not add significantly to the diagnostic evaluation is in patients with indwelling urinary catheters. In these individuals, the finding of pyuria does not necessarily indicate infection.^[8]

Etiologic Agents

Bacterial Pathogens

The gastrointestinal tract is the reservoir from which uropathogens emerge. Reflecting this, the Enterobacteriaceae and E. faecalis are the most important causes of UTI in all population groups, accounting for more than 95% of all UTIs. Of the Enterobacteriaceae, Escherichia coli is by far the most common invader, causing some 90% of UTIs in outpatients and approximately 50% in hospitalized patients (see Table 34-1 ).^{[2] [7] [9]}

Certain bacterial pathogens are especially associated with UTI in a particular population group. One notable example is the recognition that S. saprophyticus is an important cause of symptomatic UTI in young, sexually active women, and an uncommon cause of infection in men.^{[10] [11] [12]} Other reported associations include an increased frequency of Proteus infections in boys aged 1 to 12 years, particularly if uncircumcised, and E. faecalis infection in elderly men with prostatism.^{[9] [13] [14]}

In more than 95% of instances, UTI develops through the ascending route, from urethra to bladder to kidney. However, if bacteremia due to virulent organisms occurs from some other site, seeding of the kidney can occur. Hematogenous seeding is most commonly observed in association with bacteremia due to Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella species.^[9]

Hematogenously derived infection of the urinary tract is particularly common in instances of Salmonella sepsis. For example, approximately 25% of patients with S. typhi infection have positive urine cultures. An unusual example of this phenomenon occurs in areas of the world in which urinary tract schistosomiasis due to Schistosoma haematobium is common. In such patients, bacteremic seeding of the urinary tract with Salmonella species results in infection of the schistosomes and chronic Salmonella bacteriuria. Such infections can be controlled only by eradicating the schistosomal infection first.^[2]

The kidney is the most common extrapulmonary site of tuberculosis; the tubercle bacilli reach the kidney from the lung by the hematogenous route, usually with later spread down the urinary tract to the ureter, bladder, and in the male patient, prostate, seminal vesicle, and epididymis.^[15]

Fungal Pathogens

By far the most common form of fungal infection of the urinary tract is that caused by Candida species. Most such infections occur in patients with indwelling Foley catheters who have been receiving broad-spectrum antibacterial therapy, particularly if diabetes mellitus is also present or corticosteroids are being administered. Although most of these infections remain limited to the bladder and clear with removal of the catheter, cessation of the antibacterial therapy, and control of the diabetes, the urinary tract is the source of approximately 10% of episodes of candidemia—usually in association with urinary tract manipulation or obstruction.^{[16] [17]} Spontaneously occurring lower UTI caused by Candida species is far less common, although papillary necrosis, caliceal invasion, and fungal ball obstruction have all been described as resulting from ascending candidal UTI that is not related to catheterization. Candidal obstructive uropathy is particularly important in children with congenital anatomic abnormalities of the urinary tract and in kidney transplant recipients.^{[18] [19]} In the transplant patient, obstructive uropathy due to candiduria is a particularly dangerous situation, being associated with a high risk of systemic dissemination from the urinary tract.^{[18] [20] [21]}

Hematogenous spread to the kidney and other sites within the genitourinary tract may be seen in any systemic fungal infection, but it occurs particularly in coccidioidomycosis and blastomycosis.^[21] In immunosuppressed patients, a common hallmark of disseminated cryptococcal infection is the appearance of this organism in the urine. Cryptococcus neoformans commonly seeds the prostate and, far less commonly, may cause a syndrome of papillary necrosis, pyelonephritis, and pyuria akin to that seen in tuberculosis.^{[19] [21] [22]}

Other Pathogens

Several other classes of microorganisms, most notably Chlamydia trachomatis, the genital mycoplasmas, and certain viruses, can invade the urinary tract. C. trachomatis has been clearly shown to be an important cause of the acute urethral syndrome.^[3] Whether this organism could have an impact on the upper urinary tract remains to be determined.

In normal persons, the most convincing case for virally induced disease can be made for adenoviruses. Thus, adenovirus types 11 and 21, particularly type 11, have been shown to cause between one fourth and one half of cases of hemorrhagic cystitis in schoolchildren, with sporadic cases also occurring in immunologically normal adults. In immunosuppressed patients such as organ transplant and bone marrow transplant recipients, hemorrhagic cystitis, interstitial nephritis, and disseminated infection caused by adenoviruses are far more common.^{[19] [23] [24]} Similarly, tubulointerstitial nephritis due to papovaviruses, cytomegalovirus, and other agents can occur in these immunosuppressed individuals but are quite uncommon in other populations.^[23]

PATHOGENESIS

Hematogenous Infection

Although E. coli accounts for the vast majority of UTIs, it is a rare cause of infection of the urinary tract as a consequence of bacteremia, unless some other factor is introduced. The inability of most E. coli strains to cause infection via the hematogenous route is related not only to their intrinsic nonpathogenicity by this route of infection but also to the small proportion of circulating bacteria that are actually deposited in the kidney. In addition, intrinsic bacterial clearing mechanisms within the renal tissue are able to clear the kidneys of these small numbers of organisms without sequelae. In sum, the level of E. coli infection required to accomplish seeding of the kidneys via the bloodstream will have lethal consequences for the individual long before infection can be established in the kidneys.^{[2] [19]} In contrast, S. aureus can cause suppurative infection of the kidney in the face of a low level of organisms in the bloodstream, a level that is compatible with life—the exact opposite situation as is operative with E. coli.^[25]

Although the intact kidney is resistant to hematogenous E. coli infection, various processes affecting renal structure and function can increase the susceptibility of the kidney and can favor the initiation of pyelonephritis by the hematogenous route (and, presumably, via the ascending route as well). These processes include obstruction of urine flow (even for relatively short periods of time); intratubular chemical injury from drugs; vascular factors, such as renal vein constriction or arterial constriction; hemorrhagic hypotension; hypertension; K⁺ depletion; analgesics; renal massage; polycystic kidney disease; experimentally induced diabetes mellitus; and administration of estrogens.^{[2] [3] [4] [7] [19]}

The mechanism by which obstruction increases the susceptibility of the kidney to infection is not entirely clear. The leading hypothesis is that increased tissue pressure in the kidney could be impeding the renal microcirculation during the obstructive phase, interfering with the innate ability of the kidney to clear infection.^{[2] [26]}

These experimental observations offer several important insights relevant to human infection:

	1.	In patients with normal urinary tract anatomy, the simultaneous demonstration of E. coli in the urine and the blood strongly suggests the kidney as a portal of entry for the bacteremia. In contrast, the simultaneous demonstration of S. aureus, Candida, or Salmonella infection in the blood and urine suggests a portal of entry outside the urinary tract with spread to the kidney and underscores the need for a careful search for the primary source of the infection. P. aeruginosa and Proteus infection can manifest either pattern.
	2.	Patients with increased intrarenal pressures resulting from urinary tract obstruction may be at risk for metastatic infection with various organisms, including those like E. coli that are usually not pathogenic for the kidney when bacteremia is the mechanism by which bacteria are delivered.
	3.	A kidney subjected to trauma may be at particular risk for the development of pyelonephritis. This observation may be especially relevant to patients who have undergone kidney transplantation and those experiencing physical trauma.

Ascending Infection

Overwhelming clinical evidence indicates that most infections of the kidney result from the inoculation of bacteria derived from the gastrointestinal tract into the urethra, from there to the bladder, and finally, to the kidney. Specific virulence factors appear to be required to accomplish this task in the anatomically and functionally normal urinary tract.^{[2] [26] [27]} This observation has several profound implications:

	•	Females, because of the proximity of the anus to the urethra, are at increased risk for UTI (just as male homosexuals who engage in rectal intercourse are at increased risk for such infection^[28]).
	•	Modification of the normal gastrointestinal flora caused by exposure to antibiotics or by residence within a nursing home or hospital markedly changes the microbial cause of UTIs that occur in these settings—the antibiotic-susceptible E. coli is less likely to be the cause in these cases; instead, the typical responsible organism is relatively antibiotic-resistant gram-negative species.
	•	Among the characteristics that render a particular clone of E. coli uropathogenic is the ability to maintain stable residence in the colon, from which it can then be introduced into the urinary tract.
	•	People with intimate contact with farm animals receiving antibiotics or growth factors are at particular risk for the occurrence of resistant infection.

The same bacterial surface ligands that mediate attachment to the uroepithelium and the same mucosal receptors that interact with these bacterial ligands in the urinary tract are present in the gastrointestinal tract and play a significant role in the maintenance of stable colonization by the uropathogens.^{[26] [27] [28] [29] [30]} The crucial next step in the pathogenesis of UTI is the colonization of the distal urethra, the periurethral tissues, and in the female patient, the vaginal vestibule with potential urinary tract pathogens.^{[26] [27] [28] [29] [30]}

A major host defense against this first step in the pathogenesis of UTI is the presence of the normal vaginal flora, particularly the lactobacilli. Stapleton and Stamm^[31] have defined several mechanisms by which the lactobacilli, alone or in combination with other constituents of the normal vaginal flora, could protect against the initiation of UTI: (1) by maintaining an acid vaginal environment, which diminishes E. coli colonization; (2) by blocking the adherence of uropathogens, such as E. coli; (3) by producing hydrogen peroxide, which interacts with peroxidase and halides in the vagina to kill E. coli; and perhaps, (4) by elaborating other antimicrobial substances. The clinical importance of this natural defense mechanism is demonstrated by the following observations^{[26] [27] [28] [29] [30] [31] [32]}:

	1.	Postmenopausal women are often subject to recurrent UTI as a consequence of estrogen deficiency. This leads the loss of lactobacilli and an acid pH, resulting in an increased rate of vaginal colonization with uropathogens and subsequent UTI. These changes can be reversed by topical (or systemic) estrogen therapy.
	2.	Reproductive-age women, using spermicides containing nonoxynol-9, have an increased risk of UTI associated with the antilactobacillus effect of the spermicide; repopulation of the vagina with lactobacilli and other constituents of the normal flora by switching to alternative contraceptive strategies decreases the subsequent risk of both vaginal colonization and UTI.^{[31] [32]}

Whether sustained bacteriuria results from the coloniza-tion of the vaginal vestibule and distal urethra depends on the interaction of several factors^{[33] [34] [35] [36]}: whether the colonizing species possesses surface adhesins that promote the attachment of the organisms to the epithelial surface; whether the mucosal cells of a particular woman have a particularly high affinity for these bacterial adhesins; whether the subject secretes blood group antigens that block adhesin-receptor interaction; and whether the bacteria are physically translocated into the bladder. Periurethral and vaginal mucosal cells derived from women who experience recurrent UTIs adhere to uropathogenic E. coli strains to a much greater extent than do cells derived from women who are free of this problem. Women who do not secrete ABH blood group antigens in their body fluids (nonsecretors) are particularly susceptible to recurrent UTI (with a risk three to four times that of secretors). Binding of bacteria to the cells is accomplished through specific bacterial ligand-epithelial cell receptor interaction, which is physically blocked by the presence of secreted ABH blood group antigens in the urine and vaginal secretions of individuals who are secretors (approximately two thirds of the general population). The secretor gene encodes glycosyltransferases that act on cell surface glycoproteins and glycosphingolipids, resulting in the release of ABH antigens into bodily secretions. One consequence of this process is that the vaginal epithelium of nonsecretors expresses unique glycosphingolipids that bind uropathogenic E. coli; these glycosphingolipids are not expressed on the epithelial cells of secretors. In sum, two genetically determined characteristics play an important role in the initiation of UTI: the genetic constitution of the bacterial strain that is colonizing (i.e., whether it possesses adhesins that mediate attachment) and the woman's own genetic constitution. Studies in mice have confirmed the role of specific genes in determining the susceptibility to E. coli UTI.^{[26] [30] [31] [32] [33] [34] [35] [36] [37] [38]}

Men are normally protected against the initiation of UTI because of the anatomic separation of the urethral meatus and the anus, the length of the male urethra, and the bactericidal activity of prostatic secretions. Lack of circumcision has been linked to an increased risk of UTI, as have homosexual activity that involves anal intercourse and, rarely, heterosexual vaginal intercourse with a partner colonized with a uropathogen (a virulent strain, as opposed to a commensal strain, is far more efficient in transmitting infection to the male partner). Bacteriuria is unusual in the absence of prostatic dysfunction or other urogenital abnormalities.^{[28] [39] [40] [41] [42] [43] [44] [45]}

Entry of Pathogens into the Bladder

The processes by which bacteria ascend from the urethra into the bladder are incompletely understood. One clearly demonstrated mechanism by which bacteria are introduced into the bladder is by instrumentation of the urethra and bladder, such as occurs with cystoscopy, urologic surgery, and installation of a Foley catheter.

A more common mechanism for introducing bacteria into the bladder is through sexual intercourse. The frequency of bacteriuria in the general female population was 12.8 times greater than among nuns of a similar age; in another study, it was shown that the frequency of bacteriuria was inversely related to the interval since last intercourse in a popula-tion of women attending a clinic for sexually transmitted diseases.^[46] Nicolle and associates^[47] reported a high asso-ciation between the development of significant bacteriuria in women and intercourse in the previous 24 hours and noted that the frequency of intercourse was higher in infected women than in uninfected women.^[48] In this study, 75% of the episodes of UTI in women with a history of recurrent UTIs occurred within 24 hours of intercourse.

If intercourse is an important pathogenetic event in the development of UTI, then therapy directed at the immediate postintercourse period should be effective. Indeed, Vosti^[48] noted that a single dose of antibiotic taken after intercourse is effective in preventing UTI in a group of women susceptible to recurrent UTI. Perhaps the most compelling data come from a study that showed that bacteria are routinely introduced during intercourse, but that in most instances, these bacteria are components of the normal flora of the vagina and distal urethra (S. epidermidis, diphtheroids, and lactobacilli), which rarely cause UTI and are promptly cleared by voiding. However, if the vaginal vestibule is colonized with a uropathogenic strain of E. coli, then sustained bacteriuria can be established by intercourse. Once the vaginal vestibule is so colonized, the risk of UTI is approximately 10% in sexually active women.^{[9] [49]}

On balance, it appears that sexual intercourse alone does not establish bacteriuria and that bacteriuria can occur in the absence of intercourse, but if intercourse is coupled with the presence of virulent bacteria in the vagina, it leads to an increased frequency of infection.^{[9] [49]}

Bacterial Multiplication in the Bladder and Bladder Defense Mechanisms

Whatever the mode of entry of bacteria into the bladder, the normal bladder is capable of clearing itself of organisms within 2 to 3 days of their introduction. This effect appears to depend on the combined effects of three factors: (1) the elimination of bacteria by voiding, (2) the antibacterial properties of urine and its constituents, and (3) the intrinsic mucosal bladder defense mechanisms.^{[9] [26]}

Perhaps the most effective way of eliminating bacteria from the bladder is by voiding, which removes approximately 99% of bacteria present. This hydrokinetic defense mechanism is supplemented by dilution of the bladder urine by the constant inflow of urine from the kidneys, as well as the ability of the bladder mucosa to eliminate the small number of residual organisms that persist.^{[9] [26] [50]}

The net effect of urine on bacterial growth in the bladder represents an integration of the influences of a variety of physicochemical entities. Urea, organic acids, salts, and low-molecular-weight polyamines in the urine, as well as conditions of low pH and high or low osmolality, inhibit bacterial growth.^[51] Both low pH and high osmolality adversely affect polymorphonuclear leukocyte function. In addition, such urinary osmoprotective substances as glycine and proline betaine protect E. coli against the effects of hypertonic urine.^[52] Finally, inhibition of bacterial adherence to mucosal receptors acts as a useful defense against infection. These inhibitors include the layer of glycosaminoglycan that overlies the epithelial cell layer of the bladder and blocks bacterial attachment to the bladder mucosa.^[53] Adherence to the uroepithelium itself, through the adenylate cyclase signal transduction pathway, triggers the antibacterial activity mediated directly by uroepithelial cells.^{[26] [54]}

Clinically, clearing of bacteriuria does not occur in the presence of frank residual urine, inadequate micturition, foreign bodies or stones in the bladder, increased vesical pressure, or previous inflammation of the bladder mucosa. The role of residual urine, foreign bodies, and preexisting inflammatory lesions is readily recognized. Residual urine not only increases the number of bacteria remaining in the bladder but also lowers the ratio between the surface area of the bladder mucosa and the volume of urine exposed to it, thus reducing the effectiveness of potential antibacterial mucosal factors. Distention of the bladder and increased hydrostatic pressure inhibit clearance of bacteria.^[55]

The efficacy of bladder bacterial clearance mechanisms is demonstrated not only by experimental studies but also by clinical observation. A group of Swedish women with acute, uncomplicated UTI had a 70% clearance rate over a 1-month period, despite treatment with only a placebo.^[56]

UTI is the most common form of bacterial infection affecting humans throughout their lifespan. In children, by the age of 10, 2% to 8% of them will have had UTI, with girls being affected at a rate approximately 10-fold greater than that of boys. An estimated 55% to 75% of children with febrile UTI have evidence of renal parenchymal injury, with 20% to 40% them developing renal scarring. Overall, 57% of schoolgirls have episodes of bacteriuria at some time.^{[55] [56] [57] [58] [59]} Approximately 20% of women of reproductive age develop symptoms indicative of urinary tract inflammation each year, with the majority of these episodes being due to bacterial infection. Overall, 50% to 60% of adult women will have a UTI during their lifetime. UTI in women occur with a frequency 50 times that observed in men. The combination of UTI and VUR has been associated with renal scarring, hypertension, and even end-stage renal disease.^{[55] [56] [57] [58] [59] [60]}

Vesicoureteral Reflux

An important host defense against ascending infection from the bladder to the kidneys is the competency of the vesicoureteral valve mechanism. Indeed, the combination of VUR and infected urine is the most common factor predisposing to chronic pyelonephritic scarring, particularly in infants and children.^[55]

In the normal adult, the vesicoureteral valve is compe-tent despite the high bladder pressures generated during micturition. VUR is prevented by virtue of the length of the intramural segment of the ureter; the ureter is obliquely inserted into a tunnel in the bladder wall ( Fig. 34-1 ), so the intravesical portion of the ureter is compressed by the bladder musculature during micturition. Failure of this valve mechanism is most commonly due to shortening of the intravesical portion of the ureter (primary VUR). The intravesical portion of the ureter lengthens with age, increasing the competence of the valve mechanisms and rendering it less susceptible to reflux. Approximately two thirds of healthy infants younger than 6 months of age have at least mild to moderate reflux, with a rapid decrease thereafter. In the absence of infection, even antenatally demonstrated gross reflux improves or, in some cases, resolves by 2 years of age.^{[61] [62] [63] [64] [65] [66] [67] [68]}



FIGURE 34-1 Intravesical position of the ureter in the normal person (A) and in patients with vesicoureteral reflux. Types D and D¹ are by far the most common in children and infants. (From King LR, Surian MA, Wendel RM, Burden JJ: Vesicoureteral reflux: A classification based on cause and the results of treatment. JAMA 203:169–174, 1968. Copyright 1968, American Medical Association.)

In children, VUR may also be secondary, occurring in association with other anomalies such as obstruction. Neonates with neurogenic bladder disorders, such as myelodysplasia, in which high-pressure obstruction occurs, have no demonstrable VUR but eventually experience secondary VUR with typical ureteral “golf-hole” orifices as well as ureteral dilation and tortuosity. VUR develops in 45% of patients with meningomyelocele by the age of 5 years, sometimes with renal scarring.^{[66] [67] [68] [69]}

Bladder-sphincter dysfunctional disturbances in toddlers and children are associated with high-pressure VUR.^{[66] [67] [68] [69] [70]} In a study of 458 children with bladder dysfunction, two different types of reflux with contrasting urodynamic characteristics were identified. In one, the bladder contracted poorly during voiding, and overactivity of the urethral closure mechanism was present. In this group, VUR was bilateral and was associated with upper urinary tract anomalies and renal scarring. In the second type, there was bladder instability and powerful voiding contractions of the bladder; this type was associated with unilateral reflux and rare renal scarring.^{[71] [72]}

Of the congenital anatomic anomalies, VUR occurs commonly in the presence of a paraurethral diverticulum^[72]; in 25% to 50% of boys with posterior urethral valves^{[72] [73]}; in 10% of those with ureteropelvic junction obstruction^[74]; and in patients with ureteral duplications, hypospadias, and ureteroceles. Although obstructive uropathy is assumed to be the cause of fetal hydronephrosis, VUR is found to be present in 10% to 40% of these infants studied postnatally, often with advanced grades of reflux. The hope would be that the aggressive treatment of these neonates, 75% to 80% of whom are boys, would help preserve renal function and facilitate kidney growth.^{[61] [64] [75] [76] [77] [78]}

Congenital VUR is five times more common in boys than in girls and tends to occur in families. When asymptomatic siblings of children with VUR are studied, approximately 40% have been shown to also have reflux, some with evidence of clinically silent scarring. Approximately two thirds of the offspring of parents with known VUR have evidence of reflux as well when they are studied by voiding cystourethrogram.^{[66] [79] [80] [81]} White children have a threefold greater incidence of VUR than do African American children, and the severity of VUR is greater among white children. On the basis of segregation analysis of 88 affected families, Chapman and colleagues^[82] concluded that the best model was that of a single dominant gene acting together with a random environmental effect. Computer modeling indicated that the gene frequency was 1 in 600 and that mutation was uncommon.

Still unresolved is the question of whether bladder infection can precede and, in a way, cause VUR. The clinical evidence suggests that infection is not a necessary cause of reflux but that it can precipitate reflux in a ureterovesical junction that is congenitally defective or, indeed, can increase the grade of reflux.^{[83] [84] [85]}

VUR, which can be unilateral or bilateral, may vary considerably in severity. Severity of reflux is graded by means of voiding cystourethrography. The grading system adopted by the International Reflux Study Committee is as follows ( Fig. 34-2 )^[86]:

		Grade I: Reflux partly up the ureter.
		Grade II: Reflux up to the pelvis and calices without dilation; normal caliceal fornices.
		Grade III: Same as grade II, but with mild or moderate dilation and tortuosity of the ureter and no blunting of the fornices.
		Grade IV: Moderate dilation and tortuosity of the ureters, pelvis, and calices; complete blunting of fornices.
		Grade V: Gross dilation and tortuosity of the ureter, pelvis, and calices; absent papillary impressions in the calices.



FIGURE 34-2 Grades of reflux. International Reflux Study classification. I, Ureter only. II, Ureter, pelvis, and calices. No dilation, normal caliceal fornices. III, Mild or moderate dilation or tortuosity of ureter or both, and mild or moderate dilation of renal pelvis but no or slight blunting of fornices. IV, Moderate dilation or tortuosity of ureter or both, and moderate dilation of renal pelvis and calices. Complete obliteration of sharp angle of fornices but maintenance of papillary impressions in majority of calices. V, Gross dilation and tortuosity of ureter. Gross dilation of renal pelvis and calices. Papillary impressions are no longer visible in majority of calices.

Many technical and clinical factors can influence the grade of the reflux as seen on the voiding cystogram, however, and standardization has not yet been accomplished.^[86] Despite this, it is clear that there is a correlation between the severity of the reflux and the extent of renal scarring.^{[83] [84]}

Radionuclide cystography is emerging as an alternative and, in many ways, superior technique for evaluating VUR.^[85] Indirect radionuclide cystography, in which the radionuclide is injected intravenously, is noninvasive but detects only high-pressure gross VUR and requires good renal function. Conversely, cystography after direct instillation of radionuclide (technetium 99m pertechnetate) has proved to be a sensitive, quantitative, and safe procedure that also serves as a test for evaluating functional bladder disorders.^[85]

There is a clear-cut link among renal infection, VUR, and the presence of renal scarring^{[87] [88] [89] [90] [91] [92]}:

	1.	In various series, VUR can be demonstrated by voiding cystourethrography in 30% to 50% of children with recurrent infection and in 85% to 100% of children and 50% of adults with chronic pyelonephritic scarring.^{[69] [72] [89]} Furthermore, even in children and adults with renal scars who do not exhibit reflux, anatomic abnormalities of the ureteral orifices (lateral ectopia and abnormal configuration) are seen cystoscopically, which suggests that reflux had been present in the past.
	2.	Between 30% and 60% of children with VUR exhibit pyelonephritic scarring, the higher figure being derived from surgical clinics and the lower from medical studies.^{[87] [88] [89] [90] [91] [92]}
	3.	Renal scarring of the pyelonephritic type is found in up to 25% of children with UTI, and about 30% to 50% of these have VUR.^{[61] [64] [69] [87] [88] [89] [90] [91] [92] [93] [94]}
	4.	Several studies have documented the progressive development of clubbing of the calices and renal scarring after discovery of VUR in previously normal kidneys.^{[69] [95] [96]} Progressive scarring appears in the more severe forms of reflux and almost always in the presence of infected urine. It must be stressed, however, that in many infants and children with VUR, pyelonephritic scarring never develops, and VUR may disappear either spontaneously or with antibacterial therapy in up to 80% of ureters after long follow-up.^{[88] [89] [90] [91] [92] [93]} Even severe reflux associated with scarring may disappear, although reflux is more likely to cease if it is mild or moderate and if the kidneys are unscarred. Among adults, about 90% with severe VUR have renal scars.^{[94] [97]}

Intrarenal Reflux

Whereas VUR is responsible for the ascent of bacteria into the renal pelvis, the spread of infection from the pelvis into the cortex occurs by virtue of a phenomenon known as intrarenal reflux. In some children with urinary infection, contrast medium instilled into the bladder during voiding cystourethrography permeated the renal parenchyma as far as the renal capsule. Intrarenal reflux occurred with the most severe grades of VUR ( Fig. 34-3 ). Intrarenal reflux was focal in distribution and affected predominantly the two polar regions of the kidney, areas that are frequently the site of chronic scars. It was suggested that such intrarenal reflux could form the basis of the spread and distribution of infection.^{[98] [99]}



FIGURE 34-3 Cystogram shows severe grade of vesicoureteral reflux (grade IV) with scattered intrarenal reflux into all zones of the kidney. (From Hodson CJ: Reflux nephropathy. Med Clin North Am 62:1201, 1978.)

When intrarenal reflux is induced in young pigs by elevating bladder pressure, and infected urine is placed in the bladder, acute inflammation and scarring of the kidney develop. The distribution of intrarenal scars was similar to that occurring in humans, with involvement of the upper and low poles of the kidney.^{[100] [101] [102]}

Intrarenal reflux in the multipapillary kidneys of both human infants and young pigs occurred only in renal papillae with particular morphologic characteristics. They found two basic forms of renal papillae:

	1.	Nonrefluxing papillae are conic, and their papillary ducts open obliquely near the tip of the papilla onto a convex surface through slitlike orifices ( Fig. 34-4A ). These papillae may be simple, representing a single renal reniculus, or compound, in which two or more reniculi have fused. Such papillae are never associated with intrarenal reflux, because even in the presence of VUR, their orifices are closed by the rise of pressure within the calix.
	2.	Refluxing papillae are larger as a result of fusion of several adjacent reniculi (see Fig. 34-4B ). They have concave rather than convex tips, and the papillary ducts open with gaping orifices that cannot be closed by an increase in intracaliceal pressure. Of great significance is that both in infants and in young pigs, refluxing papillae are present predominantly in the upper and lower poles; the simple and compound types are present mostly in the midzones ( Table 34-3 ). In addition, although the number of refluxing papillae is less in the human than in the pig, approximately two thirds of human kidneys contained at least one potentially refluxing papilla, and in one fifth of the kidneys, the percentage of nonconvex papillae was 30% or more.^{[100] [101] [102] [103]}



FIGURE 34-4 A, Simple, nonrefluxing papilla from the pig kidney. Note the conic form, with papillary ducts opening near the tip onto a convex surface. B, Compound refluxing papilla with a concave surface and wide-open papillary duct orifices. (From Ransley PG, Risdon RA: The pathogenesis of reflux nephropathy. Br J Radiol 14:1, 1978.)

TABLE 34-3 -- Distribution of Compound Type II and III (Refluxing) Papillae in Normal Young Human and Porcine Kidneys

Species	None	Both Upper and Lower Poles	Upper Pole Only	Lower Pole Only
Human^[*] (n = 33)	6 (18%)	14 (42%)	4 (12%)	9 (27%)
Pig (n = 25)	24 (96%)	1 (4%)	0 (0%)	0 (0%)

From Ransley PG, Risdon RA: Renal papillary morphology in infants and young children. Urol Res 3:111, 1977.

^*	Only one kidney showed a refluxing papilla in the midzone.

In summary, two main determinants for the progression of ascending infection from the bladder into the renal parenchyma are:

	1.	VUR most commonly is due to a congenital abnormality involving the insertion of the ureter into the bladder.
	2.	Intrarenal reflux is determined by the presence of morphologically distinct papillae with open ducts, which allows spread of organisms into the renal parenchyma in the presence of high intracaliceal pressure. VUR and intrarenal reflux, in combination, are almost certainly the major mechanisms responsible for the renal inflammation and scarring characteristic of chronic pyelonephritis.

These findings of VUR, intrarenal reflux, and papillary morphologic characteristics can also explain some perplexing clinical observations in children. It has been amply shown that in most children with VUR who have renal scars, scarring is already evident at the initial radiologic investigation, which is usually performed because of UTI. Scarring thus appears to occur early in life, possibly even in utero. For example, 10 infants presenting with UTI and VUR from 9 days to 7 weeks of life already had evidence of renal scarring. Indeed, the development of new scars in children is unusual beyond the age of 5 years (and possibly the age of 2 years), regardless of proven episodes of UTI.^{[103] [104] [105]}

Sterile Reflux

In addition to the association between VUR in the infected child and renal scarring, renal inflammation and scarring can result from high-pressure VUR in the total absence of infection, particularly if there is sustained bladder decompensation (i.e., if bladder pressure does not return to normal between micturitions in the presence of outflow obstruction).^{[105] [106] [107]} However, considerable controversy still exists as to the frequency with which such damage occurs clinically.

Renal involvement in reflux nephropathy occurs early in childhood, before age 5 years, largely as a result of superimposition of bacterial UTI on VUR and intrarenal reflux. Because most potentially refluxing papillae are thus affected early on, additional progressive scarring occurs rarely, owing to the transformation of papillae from nonrefluxing to refluxing types. This accounts for the occurrence of new segmental scars or sequential scarring of an already scarred kidney, but such progression is rare. If sterile intrarenal reflux induces renal damage, it does so in the presence of severe obstructive uropathy with high intrapelvic pressures. Such may be the case in children with posterior urethral valves or other obstructive congenital anomalies.^{[108] [109] [110] [111] [112]}

Most cases of VUR are detected during investigations for UTI, the most common marker for this disorder. In addition to renal scarring, VUR in children is associated with reduced renal growth, and there is some question as to whether VUR or UTI or both play a role in such growth retardation. In patients with VUR, renal function may deteriorate for reasons other than UTI, particularly hypertension, an associated glomerulopathy, urinary obstruction, or analgesic abuse.^{[108] [109] [110] [111] [112] [113]}

Bacterial Virulence Factors Influencing Infection

Escherichia Coli

A limited number of clones of E. coli (and, it is assumed, other bacterial species such as Proteus) are responsible for UTIs in normal women. When outbreaks of pyelonephritis have occurred, it is clearly seen that uropathogenic clones are responsible. These virulent clones possess a variety of virulence factors that allow uropathogenic E. coli to accomplish the tasks necessary for causing UTI in the anatomically and functionally normal urinary tract. These tasks include: prolonged intestinal carriage, persistence in the vaginal vestibule, and then ascension and invasion of the anatomically normal urinary tract. The occurrence of UTI with a “nonvirulent” strain of E. coli constitutes evidence that VUR, obstruction, stasis (e.g., a neurogenic bladder), or a foreign body is present.^{[114] [115] [116]}

The virulent clones are of a limited number of serotypes (belonging to such O serotypes as O1, O2, O4, O6, O7, O8, O9, O11, O16, O18, O22, O25, O39, O50, O62, O75, and O78). Those O serotypes listed account for more than 80% of cases of pyelonephritis (as compared with 28% of fecal strains, 60% of cystitis isolates, and 30% of asymptomatic bacteriuria isolates).^{[114] [115] [116] [117] [118]} Similarly, a limited spectrum of K antigens (capsular antigen) are found on these uropathogenic clones (K1, K2, K3, K5, K12, K13, and K51) account for more than 70% of pyelonephritis isolates. In contrast, the H antigens appear not to be independently associated with virulence.^{[118] [119] [120]}

It is likely that these O antigens are not themselves responsible for the uropathogenicity of these strains of E. coli; rather, the genes that determine the O antigen structure are closely linked to other genes that are responsible for the pathogenicity of these isolates. In contrast, the acidic polysaccharide capsular K antigens do appear to be directly pathogenic by inhibiting both phagocytosis and complement-mediated bactericidal activity. The amount of K antigen expressed appears to be especially important because strains of E. coli that are particularly rich in K antigen appear to be more successful both in reaching the bladder and in ascending to and invading the kidney than are strains with low amounts of K antigen.^{[114] [115] [118] [119] [120] [121]}

A variety of additional factors have been defined that are believed to contribute to the virulence of a particular isolate. These include surface adhesins that mediate attachment to specific receptors on the uroepithelium; molecules that preferentially capture metabolites and growth factors that enhance growth and proliferation (e.g., iron); and toxins that injure the tissue of the urinary tract and induce a brisk inflammatory response. The term pathogenicity-associated islands (PAIs) is used to describe the clustering of virulence genes on the chromosome; these DNA sequences are rarely found in nonuropathogenic organisms, such as routine isolates of E. coli of fecal origin from uninfected individuals. PAI sequences are found in the great majority of uropathogenic strains, are uncommonly found in fecal isolates, and are sometimes demonstrable in other gram-negative UTI isolates.

The most clearly defined virulence factors of uropathic E. coli are surface adhesins that mediate attachment to receptors on uroepithelial cells and gut mucosa, thus accounting for the colonization of the gut, vagina, and periurethral tissue. These sites of colonization are the reservoirs from which invading organisms are derived. Within the urinary tract itself, these ligand-receptor interactions allow the bacteria to resist the “flushing” action of urine flow and bladder emptying, as well as increasing the efficiency with which mammalian cells are exposed to toxic or inflammatory products of the bacteria, the initiation of true UTI.^{[114] [115]}

Most uropathogenic E. coli possess multiple types of adhesins, with the firmness of attachment of the bacteria being the sum of the effects of different adhesins that are expressed. The majority of these adhesins are located at the tip of fimbriae extending out from the bacterial surface. It is these tips that interact with specific receptors on uroepithelial cells—these are usually mono- or oligosaccharides that occur within glycoproteins or glycolipids on host cells.^{[122] [123] [124] [125] [126] [127] [128] [129] [130]} The receptors define the specificity of the interaction. For historical reasons, the adhesins are first classified on the basis of whether or not binding of the bacteria is affected by mannose. Mannose-sensitive adhesins, usually termed type 1 fimbriae, were the first of the adhesins defined. They were defined on the basis of the ability of mannose to inhibit agglutination of red blood cells. Similarly, mannose will inhibit the adherence of bacteria to uroepithelial cells. These structures are widely distributed in gram-negative bacteria and are present on approximately 75% of E. coli. These adhesins mediate binding to mannose residues on the Tamm-Horsfall protein in the urine (thus preventing ligand-receptor interaction and sustained attachment of the bacteria to the uroepithelium), to the carbohydrate portion of secretory immunoglobulin A (IgA), and to phagocytic cells. Given the ubiquity of type 1 fimbriae, it has been difficult to define their role.^{[119] [120] [121] [122] [123] [131]}

Type 2 pili (P fimbriae) are intimately involved in the pathogenesis of pyelonephritis in individuals with normal urinary tract anatomy and physiology. The P fimbriae are not only the most important of the adhesin-receptor systems thus far identified but also the most important uropathogenic virulence factors that have been defined. These adhesins, whose binding is resistant to the effects of mannose, have been given a variety of names reflecting their association with pyelonephritis and a particular receptor: P pili, P fimbriae, Pap pili (pyelonephritis-associated pili), and Gal-Gal pili. Their binding-specificity is to the globoseries of glycolipid receptors that have a common disaccharide, aGal(1-4)-bGal. These receptors are identical to the glycosphingolipids of the P blood group system and are found on the epithelial tissues of the urinary tract, kidneys, and large intestine, but not on phagocytic cells. This provides a mechanism for sustained colonization of the large intestine by uropathogenic clones, colonization of the vaginal vestibule, and the ability to ascend the urinary tract, even in the absence of an anatomic abnormality. In addition, the absence of these receptors on granulocytes provides protection to these uropathogens. Essentially all E. coli blood isolates from normal individuals with pyelonephritis express P fimbriae; non-P-piliated isolates are isolated from individuals with compromised host defenses, especially defects in leukocyte number or function.^{[117] [119] [120] [122] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133]}

An additional binding site for piliated E. coli is fibronectin, thus providing a mechanism for attachment of the bacteria to the extracellular matrix. The presence of P fimbriae on uropathogenic E. coli clones is maintained stably, presumably related to the chromosomal localization (usually as a component of a pathogenicity island with other virulence genes). The operon for these fimbriae, known as Pap, consists of 11 genes.^{[134] [135] [136] [137] [138] [139] [140]}Expression of these pili is under a phase variation control mechanism in which individual bacterial cells alternate between being phenotypically pilus-positive and pilus-negative through a process involving DNA methylation by deoxyadenosine methylase.^[138]

Other, less well characterized adhesins have been reported to be present on uropathogenic strains of E. coli: S fimbriae, which bind to terminal sialic acid residues on both epithelial cells and phagocytes; adhesins that bind to the blood group M antigen (specifically the NH₂-terminal portion of glycophorin A); and X fimbriae, whose binding is sensitive to neuraminidase. In addition, several nonfimbrial adhesins have been defined that bind to a variety of commonly expressed human tissue antigens. Perhaps the most important of these are the AFA/Dr family of adhesins, which bind to the CD55 antigen (so-called decay-accelerating factor), which is expressed on tissues throughout the body, including the uroepithelium and the kidney. At present, it is fair to say that the major determinant of uropathogenicity is the sum of the adhesive interactions between the invading strain of bacteria and the uroepithelium, although that mediated by the P fimbriae appears to be quantitatively the most important.^{[29] [139] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153]}

In addition to surface adhesins, which are clearly associated with uropathogenicity, other characteristics have been linked with virulence. These include the production of hemolysin, the presence of the iron-binding protein aerobactin, and iron-regulating gene products such as Iha, the ability of the bacteria to resist the bactericidal effect of normal human serum, the production of colicin V and other colicins, the ability to ferment salicin and perhaps other substrates, and the ability to induce an inflammatory response.

In sum, clones of uropathogenic E. coli possessing an assortment of virulence factors have been defined. These are closely linked on the bacterial chromosome. Such uropathogenic clones are well suited to spread through communities.^{[154] [155] [156] [157] [158] [159]}

A critical determinant of the effects of UTI on the host is the inflammatory response to the presence of replicating bacteria, with certain aspects of this response qualifying as a virulence factor that helps to determine both the short-term (inflammatory and “septic” events) and the long-term (renal scarring) consequences of this particular host-microbial interaction. There is abundant clinical evidence of this inflammatory response: elevated temperature; an increased erythrocyte sedimentation rate; an acute cytokine response involving interleukin-1 (IL-1), IL-6, IL-8 (which acts as a chemotactic factor to attract polymorphonuclear leukocytes to the involved mucosa), and tumor necrosis factor (TNF); and an increased level of C-reactive protein. Soluble receptors for TNF, IL-6, IL-8, and other proinflammatory cytokines are also elaborated into the urine in response to these infections. This response is due primarily to the mobilization of nonspecific innate immunity, rather than a specific immune response. Central to this response are such chemokines as CXC and CXCR1, and others.^{[159] [160] [161] [162]}

P fimbriae and endotoxin play a significant role in initiating the inflammatory response to the replicating bacteria. A toxin termed cytotoxic necrotizing factor 1, produced by uropathogenic E. coli, appears to contribute to the inflammatory events by inducing the killing of uroepithelial cells with the exfoliation of these cells from the mucosa and by interfering with neutrophilic killing of the bacteria.^{[159] [160] [161] [162] [163] [164] [165] [166]}Lipopolysaccharide (LPS), whatever its source within the urinary tract (e.g., shed from the outer layers of the bacterial cell wall or released by bacterial lysis), binds to toll-like receptors (TLRs) and other receptors as well. This results in the activation of signal transduction pathways that culminate in an inflammatory response that is bolstered by cytokines, chemokines, and other mediators activated via this signaling mechanism. The end result is an enhanced inflammatory response. For example, bacterial isolates from patients with asymptomatic bacteriuria do not activate these mechanisms that lead to inflammation. The key receptor in this response is a particular TLR termed TLR4. Adhesins, particularly P fimbriae, provide specificity to this process by binding specific glycosphingolipid receptors, and then TLR4 is recruited to initiate transmembrane signaling and uroepthelial cell activation.^{[167] [168] [169] [170] [171] [172]}

The inflammatory response is greater and pyelonephritis more common in women who are nonsecretors of blood group antigens. Chemokine receptors such as CXC play a critical role in directing transepithelial neutrophil migration. This neutrophilic response is modulated by IL-8, the IL-8 receptor, TNF, and IL-6. IL-8 receptor deficiency increases the susceptibility to pyelonephritis and, at least in animal models, is associated with renal scarring.^{[167] [168] [169] [170] [171] [172] [173] [174]} The genetically determined nature of the cytokine response in humans appears to play an important role here as well. For example, TNF-β gene polymorphisms dictate the extent of TNF response to a particular inflammatory stimulus: Low producers of TNF have a higher incidence of UTI than high producers, particularly in the face of exogenous immunosuppressive therapy (e.g., after renal transplantation).^{[175] [176]} An impaired IL-6 response in mice is associated with an increase in the extent of pyelonephritis. There also appears to be a linkage between early inflammatory events and later consequences. Transforming growth factor-β (TGF-β) and, perhaps, platelet-derived growth factor are stimulated by the preceding inflammatory response and play an important role in repair and scarring of the kidney as a consequence of pyelonephritis. In addition, both angiotensin-converting enzyme (ACE) and angiotensin receptor antagonists down-regulate TGF-β production, perhaps providing a new therapeutic tool for preventing renal scarring.^{[177] [178] [179] [180] [181]}

Virtually all the information presented on urovirulence factors and pathogenesis was derived from studies of women and girls. Although much less complete, it is of interest that E. coli strains isolated from men with prostatitis and from patients with spinal cord injury with inflammatory manifestations of UTI have the same virulence factor profile as those isolated from females.^{[182] [183] [184]}

Other Bacterial Species

Information is beginning to accumulate as to the pathogenetic mechanisms involved when non–E. coli bacteria invade the urinary tract. Reflecting its position as the most common non–E. coli cause of UTI, Proteus mirabilis is the other bacterial species that has received the most attention. Flagellae and so-called mannose-resistant fimbriae have been identified on strains isolated from patients with UTI. These are expressed preferentially on isolates from patients with pyelonephritis. Flagellae appear to mediate penetration of renal epithelial cells, whereas the fimbriae appear to be responsible for binding to the uroepithelium. There is considerable structural homology between these fimbriae and the P pili of E. coli. A phenomenon known as swarm cell differentiation has been described among P. mirabilis isolates that facilitates the development of pyelonephritis. In this instance, very long flagellae appear to contribute to ascent of the urinary tract and an increased incidence of pyelonephritis.^{[185] [186] [187] [188] [189] [190] [191]}

After attachment to the uroepithelium, three P. mirabilis enzymes have been linked to virulence: urease, hemolysin, and a protease. Elegant studies in a mouse model of ascending infection, using isogeneic mutant strains as well as the wild-type UTI isolate, have shown that the presence of urease greatly lowered the infecting inoculum necessary to produce sustained infection, was associated with a far more virulent form of pyelonephritis, and resulted in the formation of urinary tract calculi. Both urease and, even more, hemolysin are cytotoxic for renal proximal tubule cells. Finally, an IgA protease elaborated by this organism, which destroys IgA normally present in the urine, may play a role in promoting the occurrence of ascending infection.^{[191] [192] [193] [194] [195]}

Host Factors Influencing Infection

Several host factors are important clinically in predisposing the kidney to infection.

Urinary Tract Obstruction.

Reference has already been made to the role of obstruction in hematogenous and ascending pyelonephritis. Clinically, renal infections are associated with a variety of obstructive lesions. Experimentally, even temporary obstruction markedly increases susceptibility to infection; indeed, almost 100% of rats become infected after ligation of the ureter followed by intravenous injection of E. coli. Obstruction at the level of the urinary bladder interferes with the mechanisms by which the normal bladder eradicates bacteria in at least three ways: First, the increase in residual urine volume raises the number of bacteria remaining in the bladder after voiding; second, bladder distention decreases the surface area of the mucosa relative to the total volume of the bladder and thus decreases the effect of the postulated mucosal bactericidal factors; and finally, there is some experimental evidence that bladder wall distention diminishes the flow of blood to the bladder mucosa and hence the delivery of leukocytes and antibacterial factors. The net result is that even “nonuropathogenic” strains can cause ascending infection and bacteremic pyelonephritis.

Vesicoureteral Reflux.

The role of VUR and intrarenal reflux in predisposing to ascending infection was discussed earlier.

Instrumentation of the Urinary Tract.

Any instrumentation of the urinary tract increases the possibility of infection. The following risk factors have been shown to play a role in the pathogenesis of catheter-associated infection: duration of catheterization, absence of use of a urinometer, microbial colonization of the drainage bag, diabetes mellitus, absence of antibiotic use, female sex, complex urologic problem (i.e., a requirement for a catheter other than to passively drain the urine perioperatively or to monitor urine output), abnormal renal function, and errors in catheter care. Once a urethral catheter is in place, even with closed drainage systems, the daily frequency of bacteriuria is 3% to 10%, with the great majority of patients becoming bacteriuric by the end of 1 month.^[196] An estimated 10% to 25% of these bacteriuric patients become symptomatic, with 1% to 4% developing bacteremia. Overall, UTIs are the most common cause of nosocomial infection, with the great majority of these occurring in the setting of a bladder catheter.^[197]

Diabetes Mellitus.

Bacteriuria and clinical UTI are three to four times more common in diabetic women than in nondiabetic ones. However, there is no evidence that diabetic men are at increased risk of UTI. Further, studies of schoolgirls and pregnant women with and those without diabetes have shown no difference in the incidence of UTI. These epidemiologic observations suggest that the metabolic derangements of diabetes are not the primary factors involved in the increased incidence of UTI in diabetic patients. Rather, the important effects of diabetes in this context are mediated by the end-organ damage produced by long-standing diabetes. First, diabetic neuropathy affecting the bladder can have profound effects on bladder emptying, thus increasing the risk of UTI. This is probably the most important single factor in the pathogenesis of UTI in diabetic patients, both directly and because of the increased rate of instrumentation that occurs in such patients.^[197]

There is, in addition, an increased rate of both pyelonephritis and complications of pyelonephritis such as renal papillary necrosis in diabetic patients with UTI. Presumably, this increase is due to the combined effects of diabetes-induced vascular disease, increased pressures within the urinary tract resulting from poor bladder emptying, and perhaps, the effects of hyperglycemia on subtle aspects of host defense. In this last category, for example, both complement components and immunoglobulins of diabetic patients are glycosylated, and leukocyte function may be modified.^[197]

Finally, an unusual form of necrotizing, tissue-invasive infection, usually caused by E. coli, occurs in diabetic patients—emphysematous pyelonephritis or cystitis or both. Other Enterobacteriaceae and, on occasion, streptococci and Candida species can cause this same entity. The pathogenesis of these entities is incompletely understood, but three factors seem to be necessary: (1) invasion by gas-forming bacteria, (2) high local tissue glucose levels, (3) and impaired tissue perfusion.^{[198] [199] [200] [201] [202] [203] [204] [205]}

Immunity and Inflammation in the Pathogenesis of Urinary Tract Infection.

Bacterial infection of the urinary tract induces a specific antibody response directed against the infecting organisms. The level of antibody response is proportional to the degree of tissue invasion that has occurred. The bacterial antigens that induce most of the antibody response are the O antigens, fimbriae, and to a much lesser extent, the K antigens. The serum response is primarily IgG and IgM, whereas the urinary response is largely secretory IgA.^{[206] [207]} Despite the abundance of data demonstrating the occurrence of a specific antibody response to bacterial invasions, the protective effect of these antibodies remains unclear. Perhaps the strongest argument against an important protective role for antibody is the observation that hypogammaglobulinemic individuals have neither a higher incidence of UTI nor a more complicated course when infection does occur.^{[26] [208] [209] [210]}

Cell-Mediated Immunity in Pyelonephritis.

A role for cell-mediated immunity against bacterial antigens in either the pathogenesis of pyelonephritis or the protection against bacterial invasion has not been clearly defined. T cells are present in interstitial tissue and submucosa of biopsies from patients with acute bacterial invasion. However, studies in athymic, T cell-depleted, and cyclosporine-treated animal models failed to demonstrate a role for T cells in either the susceptibility to infection or the recovery from established infection. At present, any role for T cells in the pathoge-nesis of UTI and pyelonephritis has to be regarded as speculative.^[26]

Whereas specific immune mechanisms appear to play a limited role in either kidney injury or protection against infection, inflammation is now clearly established as the key host defense response to bacterial invasion. Uropathogen virulence factors are responsible for initiating this process, with the extent of the inflammatory response being determined by the interaction of bacterial virulence and the response ability of the host.

The first step in this process is accomplished by the bacteria activating the processes that lead to mucosal inflammation by way of the innate host response. This is initiated when the bacteria adhere to the uroepithelium via specific adherence factors (e.g., P fimbriae). A series of signaling pathways are then activated that result an inflammatory response. At least two different pathways have been identified in this inflammatory process: (1) P fimbriated, and presumably other adhesin systems—bacteria act via an endotoxin (LPS)-independent ceramide-mediated signaling pathway; and (2) an LPS-dependent signaling pathway that induces nitric oxide and cytokine production. The LPS-dependent response requires interaction with a specific LPS-binding protein, CD14 receptor, and TLR4. Neutrophils are recruited by chemokines released by mucosal cells.

TLRs are transmembrane structures that bind to LPS; activation of this pathway leads to nuclear translocation of NF-kB and transcription of inflammatory response genes. A notable series of experiments has shown that the absence of TLR produces individuals highly susceptible to UTI, owing to absence of an appropriate neutrophil response.^{[163] [164] [165] [166] [167]}

Once uropathogenic E. coli bind to the mucosa (through the defined adherence mechanisms), mucosal inflammation is induced. Strong associations have been shown between specific adherence factors and the intensity of the mucosal inflammation. Conversely, strains of E. coli isolated from patients with asymptomatic bacteriuria do not possess adhesive factors. P fimbriae bind to specific glycosphingolipid receptors and recruit TLR4 for transmembrane signaling. The chemokine IL-8 is produced by these events and is the main driving force for neutrophils to cross the uroepithelium. Other mediators also contribute to these events. These chemokines act by G-protein-coupled cell surface receptors, recruiting neutrophils, which are necessary for bacterial clearance.^{[163] [164] [165] [166] [167]}

Evolution of the Renal Lesion.

The usual course of uncomplicated E. coli acute pyelonephritis in both experimental animals and humans is one of healing rather than of progressive damage. In most experimental models of E. coli pyelonephritis, the phase of acute inflammation in the kidney lasts 1 to 3 weeks. The tissue destruction is largely the result of bacterial multiplication and inflammation. With healing, an increase in the number of mononuclear cells, a decrease in neutrophils in the interstitium, and a replacement of necrotic tubules by fibrous tissue and foci of tubule atrophy occur. These changes are accompanied by a decrease in the number of bacteria present in the kidneys; by the 6th to the 10th week, the kidneys are sterile, and the resultant renal lesion is a triangular, depressed scar extending from the cortex, with its apex in the medulla and pelvis. However, a variety of bacterial and host factors can modify this sequence of events and can lead to progressive damage. Although Staphylococcus infections may eventually heal, they tend to remain active for longer periods and to result in considerable tissue destruction. In Klebsiella infection, the original infecting strain persists in the kidney for at least 24 weeks. Proteus infections do not heal as a consequence of the urinary obstruction resulting from the deposition of magnesium ammonium phosphate calculi.^[26]

In human pyelonephritis, persistence of the original infecting organism is more likely to occur with organisms such as Proteus and Klebsiella and is frequently associated with obstructive uropathy, renal calculi, renal carbuncle, or bacterial prostatitis. However, bacterial persistence within the renal parenchyma as a cause of progressive damage has been difficult to demonstrate convincingly in humans.

Because a small number of patients with the typical morphologic lesion of chronic pyelonephritis have no evidence of bacterial infection, the question has arisen whether progression of renal lesions can still occur after the bacteria have been totally eradicated. Among the mechanisms that have been postulated to explain such events are autoimmune responses , vascular disease, sterile reflux, and the persistence of bacterial variants. At present, these alternative mechanisms can be thought of as follows:

	1.	There is no conclusive evidence that antibody- or cell-mediated autoimmune reactions play a major role in progressive renal damage in chronic pyelonephritis.
	2.	Both clinical and experimental evidence suggests that superimposition of secondary hypertension in the course of chronic pyelonephritis measurably hastens deterioration of renal function and reduction of renal mass. It is possible, therefore, that progressive renal insufficiency in some cases of chronic pyelonephritis may be due to vascular disease rather than pyelonephritic scarring.
	3.	The possibility that sterile reflux may induce progressive renal damage was discussed earlier. Granted that sterile reflux may be harmful, how is the damage induced? Urodynamic factors (water-hammer effect), vascular narrowing and ischemia, and leakage of urinary constituents (e.g., Tamm-Horsfall protein) into the interstitium have all been implicated as possible mechanisms but, to date, without conclusive proof.
	4.	It has been discussed previously that the ability of bacteria to survive in the kidney as bacterial variants that lack part or all of their cell wall (spheroplasts, protoplasts, or L-forms) may account for persistent or progressive renal infection. Such variants may remain viable in the hypertonic environment of the renal medulla and may induce pathologic changes either as variants or after reversion to bacterial forms. However, despite scattered clinical studies reporting the presence of such forms in the urine after UTI and in renal biopsy specimens of patients with sterile pyuria, other studies have failed to detect such forms. Experimentally, protoplasts can indeed produce renal lesions but only after they have reverted to the parent bacterial form. More than 3 decades after the suggestion was first made, the role of bacterial variants remains speculative.

In concluding this discussion of factors affecting the evolution of renal lesions in pyelonephritis, the work of Glauser and associates^[211] should be noted. These authors evaluated the importance of suppuration, persistent infection, and scar formation in the evolution of E. coli chronic pyelonephritis by treating rats with different antibiotic regimens at different stages of the disease. They found that the magnitude of the suppuration in the acute phase of pyelonephritis was the most significant factor in predicting the eventual development of small, chronically scarred kidneys. Persistent low-grade infection did not lead to chronic pyelonephritis if the acute suppuration was suppressed; antigen load and antibody- or cell-dependent autoimmune processes did not appear to play a significant role in the progression of infection. These findings further emphasize the need for prompt and effective antibiotic treatment of the earliest pyelonephritic lesions, particularly in infants with VUR.^{[160] [163] [210]}

PATHOLOGY

Acute Pyelonephritis

On macroscopic examination, kidneys from patients with severe acute pyelonephritis are enlarged and contain a variable number of abscesses on the capsular surface and on cut sections of the cortex and medulla. Tissue between infected areas appears normal. Occasionally, areas of inflammation extend from the cortex into the medulla in the shape of a wedge. In the presence of obstruction, the calices are enlarged, the papillae are blunted, and the pelvic mucosa is sometimes congested and thickened. The papillae may be completely normal in some cases or may show outright papillary necrosis in others.

Histologic changes are characterized by involvement of the tubules and the interstitium. The interstitium is edematous and infiltrated by a variety of inflammatory cells, predominantly neutrophils. Within abscesses, the tubules show necrosis, and many tubules contain polymorphonuclear leukocytes. The patchiness of the inflammation is parti-cularly striking. Thus, completely normal tubules and interstitium may lie adjacent to a large necrotizing renal abscess. Even in areas of the most severe inflammation, normal glomeruli can be seen, and indeed, intraglomerular inflammation is rare. In the presence of total ureteral obstruction, the inflammatory reaction sometimes affects the entire kidney ( Fig. 34-5 ).^{[212] [213]}



FIGURE 34-5 Large acute lesions of acute bacterial inflammation from infected intrarenal reflux in the pig. The subsequent contraction of these lesions gives rise to focal scars (see Fig. 34-6 ). (From Hodson CJ: Reflux nephropathy. Med Clin North Am 62:1201, 1978.)

The sequence of events in the healing of acute pyelonephritis has been deduced from experimental studies. The neutrophilic exudate is rapidly replaced by one that is predominantly mononuclear, with macrophages and plasma cells and, later, lymphocytes. There is formation of granulation tissue, deposition of collagen, and eventual replacement of abscesses by scars that can be seen on the cortical surface as fibrous depressions. Such scars are characterized microscopically by atrophy of tubules, interstitial fibrosis, and lymphocyte infiltration ( Fig. 34-6 ).^{[214] [215]}



FIGURE 34-6 Typical polar scars 3 months after infected intrarenal reflux in the pig. Note dilation of the calyx underlying the scars. (From Hodson CJ, Maling RM, McManamon PJ, Lewis MJ: The pathogenesis of reflux nephropathy [chronic atrophic pyelonephritis]. Br J Radiol 13:1, 1975.)

Chronic Pyelonephritis and Reflux Nephropathy

Terminology and Frequency

Despite the long-standing controversy over the use of the term chronic pyelonephritis, there is now reasonable agreement as to the morphologic changes sufficient to distinguish this condition from the many other tubulointerstitial diseases.

Only a limited number of conditions can lead to a morphologic picture of chronic corticomedullary tubulointerstitial damage coupled with caliceal abnormality:

	1.	VUR. As detailed earlier, renal damage in VUR is associated with intrarenal reflux and is most frequently caused by infected reflux. This is the most common cause of entities referred to as “chronic atrophic” or chronic nonobstructive pyelonephritis. The term reflux nephropathy is slowly replacing chronic pyelonephritis to describe this condition. Besides emphasizing the role of VUR, the term has the virtue of including two types of changes associated with VUR: (a) the more common and widely recognizable focal scarring, which is attributed to scarring at the site of compound papillae with in-trarenal reflux, and (b) the diffuse renal damage affecting all papillae and usually associated with high-pressure obstructive reflux. Whereas most children with chronic pyelonephritic scars demonstrate VUR, only about half of adults do. However, up to 89% of adults have abnormal ureteral orifices, which suggests (but by no means proves) that ureteral reflux may have occurred in the past.^[216]
	2.	Urinary obstruction. It is frequently difficult to differentiate an uninfected obstruction from a combination of obstruction and infection, but discrete parenchymal scars usually indicate the coexistence of infection.
	3.	Analgesic nephropathy, with or without bacterial infection. This is usually readily distinguished by the widespread papillary necrosis.
	4.	Unusual forms of noninfectious acute papillary necrosis. Included in this category are acute papillary necrosis due to such conditions as sickle cell disease or dehydration in infants and diabetics. Infants with severe acute gastroenteritis and dehydration are at risk for papillary necrosis and subsequent corticopapillary scarring that resembles chronic pyelonephritis.^[217]
	5.	Segmental hypoplasia (the Ask-Upmark kidney). This condition, previously considered a developmental anomaly, is now also believed to be caused by VUR in most cases.^{[218] [219]}

Chronic pyelonephritis can be subdivided into three types: (1) chronic pyelonephritis with reflux (reflux nephropathy), (2) chronic pyelonephritis with obstruction (chronic obstructive pyelonephritis), and (3) idiopathic chronic pyelonephritis. If the morphologic criteria are adhered to, the incidence of chronic pyelonephritic scarring at autopsy is less than 2%. The frequency of chronic pyelonephritis in patients with end-stage renal disease is approximately 10% to 20%.

Gross Pathology

The most characteristic changes are seen on gross rather than microscopic examination. The most common morphologic appearance of chronic pyelonephritis and reflux nephropathy is that referred to as coarse renal scarring or focal scarring, consisting of corticopapillary scars overlying dilated, blunted, or deformed calices ( Fig. 34-7 ). The remarkable pelvocaliceal deformity is not easy to visualize grossly on pathologic examination but is particularly obvious in tracings of the calices made on excretory urograms ( Fig. 34-8 ). The kidneys are usually smaller than normal, and extreme reductions in size of one of the two kidneys are not unusual. Involvement can be bilateral or unilateral, depending on whether reflux or obstruction has occurred on one or both sides; with bilateral involvement, the kidneys are usually asymmetrically scarred. The scars vary in size but are usually broad, involve a whole lobe, are rather shallow, and have a flatter surface than do healed infarcts (see Fig. 34-7B ). The areas between scars may be smooth but are usually finely granular, reflecting hypertrophic changes. Although any part of the kidney may be involved, most scars are in the upper and lower poles, consistent with the frequency of intrarenal reflux in these areas. The medulla is distorted, and affected papillae are flattened. In cases with obstruction, the pelvis and calices are distinctly dilated, but they may be of normal caliber in the absence of obstruction (in late cases) or after obstruction has been relieved. The pelvic and caliceal mucosa can be thickened and granular, particularly in cases of chronic reflux. Kincaid-Smith and colleagues emphasized the importance of examining the ureters because thickening of the ureteral wall with or without dilation is a reliable sign of the preexistence of VUR ( Fig. 34-9 ).^{[220] [221] [222] [223]}



FIGURE 34-7 A, Chronic pyelonephritis. Note irregularly scarred kidney, dilated and blunted calices, and a thickened ureter that suggests chronic vesicoureteral reflux. B, Typical pyelonephritic broad scars in a patient with reflux nephropathy. The scars involve entire lobes. Note prominent underlying caliceal dilatation. (B, From Bhathena DB, Holland NH, Weiss JH, et al: Morphology of coarse renal scars in reflux-associated nephropathy in man. In Hodson CJ, Kincaid-Smith P [eds]: Reflux Nephropathy. New York, Masson, 1979, p 243.)



FIGURE 34-8 Tracings of urograms show common patterns of scarring and caliceal deformities in reflux nephropathy. A, Upper pole. B, Severe bipolar. C, Generalized, with one lower pole lobe spared. D, Duplex kidney, with severe deformities in the lower pole. E, Generalized diffuse caliceal involvement. (From Hodson CJ: Reflux nephropathy. Med Clin North Am 62:1201, 1978.)



FIGURE 34-9 Kidney shows the “generalized” or diffuse form of reflux nephropathy. There is more or less uniform dilation of calices and thinning of renal parenchyma. Note thickening of the pelvis and base of the ureter. (From Hodson CJ: Formation of renal scars with special reference to reflux nephropathy. Contrib Nephrol 16:83, 1979, by permission of S Karger AG, Basel.)

A second morphologic variety, referred to by radiologists as diffuse or generalized reflux nephropathy, occurs in patients with severe VUR together with obstruction (e.g., children with posterior urethral valves). The scarring is so generalized that the cortical surface appears to be relatively smooth or finely granular. In these cases, the pelvis and calices are diffusely dilated, and the renal parenchyma shows widespread atrophy resembling postobstructive atrophy (see Fig. 34-9 ). In these kidneys, the presence of a thickened pelvic and ureteral wall (or the cystoscopic appearance of ureteral orifices) suggests previous VUR. Lying somewhere between those with coarse scars and those with generalized damage are kidneys in which two or more areas of coarse scarring are associated with generalized dilation of calices and overall reduction in kidney size. Thus, a mixed picture can be seen in which both processes are present in a single patient.^[223]

Microscopic Findings

The histologic appearance is one of tubule damage plus interstitial inflammation and scarring, and it varies according to the evolutionary stage of the lesion. Old, extensive scars can be composed almost entirely of atrophic or dilated tubules, separated by fibrous tissue, with remaining large blood vessels ( Fig. 34-10 ). More recent scars show variable amounts of interstitial mononuclear inflammation, tubule atrophy and necrosis, increase in interstitial fibrous tissue, and periglomerular fibrosis. Many tubules are dilated, lined by flattened epithelium, and filled with colloid casts (thyroidization). The inflammatory infiltrate is variable. Lymphocytes and monocytes predominate, but occasionally, one can see large foci of plasma cells; in the presence of active inflammation, neutrophils can be plentiful. Pus casts are also frequently present, particularly when there is active infection. However, pus casts can also be present in the absence of bacteriuria, presumably owing to ischemic damage.



FIGURE 34-10 Pyelonephritic scar composed of atrophic or dilated tubules, a few sclerosed or sclerosing glomeruli, and thickened vessels. Note the dilated calyx with prominent lymphoid infiltrate beneath the mucosa.

Vascular changes within the scars can be either mild or more severe. Both arteries and arterioles may show medial and intimal thickening; the intimal thickening is of the fine, concentric cellular type. In some cases, there is clear-cut elastic reduplication. Vascular changes within the scarred areas are present even in patients who are not hypertensive, although they become more severe in the presence of hypertension. In the nonscarred areas, hyaline arteriolar changes are limited to those patients with secondary hypertension.

The pelvis and calices are universally affected. Usually, there is infiltration of the subendothelial connective tissue by inflammatory cells, which often form large masses or lymphoid follicles (see Fig. 34-10 ). Neutrophils, eosinophils, and occasionally, giant cells may also be present. The mucosal epithelium may be severely thickened and infiltrated with inflammatory cells. The amount of collagen in the underlying connective tissue is also usually increased.

Of interest is the presence of interstitial deposits of Tamm-Horsfall protein precipitates in the kidneys with chronic pyelonephritis associated with reflux or obstruction. Tamm-Horsfall protein can be localized specifically by immunofluorescence microscopy, but its presence in casts and in interstitial tissue can be suspected by histologic examination as a strongly periodic acid-Schiff (PAS) reaction-positive amorphous or fibrillar material. Interstitial deposits of Tamm-Horsfall protein have been detected in kidneys from patients with chronic pyelonephritis, reflux nephropathy, urinary tract obstruction, and other interstitial diseases. These deposits are sometimes surrounded by an intense inflammatory infiltrate consisting of mononuclear cells, occasional neutrophils, and even giant cells. Deposits probably result from tubule disruption, with discharge of urinary contents into the interstitium. Tamm-Horsfall protein has also been seen in thin-walled renal veins and lymphatics, possibly from pyelovenous or pyelolymphatic ruptures.^{[224] [225]}

Although glomeruli may be entirely normal or may show only periglomerular fibrosis, a variety of glomerular changes may be present. These have been well described and illustrated by Heptinstall.^[225] Ischemic changes, consisting of solidification of glomerular tufts and deposition of collagen within the Bowman space, are frequent, as are small shrunken glomeruli. Focal or diffuse proliferation and necrosis can also be present; these have been considered secondary to hypertension. Kincaid-Smith^{[226] [227]} has drawn attention to the association of chronic pyelonephritis and reflux nephropathy with a glomerular lesion best described as focal segmental sclerosis and hyalinosis, similar to that seen in some patients with focal sclerosis and the nephrotic syndrome. She noted that, in patients with reflux nephropathy, those with proteinuria were more likely to progress to renal failure, even in the absence of hypertension, overt infection, or persistent VUR. Renal biopsy specimens showed focal and segmental hyalinosis and sclerosis in most of these patients.

NATURAL HISTORY OF BACTERIURIA AND PYELONEPHRITIS

Frequency and Epidemiology of Urinary Tract Infection

The frequency of UTI and its clinical impact are different for the two sexes at different stages of life ( Fig. 34-11 ). Approximately 1% of neonates are bacteriuric, with a twofold to fourfold higher frequency among boys, presumably because of an increased occurrence of congenital urogenital anomalies in male infants. Equally striking is a fourfold increase in bacteriuria among premature infants (2.9% vs. 0.7% among full-term infants); approximately half of these premature infants demonstrate VUR. Uncircumcised male infants are at increased risk for UTI and pyelonephritis in the neonatal period, with some of this increased risk continuing into adulthood.^{[228] [229] [230] [231]}



FIGURE 34-11 Overview of the frequency of symptomatic urinary tract infection and of asymptomatic bacteriuria according to age and sex (modified from the original concept of Jawetz). (From Kunin CM: Detection, Prevention and Management of Urinary Tract Infections, 3rd ed. Philadelphia, Lea & Febiger, 1979.)

After infancy and until age 55 years, when prostatic hypertrophy starts becoming apparent in men, UTI is predominantly a female disease. From infancy until age 10 years, the frequency of UTI in girls is about 1.2%, with approximately one third of these infections being symptomatic. After an initial episode of bacteriuria, approximately 80% of schoolgirls have one or more recurrences; more than 80% of these recurrences are due to reinfections rather than relapses of sequestered deep tissue infection. It has been estimated that a minimum of 5% to 6% of schoolgirls have at least one episode of UTI between the ages of 5 and 18 years. Approximately 20% of schoolgirls with bacteriuria have demonstrable VUR.^{[9] [232] [233] [234]}

When cohorts of schoolgirls with and without bacteriuria are observed for periods as long as 18 years, some important observations emerge. Although the urine may have remained sterile for long periods in many of these bacteriuric schoolgirls, bacteriuria usually redeveloped shortly after marriage or during the first pregnancy. This increase is most marked during pregnancy, with a 63.8% frequency of pregnancy-associated bacteriuria in women who were bacteriuric as schoolgirls, as opposed to a 26.7% frequency for those who were not. Approximately 10% of the children of the bacteriuric schoolgirls who were studied became bacteriuric themselves, as opposed to none of the children of the nonbacteriuric control patients. Persistence of bacteriuria appears to be more common in children with VUR than in those with normal urinary tracts.^{[9] [232] [233] [234]}

Among adult women, the incidence and prevalence of bacteriuria are related to age, degree of sexual activity, and form of contraception employed. Approximately 1% to 3% of women between the ages of 15 and 24 years have bacteriuria; the incidence increases by 1% to 2% for each decade thereafter up to a level of about 10% to 15% by the 6th or 7th decades. Approximately 40% to 50% of women will have at least one UTI in their lifetimes. College women who have a first episode of E. coli UTI are three times as likely to have a second UTI in the next 6 months than those with other forms of UTI. In noninstitutionalized elderly patients, UTIs cause one fourth of all infections.^{[9] [232] [233] [234]}

There is an incomplete correlation between the presence of bacteriuria and the occurrence of clinical symptoms. Dysuria occurs each year in approximately 20% of women between the ages of 24 and 64 years, half of whom come to medical attention. Of the group seeking medical care, one third have the acute urethral syndrome, and two thirds (approximately 6% of the adult female population) have significant bacteriuria in association with clinical symptoms referable to the urinary tract.^{[232] [233] [234] [235]}

Bacteriuria, whether asymptomatic or clinically overt, is unusual in males before they reach their 50s in the absence of urinary tract instrumentation. The frequency of bacteriuria among schoolboys is between 0.04% and 0.14%. One male population that appears to be at an increased risk for UTI is sexually active male homosexuals, who become infected with the same uropathogenic E. coli clones that infect women. Human immunodeficiency virus infection does not increase the incidence of UTI, but once UTI occurs, the higher the viral load the greater the inflammatory consequences of the UTI. Heterosexual transmission of virulent strains of E. coli from infected women to their sexual partners has been clearly documented. Several investigators have noted a high frequency of Proteus infection, as opposed to E. coli infection, among boys with UTI, perhaps related to a high rate of colonization of the preputial sac with Proteus species.^{[236] [237] [238] [239] [240]}

As the aging process progresses and prostatic disease becomes more common, the frequency of UTI in men rises dramatically. By age 70 years, the frequency of bacteriuria reaches a level of 3.5% in otherwise healthy men and a level of greater than 15% in hospitalized men. With the onset of chronic debilitating illness and long-term institutionalization, bacteriuria rates in both sexes reach levels of 25% to 50%, with the frequency in women now only slightly greater than that in men.^{[241] [242] [243] [244]}

Pregnant women have a 4% to 10% frequency of bacteriuria—a rate at least twice that for similarly aged nonpregnant women. Symptomatic infection develops in as many as 60% of pregnant women with asymptomatic bacteriuria early in pregnancy if it is untreated, with symptomatic pyelonephritis developing in approximately one fourth to one third.^{[245] [246] [247]}

About 25% to 33% of women with pregnancy-associated bacteriuria have infection at postpartum follow-up, even if this follow-up occurs as many as 10 to 14 years postpartum, as opposed to a rate of 5% of similarly aged women who never had pregnancy-associated bacteriuria. Approximately 30% of women with a history of bacteriuria of pregnancy have changes on the excretory urogram that suggest chronic pyelonephritis. This is not to say, however, that bacteriuria of pregnancy is responsible for these changes. Currently available data would suggest that the kidneys of the women with postpartum infection after pregnancy-associated infection were probably damaged during childhood, with recurrent infection being exacerbated by the hormonal and mechanical changes induced by pregnancy. There is little evidence that infection developing for the first time during pregnancy is responsible for long-term effects.^{[245] [246] [247] [248] [249] [250] [251]} The frequency of bacteriuria during pregnancy is significantly higher in women with a history of past childhood UTI.^[248] As in other populations, the occurrence of pyelonephritis among pregnant women is particularly associated with infection with uropathogenic strains possessing P pili.^[249]

Epidemics of pyelonephritis have been reported in newborn infants being provided care on neonatal wards. These have been shown to be due to the patient-to-patient spread of P-fimbriated E. coli strains on the ward, resulting in intestinal colonization of these children. Once such intestinal colonization with uropathogenic strains occurs, invasion of the urinary tract can then develop.^{[250] [251] [252]}

Patients with anatomic or neurologic disorders of the urinary tract of any type that result in obstruction or incomplete voiding have an increased frequency of UTI and pyelonephritis. A particularly important group of such patients are those rendered paraplegic or quadriplegic as a result of spinal cord injury. Bacteriuria, urosepsis, and the eventual development of VUR and progressive renal scarring are common in these individuals. It is of great interest that the organisms causing UTI in these patients are the same nonuropathogenic strains of bacteria associated with scarring in children with VUR. Risk factors associated with the development of UTI in these patients include overdistention of the bladder, VUR, high-pressure voiding, large postvoid residuals, presence of stones in the urinary tract, bladder outlet obstruction, indwelling catheterization, and urinary diversion.^{[253] [254]}

Recipients of kidney transplants are another population at particular risk for UTI, with a reported frequency of 35% to 79% of such infections if no antimicrobial prophylaxis is administered. The major factors associated with the occurrence of UTI in this population include the technical complications associated with the ureteral anastomosis, a UTI present before transplantation that has not been eradicated (by antibiotics or native nephrectomy before or at the time of transplantation), the postoperative urinary catheter, the physical and immunologic trauma that the kidney suffers, and the immunosuppressive therapy that is administered. The first two of these have been largely eliminated because of advances in the preparation of the patient for transplantation and in the technical aspects of the operation. However, the requirement for bladder catheters for 1 to 7 days after transplantation provides a reservoir from which infection is derived. In animal models, the combination of bacteria inoculated into the bladder and trauma to the kidney results in pyelonephritis, whereas bladder infection without renal trauma results only in a transient cystitis. It is reasonable to postulate that the kidney is rendered susceptible to invasive infection as a result of the physical trauma of the transplant procedure as well as the immunologic trauma. Once infection develops, its impact can be greatly amplified by the effects of immunosuppressive therapy.^{[19] [255]}

UTI occurring in the first 3 months after transplantation is frequently associated with invasion of the allograft, bacteremia, and high rate of relapse when it is treated with a conventional course of antibiotics. In contrast, UTI occurring at a later time is usually benign, can be managed with a conventional 10- to 14-day course of antibiotics, is rarely associated with bacteremia or requires hospitalization, and has an excellent prognosis. Exceptions to this general pattern should be evaluated for functional or anatomic abnormalities of the urinary tract, such as a stone, an obstructive uropathy, or a poorly functioning bladder. Pancreatic transplantation for diabetes in which exocrine drainage is accomplished through a bladder (as opposed to an enteric) anastomosis is associated with a relatively high rate of urologic complications and UTI, including that due to Candida species.^{[19] [255] [256] [257]}

Clinical Impact of Urinary Tract Infection

The most important issues regarding UTI have to do with whether there are long-term consequences of bacteriuria over and above the direct infectious disease morbidity and mortality these infections cause. The particular questions that have received the most attention are:

	1.	Does UTI, particularly when it is chronic or recurrent, lead to significant loss of renal function, to hypertension, or to both? If it does, is there a particular subset of patients at special risk for these complications?
	2.	Does UTI have an adverse effect on the outcome of pregnancy—on the mother, the fetus, or both?
	3.	Is UTI associated with an increased mortality? If it is, is it a causative factor or just a marker for poor health, and will effective therapy decrease the mortality rate?

Urinary Tract Infection, Renal Failure, and Hypertension

A retrospective review of all the cases of chronic renal disease seen at the Hospital of the University of Pennsylvania between 1969 and 1972 provided important information. A total of 101 patients with chronic interstitial nephritis were identified, approximately one third of the patients with chronic renal disease—a figure similar to that attributed previously to chronic pyelonephritis. However, in none of these 101 cases of chronic interstitial nephritis was infection the primary cause of the renal disease; instead, analgesic abuse and anatomic abnormalities of the urinary tract accounted for most cases. It was suggested, however, that in approximately one third of these patients, infection played a contributory role, but only when it was superimposed on such primary problems as anatomic abnormalities, calculous disease, or analgesic abuse.^[258]

These concepts have since been confirmed in several prospective, long-term studies of bacteriuria in adults. Freedman and Andriole^[259] observed 250 women with UTI for periods up to 12 years and found no evidence of deterioration in renal function or blood pressure elevation. Freeman and colleagues^[260] prospectively studied 249 men with bacteriuria for periods up to 10 years and again found no deterioration in renal function in the absence of severe urologic disease or concomitant noninfectious renal disease. Even in a particularly high-risk group of adult patients, the 25% of adult patients with asymptomatic bacteriuria who had renal scars demonstrable by urography at the time of entry into the study, renal damage did not seem to progress, and no new scars developed unless such complicating factors as obstruction, hypertension, analgesic abuse, or diabetes mellitus were present concurrently.^{[258] [260]}

Thus, in adults, there is little evidence that UTI beginning in adult life, by itself, leads to progressive chronic renal injury. It is still possible that bacteriuria, when superimposed on other urinary tract lesions, could accelerate the development of renal damage. However, there is clearly no justification for mass screening for bacteriuria.

Studies of children between the ages of 5 and 15 years have demonstrated that, if scarring has not occurred by the age of 5 years, the kidneys, sometimes in the face of continued bacteriuria and VUR, remain unscarred and renal growth remains unimpaired. It is primarily the children who have pyelonephritis before the age of 5 years who manifest not only renal scarring but also a decreased glomerular filtration rate and a failure of compensatory renal growth. Experimental studies in young rats have confirmed that ascending pyelonephritis inhibits renal growth.^{[261] [262] [263] [264]}

Edwards and associates^[265] have reported extremely encouraging results with long-term continuous low-dose antimicrobial prophylaxis in children who initially presented with symptomatic UTI and were found to have VUR. Whereas Lenaghan and colleagues^[266] noted a 20% frequency of fresh scarring and a 66% frequency of increased scarring in children treated with intermittent antimicrobial therapy, Edwards and associates,^[265] in an apparently similar population of children, found only one new scar and only one extension among 75 children treated continuously for a 7- to 15-year period.

Thus, there is little question that the combination of VUR and UTI can have potentially disastrous consequences, which might be amenable to early recognition and prolonged therapy. Long-term studies of these children have shown that, once scarring has occurred, the prognosis depends on the severity of initial damage and the presence of proteinuria, which is a measure of the degree of secondary glomerulosclerosis. As discussed in Chapter 25 , secondary glomerulosclerosis is believed to be due to glomerular hyperfiltration and hypertension in remnant nephrons, causing changes in permselectivity to macromolecules that are delivered to the kidney. Progressive damage to the remaining glomeruli then ensues, with progression of the degree of proteinuria from microalbuminuria to frank nephrotic syndrome and progressive azotemia.^{[263] [264] [265] [266] [267] [268] [269]}

Chronic pyelonephritis appears to be the most common cause of hypertension in children, accounting for some 30% of childhood hypertension, and is also a frequent cause of secondary hypertension in adults.^{[263] [264] [269]}

Urinary Tract Infection and the Outcome of Pregnancy

The clearest demonstration that untreated, asymptomatic bacteriuria has an adverse effect on the human host comes from studies carried out in the pregnant woman. Approximately half of such untreated women subsequently have symptomatic UTI, and 25% to 30% have acute pyelonephritis. Such pyelonephritis may be associated with systemic sepsis. An association of pregnancy bacteriuria with anemia, hypertension, decreased glomerular filtration rate, and decreased urinary concentrating ability, which is alleviated by therapy, has also been noted.^{[245] [246] [247] [248] [249] [250] [251]} There also appears to be an increased risk of preeclampsia in pregnant women with UTI, with this being most marked among primiparous women (a fivefold increase in risk).^[270]

More controversial has been the question of an increased risk of maternal toxemia and neonatal prematurity, low birth weight, and perinatal mortality in pregnancies complicated by bacteriuria. An increased rate of spontaneous abortion in pregnancies complicated by bacteriuria has been reported.^[271] In addition, there appears to be a higher frequency of low-birth-weight-for-date infants born to bacteriuric mothers, particularly those with hypertension or those in whom treatment programs have failed to eradicate the bacteria.^{[270] [271] [272]} In addition to the increase in low-birth-weight infants, acute UTI is associated with an increased fetal mortality rate.^[273]

Most compelling are two reports derived from data generated in a multicenter study of more than 55,000 pregnant women.^[274] A higher frequency of low birth weights and stillbirths resulted from the pregnancies of the 3.5% of women with symptomatic UTI. A frequency of perinatal death of 42 per 1000 has been reported when the mothers were bacteriuric as opposed to 21 per 1000 when they were not. In this study, virtually all the excess mortality occurred when the UTI was present within 15 days of delivery, with the highest death rates occurring when UTI coexisted with maternal hypertension and acetonuria. Women who had pyuria and bacteriuria close to the time of delivery had a 24% greater frequency of amniotic fluid infection than did women without pyuria. Hypertension was 88% more common in mothers who had pyuria and bacteriuria than in those who did not have pyuria. In addition, bacteriuria was associated with growth-retarded placentas.^{[274] [275] [276] [277] [278]}

Proof that eradication of the bacteriuria prevents fetal complications is incomplete. However, we believe that routine screening for, and treatment of, bacteriuria of pregnancy are indicated for both the mother's and the child's health. Although complete evidence that treatment prevents all of the complications of pregnancy-associated bacteriuria will probably never become available, the withholding of therapy for such bacteriuria, whether symptomatic or asymptomatic, must be regarded as both ethically wrong and medically insupportable.^{[275] [276] [277]}

Long-term studies of schoolgirls with previously diagnosed bacteriuria and renal scarring have shown that, when they reach adulthood and become pregnant, they have a greater than threefold increased risk of hypertension and a greater than sevenfold risk of preeclampsia. Despite these findings, with skilled obstetric management, the outcome of the pregnancy in terms of the health of both the mother and the child should be satisfactory.^[278]

Urinary Tract Infection and Survival of the Patient

The final question regarding the biologic impact of UTI has to do with the patient's survival. Although it is absolutely clear that gram-negative sepsis originating in the urinary tract can have lethal consequences, occasionally even with the best of treatment, the question has been raised whether survival of the patient can be adversely influenced outside of the direct infectious disease effects of UTI. Several reports have suggested that bacteriuria, particularly in the elderly, is associated with an increased risk of subsequent mortality. The occurrence of bacteriuria appears to be related to the degree of functional impairment present and is a marker for how seriously ill the individual is. Bacteriuria is not an independent variable that evolves with mortality. It is not surprising, then, that antimicrobial therapy aimed at bacteriuria has no effect on subsequent mortality rates. Indeed, in the elderly patient, antimicrobial therapy has little long-term benefit in terms of the occurrence of the bacteriuria itself. Therefore, there appears to be little justification for either screening adult patients, particularly elderly patients, for asymptomatic bacteriuria or treating them with antimicrobial agents.^{[243] [244] [245] [279] [280] [281] [282] [283] [284]}

CLINICAL PRESENTATIONS

The clinical evaluation of the patient with UTI can be surprisingly difficult because the range of clinical illness is remarkably broad: from the dysuria-frequency syndrome to full-blown pyelonephritis, from symptomatic to asymptomatic bacteriuria (the acute urethral syndrome). It is also clear that the ability of the clinician to accurately define the cause of the urinary tract symptoms or the anatomic site of involvement is limited. On the one hand, the patient who presents with frank rigors, a temperature of 104°F, exquisite loin pain, and signs suggesting gram-negative sepsis clearly has acute pyelonephritis. On the other hand, the absence of such findings does not rule out the presence of renal involvement, that is, covert pyelonephritis.

Acute Urinary Tract Infection

Acute Uncomplicated Cystitis

By far the most common clinical symptoms associated with UTI that bring patients to medical attention are those referable to the lower urinary tract: dysuria (burning or discomfort on urination), frequency, nocturia, and suprapubic discomfort. Approximately 10% of women of reproductive age come to medical attention each year with these symptoms.^[235] Of these, two thirds have significant bacteriuria, whereas one third (those with the acute urethral syndrome) do not. Of the patients with significant bacteriuria, 50% to 70% have infection restricted to the bladder, but fully 30% to 50% have covert infection of the upper urinary tract as well.^{[2] [235] [285] [286]} As demonstrated inTable 34-4 , patients with and patients without covert renal involvement cannot be differentiated on clinical grounds alone.

TABLE 34-4 -- Relationship Among Clinical Syndromes, Presence of Significant Bacteriuria, and Anatomic Site of Urinary Tract Infection in a General Practice Population (% with Symptoms)

	Insignificant or Absent Bacteriuria (Acute Urethral Syndrome)	Renal Bacteriuria	Bladder Bacteriuria
Symptoms suggesting lower UTI
Frequency	95	98	70
Burning	70	68	70
Suprapubic pain	70	68	51
Symptoms suggesting upper UTI
Loin pain	50	48	19
Fever	35	44	4
Rigors	15	32	15
Nausea and vomiting	25	24	8
Macroscopic hematuria	25	20	12

Modified from Fairley F, Carson NE, Gutch RC, et al: Site of infection in acute urinary tract infection in general practice. Lancet 2:615, 1971. Copyright by The Lancet Ltd., 1971.

UTI, urinary tract infection.

Women with the acute urethral syndrome can be divided into two groups. Approximately 70% have pyuria on urinalysis and have true infection. For the most part, these patients have infection with C. trachomatis or with the usual bacterial uropathogens (e.g., E. coli, S. saprophyticus) but in “less than significant” numbers (10²-10⁴/mL). The remaining 30% of patients with the acute urethral syndrome, but no pyuria, have no known microbial etiologic agent for their symptoms.^{[285] [286]}

Recurrent Cystitis

Recurrent symptoms of lower urinary tract inflammation may be due to either relapsing infection or reinfection. Relapse is caused by reappearance of the same organism from a sequestered focus, usually within the kidney or prostate, shortly after completion of therapy. In reinfection, the course of therapy has successfully eradicated the infection, and there is no sequestered focus, but organisms are reintroduced from the fecal reservoir. More than 80% of all recurrences are due to reinfection.^{[285] [286]}

Among schoolgirls with symptomatic UTI, about 20% remain infection-free after each course of treatment, with 25% having repeated bouts of infection. Among the group of adult women susceptible to recurrent UTIs (defined as three or more infections in a calendar year), the attack rate over several years is approximately 0.15 infection per month, with virtually all such infections being symptomatic. Approximately one third of such infections are followed by an infection-free interval of at least 6 months, the average infection-free interval being approximately 1 year. Unfortunately, even prolonged remission in these individuals does not mean cure because infections tend to recur even after an infection-free interval of a year or longer.^{[285] [287] [288]}

The most important cause of recurrent symptoms of lower urinary tract inflammation in adult men is prostatitis caused by either E. coli or the other bacterial uropathogens seen in women. Acute bacterial prostatitis is a febrile illness associated with chills; perineal, back, or pelvic pain; dysuria; and urinary frequency and urgency. There may be bladder outlet obstruction; on physical examination, the prostate is enlarged, tender, and indurated. Chronic prostatitis, in contrast, may be more occult; asymptomatic infection is manifested as recurrent bacteriuria or variable low-grade fever with back or pelvic discomfort. Urinary symptoms are usually due to reintroduction of infection into the bladder from a chronic prostatic focus that has been inadequately treated and only temporarily suppressed by a previous course of antimicrobial therapy.^{[288] [289]}

Acute Pyelonephritis

The clinical findings associated with full-blown acute pyelonephritis are familiar: rigors and fever, back and loin pain (with exquisite tenderness or percussion of the costovertebral angle), often with colicky abdominal pain, nausea and vomiting, dysuria, frequency, and nocturia. Although bacteremia may complicate the course of symptomatic pyelonephritis in any patient, such bacteremias are seldom associated with the more serious sequelae of gram-negative sepsis, that is, the triggering of the complement, clotting, and kinin systems, which may lead to septic shock, disseminated intravascular coagulation, or both. When shock or disseminated intravascular coagulation occurs in the setting of pyelonephritis, the possibility of complicating obstruction must be ruled out. In one particularly important form of obstructive uropathy, which is associated with acute papillary necrosis, the sloughed papilla may obstruct the ureter. This form should be particularly suspected in diabetic patients with severe pyelonephritis and high-grade bacteremia, especially if the response to therapy is delayed.^[290]

In children younger than 2 years, fever, vomiting, nonspecific abdominal complaints, or failure to thrive may be the only manifestations of significant acute pyelonephritis. Indeed, UTI accounts for approximately 10% of these febrile episodes. In older children, clinical manifestations resemble more closely those seen in the adult, although the reappearance of enuresis may be a marker for the decreased urinary concentrating ability that is sometimes associated with renal infection (see later).^{[291] [292]}

Complicated Urinary Tract Infection

The term complicated UTI encompasses a wide range of clinical syndromes that include asymptomatic bacteriuria, cystitis, pyelonephritis, and frank urosepsis. The common element is the presence of bacterial infection of the urinary tract in patients with structurally abnormal (e.g., ureteral and bladder neck obstruction—including that due to prostatic enlargement, polycystic kidney disease, obstructing stones, or the presence of a catheter or some other foreign body) or functionally abnormal (e.g., a neurogenic bladder from spinal cord injury, diabetes mellitus, and multiple sclerosis) urinary tracts, intrinsic renal disease, or a systemic process that renders the patient particularly susceptible to bacterial invasion. The range of organisms causing such infections is far broader than that noted in patients with uncomplicated infection, and the level of antibiotic resistance of these bacteria is also greater than that seen in isolates from the general population. Because the therapeutic requirements and management strategies for complicated UTI are different from those for uncomplicated infection (see later), this differentiation is clinically important.^{[2] [40]}

Chronic Pyelonephritis and Reflux Nephropathy

Unlike the dramatic clinical presentation of many patients with acute pyelonephritis, chronic disease typically has a more insidious course. Clinical signs and symptoms may be divided into two categories: (1) those related directly to infection and (2) those related to the extent and the location of injury within the kidney. Surprisingly, the infectious aspects of the disease may be minor. Although intermittent episodes of full-blown pyelonephritis may occur, these are the exception . More common is asymptomatic bacteriuria, symptoms referable to the lower urinary tract (dysuria and frequency), vague complaints of flank or abdominal discomfort, and intermittent low-grade fevers.

As important as the infectious or inflammatory symptoms are the physiologic derangements that result from the long-standing tubulointerstitial injury. These derangements include hypertension, inability to conserve Na⁺, decreased concentrating ability, and tendency to develop hyperkalemia and acidosis. Although all of these are seen to some extent in all forms of renal disease, in patients with tubulointerstitial nephropathy such as this, the degree of physiologic derangement is out of proportion to the degree of renal failure (or serum creatinine elevation). Thus, in other forms of renal disease, physiologic derangements are minimal at serum creatinine levels of 2 to 3 mg/dL; in the patient with chronic pyelonephritis and reflux nephropathy with serum creatinine at this level, polyuria, nocturia, hyperkalemia, and acidosis may all be observed. Clinically, it is particularly important to recognize that such patients are especially susceptible to dehydration because of their inability to excrete a concentrated urine (see Fig. 34-9 ).

Considerable progress has been made in the radiologic assessment of VUR and renal scarring. The standard tests have long been voiding cystourethrography or radionuclide cystourethrography—both with significant radiation exposure. Recently, contrast-enhanced voiding ultrasono-graphy and magnetic resonance cystography have been developed to provide useful information without the radiation burden.^{[66] [293] [294] [295] [296] [297] [298] [299] [300]}

Routine laboratory findings are as nonspecific as the clinical findings. Although pyuria is usually present, it may be absent, particularly if there is no active infection. Less common is the presence of white blood cell casts on urinalysis. Bacteriuria may or may not be demonstrable. The determination of 24-hour protein excretion may be an important prognostic indicator in patients with chronic pyelonephritis and reflux nephropathy. Most patients with this condition excrete less than 1 g/day of protein. However, heavy proteinuria, including the nephrotic syndrome, may develop in a subset of patients, owing to the superimposition of focal and segmental glomerulosclerosis on the basic tubulointerstitial injury.^{[291] [292]}

Natural History of Vesicoureteral Reflux and Reflux Nephropathy

The natural history of VUR and reflux nephropathy is variable, depending on the severity of the VUR, the concurrence of other congenital anomalies or obstruction, the age at presentation, the surgical or antibacterial intervention, and the development of complications as such hypertension and glomerulosclerosis. Although coarse scar formation is closely linked to VUR and infection, the progressive deterioration of renal function can result from numerous secondary mechanisms.

Formation of Scars

Scar development usually represents the combined effects of infection, VUR, and intrarenal reflux. The severity of VUR is the single most important determinant of whether renal damage will occur. The importance of infection in the development of new scars was shown by Smellie and associates,^{[110] [111]} who found only two fresh scars developing among 75 compliant children observed for 15 years and given low-dose prophylactic antibacterial therapy. It has been suggested that infection and high pressure may alter some borderline papillae to the refluxing state. Children who have UTI but unscarred kidneys after age 3 years have an estimated risk of developing new scars of 2% to 3%.^{[301] [302] [303] [304]}

Progressive Renal Failure

The progressive renal failure seen in patients with reflux nephropathy is frequently caused not by infection nor by continued VUR but by other complicating or related conditions. These include (1) retardation of renal growth, (2) obstruction or other congenital anomalies, (3) hypertension, and (4) progressive glomerulosclerosis.

Retardation of Renal Growth.

The effect of VUR on renal growth is a measure of the health of a kidney. It is apparent that focal scarring and growth impairment are two difference consequences of renal infection.^[304] The prognosis for renal growth is generally excellent with VUR, particularly if the kidneys are unscarred and there is no recurrence of infection. The prognosis for growth is poorest for patients with gross, persistent VUR; severe generalized scarring; and increased tendency toward recurrent infection.^{[261] [262] [305] [306] [307]}

The balance of the evidence suggests that renal growth may be transiently impaired in children with VUR, but mainly in those with renal scarring and usually in the presence of infection. However, this reduction in renal growth does not seem to be a major determinant of the later progressive deterioration of renal function in patients with reflux nephropathy.^{[66] [261] [262] [301] [302] [306] [307]}

Obstruction and Other Congenital Anomalies.

Children with UTI with or without VUR may have a variety of renal and lower urinary tract anomalies that contribute to renal damage. These include duplex kidneys, cysts, hydronephrosis due to ureteropelvic obstruction, renal calculi, vesicoureteral or urethral obstruction, and bladder diverticula.^{[110] [111]} These anomalies predispose to repeated renal infection. The coexistence of VUR and an obstructive anomaly, such as posterior urethral valves, is particularly harmful, and it is under these conditions that sterile reflux may cause renal damage.

Hypertension.

The association between chronic pyelonephritis or reflux nephropathy and hypertension is well documented; the frequency of the hypertension varies with both age and severity of the kidney disease.^[269]

Reflux nephropathy is one of the most common causes of hypertension in children. For example, 83% of 100 severely hypertensive children had associated renal disease and 14% of these had reflux nephropathy. Of 177 children with malignant hypertension and scarred atrophic kidneys, the majority had reflux nephropathy,^{[306] [307]} and 29 (30%) of 96 children with persistent hypertension had chronic pyelonephritis, making it the most common etiologic factor in the group. About 10% of children with renal scarring become hypertensive, and 15% of patients with reflux nephropathy who reach adulthood have hypertension.^{[308] [309]} Reflux nephropathy diagnosed for the first time in adulthood is highly associated with UTI, proteinuria, back pain, and renal calculi in addition to hypertension.^[310]

The pathogenesis of hypertension in reflux nephropathy is unclear. In humans, there is some evidence both for and against a role for hyperreninemia. Although it has been difficult to produce hypertension in rats and rabbits that have been made pyelonephritic, studies in pigs show that hypertension develops in some animals 1 to 2 years after the induction of VUR with scarring and that such hypertension is associated with pronounced arterial lesions and activation of the renin-angiotensin system (C.J. Hodson, unpublished data). Hypertension also occurs in unilateral reflux nephropathy, but there is uncertainty about whether such hypertension can be prevented or ameliorated by unilateral nephrectomy.^[311]

Proteinuria and Progressive Glomerulosclerosis.

There is a prognostically important association among the development of proteinuria, focal segmental glomerulosclerosis, and progressive renal insufficiency in patients with reflux nephropathy.^{[267] [268] [269] [312]} Although several authors had reported occasional severe proteinuria or overt nephrotic syndrome in patients diagnosed as having chronic pyelonephritis,^[313] it was Kincaid-Smith^{[220] [226] [227] [314] [315]} who first stressed the occurrence of proteinuria and glomerulosclerosis in patients with chronic pyelonephritis and reflux nephropathy. In 55 adult patients with reflux nephropathy, she found that 19 had proteinuria. All but 1 of 11 patients whose renal function subsequently declined had significant proteinuria, with the mean being 2.36 g/24 hr, whereas all patients whose serum creatinine level remained stable had either no proteinuria (7 patients) or proteinuria of less than 1 g/24 hr (2 patients). The degree of proteinuria correlated well with the presence and the extent of glomerular lesions, most of which consisted of focal and segmental glomerulosclerosis and hyalinosis. Microalbuminuria (a urinary albumin excretion rate of 20-200 mg/min) may be the first sign of glomerular injury in these patients, as it is in diabetic patients.^[315]

Other studies have confirmed the association of proteinuria, glomerulosclerosis, and reflux nephropathy. In one such study of 23 patients with end-stage reflux nephropathy, all had focal glomerulosclerosis, and their average protein excretion ranged from 1.2 to 5.8 g/24 hr. In 29 of the 54 patients described by Torres and associates, the 24-hour urinary protein excretion ranged from 0.5 to 10.4 g. There was a significant positive correlation between the 24-hour protein excretion and the simultaneous determination of creatinine clearance. The clinical course to end-stage renal disease was not appreciably altered by late surgical correction of the VUR, by infection, or by hypertension. In our series of patients with chronic pyelonephritis or reflux nephropathy, half of those with focal glomerulosclerosis had radiologic or morphologic evidence of bilateral renal disease and a serum creatinine level of more than 2.5 mg/dL, and 63% had a 24-hour urinary protein excretion of greater than 1 g. In contrast, patients without focal sclerosis had normal serum creatinine levels, minimal proteinuria, and unilateral disease.^[312]

The most attractive explanation for glomerulosclerosis in reflux nephropathy is that it results from the adaptive changes occurring in glomeruli because of reductions in renal mass.^{[316] [317]} With certain exceptions, the clinical data are consistent with this hypothesis. In most series, proteinuria and glomerulosclerosis are most prominent in patients with bilateral disease and impaired renal function, although they have occasionally been reported in patients with unilateral disease and those with normal renal function. In patients with normal renal function, it is probable that the adapted glomeruli have maintained normal function and that this continues until progressive sclerosis of the remaining glomeruli leads to reduction of the glomerular filtration rate. Occasionally, proteinuria occurs in patients with unilateral reflux nephropathy,^[318] and the glomerulosclerosis is present in the normal hypertrophied kidney. Although this has been cited as evidence against the hemodynamic mechanism, it is consistent with it because hemodynamic changes have been well documented in uninvolved kidneys of patients with unilateral scars.^[319] Finally, morphometric studies confirm the hypertrophy of glomeruli in biopsy specimens of patients with reflux nephropathy and show a relationship between renal size, glomerular size, and renal function in these patients.^[320]

Whatever the mechanisms, it is now clear that progressive glomerulosclerosis is a major determinant of the development of chronic renal failure in reflux nephropathy.

DIAGNOSTIC EVALUATION

History and Physical Examination

Despite the incomplete relationship between clinical symptoms and the presence of infection at various sites in the urinary tract, useful information can be gained from a skillfully obtained history. When a patient with a single acute episode of symptomatic UTI is examined, the first consideration is whether there are signs or symptoms suggesting the presence or imminent development of systemic sepsis: spiking fevers, rigors, tachypnea, colicky abdominal pain, and exquisite loin pain. Such patients require immediate attention and effective antimicrobial therapy. If the patient is not acutely septic, attention turns to such concerns as previous history of UTIs, renal disease, and such conditions as diabetes mellitus, multiple sclerosis, other neurologic conditions, history of renal stones, and previous genitourinary tract manipulation—conditions that could predispose to UTI and could affect the efficacy of therapy. A careful neurologic examination can be particularly important in suggesting the possibility of a neurogenic bladder.

The patient with a history of recurrent UTIs merits special attention in terms of obtaining a clear history of sexual activity, response to therapy, and temporal relationships of recurrences to the cessation of therapy. Thus, women with recurrent bacterial UTIs temporally related to intercourse could benefit from the administration of antibiotics after each sexual exposure.^[48] The woman with the acute urethral syndrome due to C. trachomatis infection may respond only temporarily to antichlamydial therapy because of reinfection from the untreated sexual partner (so-called ping-ponging infection); cure occurs when both individuals are treated simultaneously. Women with recurrent UTIs who have relapsing infection as opposed to reinfection often give a different history of the temporal relationship between the end of therapy and the onset of new symptoms. The majority of women with relapsing infection relapse within 4 to 7 days of completing a course of therapy of 14 days or less, whereas those with recurrent reinfection usually have a longer interval between episodes unless bladder dysfunction or some other disturbance of urinary tract function is present. Similarly, men with persistent prostatic foci of infection often relapse promptly after a similar conventional course of therapy.^{[10] [38]} In addition, a history of prostatic obstruction to urine flow should be sought (e.g., narrowing of the urine stream, hesitancy, nocturia, and dribbling).

When the patient with possible chronic pyelonephritis and reflux nephropathy is examined, two types of information should be sought: the history of UTI in childhood and during pregnancy, and the possible presence of such pathophysiologic consequences as hypertension, proteinuria, polyuria, nocturia, and frequency.

Urine Tests

Four major chemical tests have been evaluated as rapid diagnostic tools. By far the most commonly used is the Griess nitrate reduction test, which is dependent on the bacterial reduction of nitrate in the urine to nitrite, with a variety of commercially available tapes or dipsticks employed to measure the presence of nitrites. This test is most accurate on first-morning urine specimens and is reasonably effective in identifying infection due to Enterobacteriaceae but fails to detect infection due to gram-positive organisms or Pseudomonas. False-negative results may also be caused by lack of dietary nitrate or diuresis because bladder incubation time is necessary for bacteria to reduce the nitrates. Because of its simplicity, this test is best used as part of a home or epidemiologic screening program, particularly if multiple specimens can be evaluated from a single individual.^{[321] [322] [323]} The combination of the nitrate test with a test for leukocyte esterase on a single, inexpensive dipstick that can be read in less than 2 minutes has greatly increased the utility of this approach. This system provides a useful assessment for the presence of more than 10⁵Enterobacteriaceae per milliliter of urine and of pyuria. A negative test result has a predictive value of 97%. False-negative test results can be caused by proteinuria and the presence of gentamicin or cephalexin in the urine. Overall, this test has an 87% sensitivity and a 67% specificity (false-positives usually result from vaginal contamination). This approach is far more effective in screening urine specimens from patients with symptoms as opposed to screening asymptomatic patients, such as occurs in obstetric practice.^{[323] [324] [325] [326]}

The other commonly employed chemical test is the reduction of triphenyltetrazolium chloride to triphenylformazan (which has a red color) by bacteria. False-positive test results are caused by the ingestion of large amounts of vitamin C or a urine pH of less than 6.5. False-negative test results are due to deterioration of the reagent (common) and infection with staphylococci, some enterococci, and Pseudomonas species.^{[321] [322] [323] [324] [325] [326] [327]}

Radiologic and Urologic Evaluations

The primary objective of radiologic and urologic evaluations in UTI is to delineate abnormalities that would lead to changes in the medical or surgical management of the patient. Such studies are particularly useful in the evaluation of children and adult men. In women, there is more controversy regarding their appropriate deployment. The following guidelines would appear to be reasonable:

	1.	An ultrasound study or computed tomography (CT) scan is indicated to rule out obstruction in patients requiring hospital admission for bacteremic pyelonephritis, particularly if the infection is slow to respond to appropriate therapy. Patients with septic shock in this setting require such procedures on an emergency basis because these patients often cannot be effectively resuscitated unless their “pus under pressure” is relieved by some form of drainage procedure that bypasses the obstruction.
	2.	Children with first or second UTIs, particularly those younger than 5 years, merit both excretory urography and voiding cystourethrography for detection of obstruction, VUR, and renal scarring. Dimercaptosuccinic acid scanning is a sensitive technique for detecting scars, and serial studies can be useful in assessing the course of scarring and the success of preventive regimens. However, this approach does not delineate anomalies in the pyelocaliceal system or the ureters. A newer approach utilizing magnetic resonance imaging (MRI) is gaining favor for children, because of the lack of radiation exposure.^[328] This imaging effort in children is aimed at identifying those who might benefit from intensive medical attention (e.g., prolonged antimicrobial prophylaxis). Because active infection by itself can produce VUR, it is usually recommended that the radiologic procedures be delayed until 4 to 8 weeks after the eradication of infection, although some groups perform these studies as early as 1 week after infection.^{[328] [329] [330] [331] [332] [333] [334]} However, few other parameters are available for delineating the pediatric population at highest risk for anatomic abnormalities of the urinary tract.
	3.	Most men with bacterial UTI have some anatomic abnormality of the urinary tract, most commonly bladder neck obstruction secondary to prostatic enlargement. Therefore, anatomic investigation, starting with a good examination of the prostate and then proceeding to excretory urography or urinary tract ultrasound studies with postvoiding views, should be seriously considered in all male patients with UTI.
	4.	Although there is general agreement that first UTIs in women do not merit radiologic or urologic study, the management of recurrent infection is more controversial. In such women, the once-routine cystoscopic study with urethral dilatation has fallen out of fashion. In addition, several studies have demonstrated the lack of cost-effectiveness of radiologic and urologic studies in the evaluation of women with recurrent UTIs.

Therefore, it would appear that the routine anatomic evaluation of women with recurrent UTIs cannot be recommended. This is not to say that a few patients might not benefit from such studies. Characteristics of a population of women who might benefit from such anatomic studies include patients who fail to respond to appropriate antimicrobial therapy or who rapidly relapse after such therapy; patients with continuing hematuria; patients with infection with urea-splitting bacteria; patients with symptoms of continuing inflammation, such as night sweats; and patients with symptoms of possible obstruction, such as back or pelvic pain that persists despite adequate antimicrobial therapy.^{[335] [336] [337] [338] [339] [340]} In our experience, a disappointing response to antimicrobial therapy has been the most useful indicator for the need for radiologic and urologic evaluation.

TREATMENT

General Principles of Antimicrobial Therapy

The goals of treatment of UTI are to prevent or treat systemic sepsis, to relieve symptoms, to eradicate sequestered infection, to eliminate uropathogenic bacterial strains from fecal and vaginal reservoirs, and to prevent long-term sequelae—all at minimal cost, with the lowest rate of side effects, and with the least selection of an antibiotic-resistant bacterial flora. These goals can be best achieved by prescribing different forms of therapy for different types of UTIs.^[341]

Specific Recommendations

Acute Uncomplicated Cystitis in Young Women

Therapy for healthy women of reproductive age who present with symptoms of lower urinary tract inflammation (dysuria, frequency, urgency, nocturia, and suprapubic discomfort) in the absence of signs and symptoms of vaginitis (vaginal discharge or odor, pruritus, dyspareunia, external dysuria without frequency, and vulvovaginitis on examination) should be approached with two objectives in mind: (1) eradication of superficial mucosal infection of the lower urinary tract, and (2) eradication of uropathogenic clones from the vagina and the lower gastrointestinal tract. Since the 1990s, the treatment of choice has been short-course therapy with trimethoprim-sulfamethoxazole (TMP-SMX) or a fluoroquinolone; both of these are superior to β-lactams in the treatment of UTI. Both these drugs achieve high concentrations in vaginal secretions that are more than sufficient to eradicate the usual E. coli and other major uropathogens (with the notable exception of enterococci). At the same time, the antibacterial spectrum of activity of these drugs is such that the normal anaerobic and microaerophilic vaginal flora, which provides colonization resistance against the major uropathogens, is left intact. In contrast, β-lactam drugs, such as amoxicillin, appear to promote vaginal colonization with uropathogenic E. coli.^{[2] [3] [41] [336] [342]}

Unfortunately, antimicrobial resistance has increased significantly since the early 1990s, particularly to TMP-SMX, which has been the primary choice for treatment of acute uncomplicated cystitis because of cost and efficacy. Widespread distribution of a uropathogenic clone of E. coli that has acquired resistance to TMP-SMX has been documented in several geographic areas of the United States. When TMP-SMX is prescribed for a resistant organism, a failure rate higher than 50% is expected. Isolates from women younger than 50 years are more likely to be resistant than are those from older women. There is wide variation in different geographic areas in terms of the incidence of TMP-SMX resistance, and the prescribing physician is obligated to obtain such information for his or her community of practice. If the incidence is higher than 20%, then it is recommended that a fluoroquinolone be prescribed as the drug of choice. However, it must be emphasized that monitoring of resistance to this class of drugs will be also important, as it is likely that resistance will slowly develop to these drugs as well.^{[157] [158] [341] [342] [343] [344] [345] [346] [347] [348] [349] [350] [351] [352] [353]}

There are two forms of short-course therapy: single-dose therapy and a 3-day course of therapy. There is now compelling evidence that a 3-day course of therapy is superior to a single dose, with either TMP-SMX or a fluoroquinolone, provided the infecting organism is susceptible. Both forms of short-course therapy are probably equally efficacious in eradicating bladder infection in women. However, single-dose therapy is not as effective in eradicating the uropathogenic clones from the vaginal or intestinal reservoir. As a result, early recurrence, predominantly resulting from reinfection from these reservoirs, is significantly more common with single-dose therapy.^{[354] [355] [356] [357] [358] [359] [360] [361] [362]}

Short-course therapy is specifically designed for the treatment of superficial mucosal infection and to serve as a guide for those with unsuspected deep tissue infection who would benefit from a more extended course of therapy (e.g., women with occult pyelonephritis). Short-course therapy should therefore never be given to individuals who fall into the following categories of patients with a high probability of deep tissue infection: any man with UTI (in whom tissue invasion of at least the prostate should be assumed), anyone with overt pyelonephritis, patients with symptoms of longer than 7 days' duration, patients with underlying structural or functional defects of the urinary system, immunosuppressed individuals, patients with indwelling catheters, and patients with a high probability of infection with antibiotic-resistant organisms.^{[357] [358] [359] [360] [361]}

Acute uncomplicated UTI in otherwise healthy women is so common, the range of organisms causing the infection is so well defined, the susceptibility of these organisms to the antimicrobial agents recommended is so uniform, and the efficacy and lack of side effects of short-course therapy are now so well established that all have combined to lead to a cost-effective approach that minimizes both laboratory studies and the need for visits to the physician ( Fig. 34-12 ). The first step is to initiate short-course therapy in response to the compliant of dysuria and frequency without evidence of vaginitis. If a urine specimen is readily available, a leukocyte esterase dipstick test can be carried out (which has a reported sensitivity of 75%–96% in this situation)^{[352] [353] [354] [355] [356] [357] [358] [359] [360] [361] [362] [363]}; urine culture and microscopic examination of the urine are reserved for the patient with atypical presentations. Alternatively, a reliable patient who reports a typical clinical presentation by telephone could have short-course therapy prescribed without initial examination of the urine. Because short-course therapy is both safe and inexpensive, and because most practitioners begin therapy on the basis of symptoms before culture data are available, this approach appears to be cost-effective.^{[347] [355] [358]}



FIGURE 34-12 Clinical approach to the woman with dysuria and frequency. (Modified from Tolkoff-Rubin NE, Wilson ME, Zuromskis P, et al: Single-dose amoxicillin therapy of acute uncomplicated urinary tract infections in women. Antimicrob Agents Chemother 25:626, 1984.)

The critical practitioner-patient interaction comes after the completion of therapy: If the patient is asymptomatic, nothing further needs to be done. If the patient is still symptomatic, both urinalysis and urine culture are necessary. If the symptomatic patient has a negative urinalysis and bacterial culture, no clear microbial etiologic agent is present, and the physician's attention should be directed toward analgesia and concerns about trauma, personal hygiene, allergy to clothing dyes, or primary gynecologic conditions. If the patient is pyuric but not bacteriuric, the possibility of C. trachomatis urethritis should be considered, particularly if the woman is sexually active with multiple partners. Optimal therapy for C. trachomatis infection consists of a 7- to 14-day regimen of a tetracycline or sulfonamide for the patient and her sexual partner. Finally, patients with symptomatic bacteriuria due to an organism susceptible to the antibiotic that had been prescribed in a short-course regimen should be regarded as having covert renal infection. A more prolonged course of therapy should be administered, initially 14 days, with the potential for a more extended course if needed. Again, either a fluoroquinolone or TMP-SMX (assuming the isolate is sensitive) would be the most effective drug in this circumstance.^{[347] [355] [358] [362]}

Recurrent Urinary Tract Infection in Young Women

Recurrent bacterial UTI is common in women, accounting for more than 5 million visits to physicians in the United States each year. Approximately 20% of young women with a first episode of UTI will have recurrent infection. Various regimens have been designed to prevent repeated reinfections, which account for more than 90% of UTI recurrences. Before the physician embarks on these antimicrobial approaches, however, such simple interventions as voiding immediately after sexual intercourse and switching from a diaphragm and spermicide-based contraceptive strategy to some other approach should be implemented. If these measures are not effective, it is then time to consider which of a variety of preventive strategies is most appropriate for a particular patient. For such preventive regimens to be acceptable, they should be effective at low doses, have minimal side effects, and should have minimal impact on bowel flora, the reservoir from which UTIs are derived.^{[358] [362]}

Several prospective studies have now demonstrated the efficacy of either nitrofurantoin, 50 mg, or nitrofurantoin macrocrystals, 100 mg, at bedtime for prophylaxis against recurrent reinfection of the urinary tract. Such a regimen has little if any effect on the fecal flora and presumably acts by providing intermittent urinary antibacterial activity. Although this regimen is effective, a report from Sweden has suggested that long-term nitrofurantoin prophylaxis against UTI is associated with an alarming rate of adverse side effects. These adverse effects include chronic interstitial pneumonitis, acute pulmonary hypersensitivity reactions, liver damage, blood dyscrasias, skin reactions, and neuropathy. In addition, nitrofurantoin should not be used in patients with renal impairment.^[364]

Perhaps the most popular prophylactic regimen currently used in women susceptible to recurrent UTI is low-dose TMP-SMX; as little as half a tablet (trimethoprim, 40 mg; sulfamethoxazole, 200 mg) three times weekly at bedtime is associated with an infection frequency of less than 0.2 per patient-year. The efficacy of this prophylactic regimen appears to remain unimpaired even after several years. This regimen would be cost-effective in most practice settings for women who have more than two UTIs per year. Like TMP-SMX, the fluoroquinolones may be used in a low-dose prophylactic regimen. The efficacy of these prophylactic regimens is further delineated by their potency in preventing UTI in the far more challenging population of kidney transplant recipients. A variation on these efficacious continuous prophylaxis programs is to use a fluoroquinolone or trimethoprim-sulfamethoxazole as postcoital prophylaxis.^{[19] [362] [365] [366] [367]}

An important unanswered question is the duration of prophylactic therapy against recurrent UTI: Our practice has been to continue such therapy for 6 months and then to discontinue it. If infection then recurs, prophylaxis is reinstituted for periods of 1 to 2 years or longer. An alternative approach is for the women to self-treat at the first sign/symptom of a UTI. Such treatment with a single-dose regimen of TMP-SMX or a fluorquinolone is both effective and well tolerated.^{[41] [365] [366] [367]}

A nonantibiotic approach to preventing recurrent infection is to drink cranberry juice. Apparently, proanthocyanidins derived from cranberry juice block bacterial adhesion at the epithelial level, presumably through binding to and blocking access to the mucosal receptor. In our experience, this has been moderately effective, and we advocate a trial of such an intervention before one of the antimicrobial approaches detailed previously is prescribed.^{[368] [369] [370] [371] [372]}

The approach to the minority of patients with relapsing infection is different. Two factors may contribute to the pathogenesis of relapsing infection in women: (1) deep tissue infection of the kidney that is suppressed but not eradicated by a 14-day course of antibiotics and (2) structural abnormality of the urinary tract (e.g., calculi). At least some of these patients respond to a 6-week course of therapy.^[373] We have found that the response to short-course therapy in such women is helpful in making the management decision: If the patient responds to short-course therapy, it is likely that she has been having recurrent reinfection and is thus a candidate for long-term prophylaxis (or one of the self-treatment regimens). If the patient does not respond to short-course therapy, it is probable that she has been having relapsing infection and is thus a candidate for an intensive course of prolonged therapy. Thus, one can more exactly delineate those patients in whom the greatest clinical benefit would compensate for the increased costs and side effects of prolonged treatment ( Fig. 34-13 ).



FIGURE 34-13 Clinical approach to the woman with recurrent urinary tract infections.

Acute Uncomplicated Cystitis in Older Women

Several aspects of UTI in postmenopausal women merit special attention. The frequency of both symptomatic and asymptomatic bacteriuria is considerably higher than in younger age groups, probably as a result of at least two factors: (1) Many postmenopausal women have significant amounts of residual urine in their bladders after voiding as a consequence of childbirth and loss of pelvic tone, and (2) the lack of estrogens causes a marked change in the susceptibility of the uroepithelium and vagina to pathogens. This is at least partly due to such changes in the vaginal microflora as the loss of lactobacilli, which causes a rise in vaginal pH. Whereas symptoms referable to the lower urinary tract in younger women are almost invariably due to uropathogens and C. trachomatis (see earlier), other possibilities exist in older women. In particular, in symptomatic women with pyuria and negative cultures, the possibility of genitourinary tuberculosis, systemic fungal infection, and diverticulitis or a diverticular abscess impinging on the bladder or ureters merits consideration, rather than the chlamydial infection that represents a major cause of such infections in younger women.^{[41] [373] [374] [375] [376] [377] [378]}

The antimicrobial strategies discussed previously for the management of acute cystitis in younger women are applicable in postmenopausal women as well. In addition, however, other interventions have an important role in this population. Several studies have now shown that estrogen replacement therapy, either locally by use of a vaginal cream or systemically with oral therapy, restores the atrophic genitourinary tract mucosa of the postmenopausal woman, is associated with a reappearance of lactobacilli in the vaginal flora and a fall in vaginal pH, and decreases vaginal colonization by Enterobacteriaceae.^{[373] [374] [375] [376] [377]} Thus, estrogen therapy can be translated into significant protection against recurrent UTI in postmenopausal women.^{[374] [375] [376] [377] [378]}

The regular intake of cranberry juice significantly reduced the frequency of both bacteriuria and pyuria in a population of elderly women. Although the possibility of this effect has been postulated for many years, it has in the past been linked to urinary acidification. Because consistent acidification with oral intake of cranberry juice requires the consistent ingestion of prodigious volumes, this approach had fallen out of favor. What is noteworthy in this study is that the therapeutic effect was clearly independent of any changes in urine pH. Rather than an acidification effect, it has been postulated that cranberry and blueberry juices contain materials that are excreted in the urine that inhibit the attachment of bacterial adhesins to the uroepithelium (see later).^{[379] [380] [381]}

Asymptomatic bacteriuria is particularly common in elderly women, especially those not receiving hormonal replacement therapy. It is now clear that treatment of this serves no purpose, and thus, screening for asymptomatic bacteriuria in this population is not indicated.^[382]

Acute Uncomplicated Pyelonephritis in Women

Patients with clear-cut symptomatic pyelonephritis have deep tissue infection, have or are at risk for bacteremia, and merit intensive antimicrobial therapy. The key principle in the management of these patients is the immediate delivery to the bloodstream and to the urinary tract of effective concentrations of an antimicrobial agent to which the invading organism is susceptible. A variety of strategies are available to accomplish this; the following general principles are a useful guide^[2]:

	1.	The three goals in the antimicrobial therapy of symptomatic pyelonephritis are control or prevention of urosepsis (i.e., the consequences of bloodstream invasion), eradication of the invading organism, and prevention of recurrences.
	2.	To accomplish these aims, it is useful to divide the therapeutic program into two parts: the immediate control of systemic sepsis, which may require parenteral therapy; and the eradication of the infecting organism (and prevention of early recurrence) with an oral agent, after initial control of the systemic sepsis and acute inflammatory consequences of pyelonephritis.
	3.	Initial antimicrobial programs to obtain control of systemic sepsis are prescribed to fulfill two objectives: The infecting organism has a greater than 99% probability of being sensitive to the regimen chosen, and adequate blood levels of the drugs can be reliably achieved promptly in the particular patient. At present, there is no evidence to suggest that one antibiotic or program is inherently superior to another for control of systemic sepsis, provided that these two requirements are fulfilled. Similarly, the merits of intravenous therapy have to do with the reliability of drug delivery, rather than something inherently more desirable about intravenous drugs (indeed, as is well recognized, vascular access devices have their own infectious disease complications). In patients with milder disease, who are free of nausea and vomiting, advantage can be taken of the excellent antimicrobial spectrum and bioavailability (with the easy achievement of high blood levels with oral administration provided that the gastrointestinal tract is functioning adequately) of such drugs as TMP-SMX and the fluoroquinolones to prescribe oral therapy for the entire therapeutic course.
	4.	Once the patient has been afebrile for 24 hours (usually within 72 hours of initiation of therapy), there is no inherent benefit to maintaining parenteral therapy. At this point, prescription of TMP-SMX or a fluoroquinolone to complete a 14-day course of therapy appears to be the most effective means of eradicating both tissue infection and residual clones of uropathogen present in the gastrointestinal tract that could cause early recurrence if left in place.

If possible, a Gram stain of the urine should be performed to establish whether enterococcal infection could be present. If gram-positive cocci are present, or if that information is not available, initial therapy should include intravenous ampicillin (or vancomycin) plus gentamicin to provide adequate coverage of both enterococci and the more common gram-negative uropathogens. If only gram-negative bacilli are present, there are a large number of choices ranging from parenteral TMP-SMX and fluoroquinolones to gentamicin; such broad-spectrum cephalosporins as ceftriaxone, aztreonam, the β-lactam-b-lactamase inhibitor com-binations (ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam); and imipenem-cilastatin. In general, these last agents on the list (beginning with aztreonam) are reserved for patients with more complicated histories, previous episodes of pyelonephritis, and recent urinary tract manipulations.

Urinary Tract Infection in Pregnancy

As previously discussed, pregnant women are the one population in whom screening for asymptomatic bacteriuria is not only cost-effective but also obligatory to prevent consequences for the developing fetus and the mother. Treatment of pregnant women with asymptomatic bacteriuria or symptoms of lower urinary tract inflammation (dysuria and frequency, akin to acute uncomplicated cystitis in the nonpregnant woman of reproductive age) is similar to that in nonpregnant women: short-course therapy.^{[383] [384] [385] [386] [387] [388]}

Sulfonamides, nitrofurantoin, ampicillin, and cephalexin have been considered relatively safe for use in early pregnancy; sulfonamides are avoided near term because of a possible role in the development of kernicterus. Trimethoprim is usually avoided because of evidence of toxic effects in the fetus at high doses in experimental animals, although it has been used successfully in humans during pregnancy without evidence of toxicity or teratogenicity. Fluoroquinolones are avoided because of possible adverse effects on fetal cartilage development. Our preference is the use of nitrofurantoin, ampicillin, or cephalosporins—the drugs that have been used most extensively in pregnancy—in pregnant women with asymptomatic or minimally symptomatic UTI whenever possible. In pregnant women with overt pyelonephritis, admission to the hospital for parenteral therapy should be the standard of care; β-lactam drugs, aminoglycosides, or both are the cornerstones of therapy.^{[2] [383] [384] [385]}

Effective prevention of UTI, including pyelonephritis, can be accomplished during pregnancy with postcoital prophylaxis with nitrofurantoin, cephalexin, or ampicillin. Alternatively, these drugs may be given at bedtime without relation to coitus. Patients who should be considered for such prophylaxis during pregnancy include patients with histories of acute pyelonephritis during pregnancy, patients with bacteriuria during pregnancy who have had a recurrence after a treatment course, and patients with a history of recurrent UTI before pregnancy that has required a prophylaxis program outside the added stresses of pregnancy.^{[386] [387] [388]}

Urinary Tract Infection in Men

UTI is uncommon in men younger than 50 years, although UTI without associated urologic abnormalities can occur under the following circumstances: in homosexual men, in men having intercourse with women colonized with uropathogens, and in men with the acquired immunodeficiency syndrome (AIDS) with a CD4+ lymphocyte count of less than 200/mm³. Men should never be treated with short-course therapy; rather, 10- to 14-day regimens of TMP-SMX or a fluoroquinolone should be regarded as standard therapy unless antimicrobial intolerance or an unusual pathogen requires an alternative approach.^{[389] [390] [391]}

In men older than 50 years with UTI, tissue invasion of the prostate, the kidneys, or both should be assumed, even in the absence of overt signs of infection at these sites. Because of the inflammation usually present, acute bacterial prostatitis initially responds well to the same array of antimicrobial agents used to treat UTIs in other populations. However, after a conventional course of therapy of 10 to 14 days, relapse is common. Recurrent infection in men usually connotes a sustained focus within the prostate that has not been eradicated by previous courses of therapy. Several factors at work here make the eradication of prostatic foci so difficult:

	•	Many antimicrobial agents do not diffuse well across the prostatic epithelium into the prostatic fluid, where the infection lies.
	•	The prostate may harbor calculi, which can serve to block drainage of portions of the prostate gland or act as foreign bodies around which persistent infection can be hidden.
	•	An enlarged (and inflamed) prostate gland can cause bladder outlet obstruction, resulting in pools of stagnant urine in the bladder that are difficult to sterilize.^{[40] [41] [392] [393] [394] [395]}

As a result of these factors, it is now recognized that intensive therapy for at least 4 to 6 weeks and as many as 12 weeks is required to sterilize the urinary tract in many of these men. The drugs of choice for this purpose, assuming that the invading organisms are susceptible, are TMP-SMX, trimethoprim (in the individual allergic to sulfonamide), and the fluoroquinolones. Prolonged treatment with each of these has a greater than 60% chance of eradicating infection. Most of the failures are due to one of two factors: The anatomic factors listed previously are too abnormal to permit cure, and the infection that is present is a result of E. faecalis or P. aeruginosa, two organisms with a particularly high rate of relapse after treatment with antimicrobial agents. When relapse occurs, a choice then has to be made among three therapeutic approaches: (1) long-term antimicrobial suppression, (2) repeated treatment courses for each relapse, and (3) surgical removal of the infected prostate gland under coverage of systemic antimicrobial therapy. The choice from among these approaches depends on the age, sexual activity, and general condition of the patient; the degree of bladder outlet obstruction present; and the level of suspicion that prostate cancer could be present.^{[40] [392] [393] [394] [395]}

In addition to the usual uropathogens that cause a UTI in men, one additional entity merits attention. After instrumentation of the urinary tract, most commonly after repeated insertion of a Foley catheter, infection with S. aureus may occur; the use of antistaphylococcal therapy and the removal of the foreign body are required for cure.

Treatment of Childhood Urinary Tract Infection

The treatment of full-blown pyelonephritis in the child is similar to that in the adult: Broad-spectrum parenteral therapy until the antimicrobial susceptibility pattern of the infecting organism is known, followed by narrow-spectrum, least-toxic therapy parenterally until the patient is afebrile for 24 to 48 hours. A prolonged 1- to 3-month course of oral therapy is then instituted. Follow-up urine cultures within a week of completion of therapy and at frequent intervals for the next year are indicated. In children with acute, uncomplicated UTI, conventional 7- to 14-day regimens appear to be preferable, although many respond to short-course therapy. One potential exception to this observation is adolescent girls, for whom the increased compliance associated with short-course therapy can be a significant advantage. The one major difference in the approach to children as opposed to adults is that fluoroquinolones are not used in children because of possible adverse effects on developing cartilage.^{[396] [397] [398] [399] [400] [401]}

Recurrent UTI in children, particularly in those with renal scarring or demonstrable VUR, is dealt with by long-term prophylaxis with agents such as TMP-SMX or methenamine mandelate (50 mg/kg/day in three divided doses). Sulfonamides are less effective because of the emergence of resistance. TMP-SMX and nitrofurantoin macrocrystals have been particularly effective in this regard.^{[400] [401] [402] [403]} An auxiliary intervention that can be effective in some children with recurrent UTI is the aggressive treatment of constipation, particularly if this is present in conjunction with urinary incontinence.^[404]

Results of trials comparing medical therapy with surgical correction of VUR in children have failed to show significant benefit from the surgical approach in terms of renal function, progressive scarring, or renal growth, despite the fact that the technical aspects of the surgical repair could be accomplished satisfactorily . As a result, current views are to aggressively prevent scarring with prolonged antimicrobial therapy and close monitoring as primary therapy. Surgical correction is reserved for the child who, in a 2- to 4-year period, appears to not be responding to medical therapy.^{[405] [406] [407] [408] [409] [410] [411] [412] [413] [414] [415]}

Complicated Urinary Tract Infection

The term complicated UTI, by its nature, encompasses symptoms in a heterogeneous group of patients with a wide variety of structural and functional abnormalities of the urinary tract and kidney. In addition, the range of organisms causing infection in these patients is particularly broad, with a high percentage of these organisms being resistant to one or more of the antimicrobial agents frequently used in other populations of patients with UTI. Having said this, the following general principles appear to be reasonable in approaching patients with complicated UTI^{[2] [3] [416]}:

	1.	Therapy should be aimed primarily at symptomatic UTI because there is little evidence that treatment of asymptomatic bacteriuria in this population of patients either alters the clinical condition of the patient or is likely to be successful. The one exception to this rule is if the asymptomatic patient is scheduled for instrumentation of the urinary tract. In this instance, sterilization of the urine before manipulation and continuation of antimicrobial therapy for 3 to 7 days after manipulation can pre-vent serious morbidity and even mortality from urosepsis.
	2.	Because of the broad range of infecting pathogens and their varying sensitivity patterns, culture data are essential in prescribing therapy for symptomatic patients. If therapy should be needed before such information is available, initial therapy must encompass a far broader spectrum than that used in other groups of patients. Thus, in a patient with apparent pyelonephritis or urosepsis in a complicated setting, initial therapy with regimens such as ampicillin plus gentamicin, imipenem-cilastatin, or piperacillin-tazobactam is indicated. In the patient who is more subacutely ill, a fluoroquinolone appears to be a reasonable first choice.
	3.	Every effort should be made to correct the underlying complicating factor, whenever possible, in conjunction with the antimicrobial therapy. If this is possible, a prolonged 4- to 6-week “curative” course of therapy in conjunction with the surgical manipulation is appropriate. If such correction is not possible, shorter courses of therapy (7–14 days), aimed at controlling symptoms, appear to be more appropriate. Frequent symptomatic relapses are worth an attempt at long-term suppressive therapy.

A particular subgroup of patients susceptible to complicated UTI is those with neurogenic bladders secondary to spinal cord injury. In these, intermittent self-catheterization with clean catheters and methenamine prophylaxis have been shown to decrease the morbidity associated with UTI.^{[253] [417] [418] [419] [420]}

Catheter-Associated Urinary Tract Infection

Infections of the urinary tract are by far the most common cause of hospital-acquired infection. Most such nosocomial UTIs are due to the use of bladder catheters. More than 900,000 episodes of catheter-associated bacteriuria occur in acute care hospitals in the United States each year. Approximately 2% to 4% of these patients develop gram-negative sepsis, and such events can contribute to the mortality of patients.^{[41] [421] [422]}

The development of a biofilm on the surface of the catheter is important in determining the effectiveness of antibiotic treatment of catheter-associated UTI. Bacteria adhering to the surface of the catheter initiate the formation of a complex biologic structure containing the bacteria, bacterial glycocalices, Tamm-Horsfall protein, apatite, struvite, and other constituents. This structure protects bacteria from antimicrobial therapy, which leads to prompt relapse once therapy is stopped. Thus, replacement of the bladder catheter should be part of the treatment of catheter-associated UTI, when treatment is believed to be indicated.^{[41] [422] [423] [424]}

Although bacteriuria is inevitable with long-term catheterization, certain guidelines can be employed to delay the onset of such infections and to minimize the rate of acquisition of antibiotic-resistant pathogens ( Table 34-5 ). Critically important in this regard are sterile insertion and care of the catheter, use of a closed drainage system, and prompt removal. Isolation of patients with catheter-associated bacteriuria from other patients with indwelling bladder catheters will also decrease the spread of infection. Whether such additions as silver ion-coated catheters, the use of disinfectants in collecting bags, and other local strategies offer additional benefit is still unclear, although topical meatal care with povidone-iodine may be useful. Systemic antimicrobial therapy can delay the onset of bacteriuria and can be useful in those clinical situations in which the time of catheterization is clearly limited (e.g., in association with gynecologic or vascular surgery and kidney transplantation).^{[41] [422] [425] [426] [427] [428]}

TABLE 34-5 -- Guidelines for Bladder Catheter Care to Prevent Infection

	1.	Use catheter only when absolutely necessary; remove as soon as possible.
	2.	Insert catheters aseptically and maintain by trained personnel only; the use of “catheter teams” is preferable.
	3.	A sterile closed drainage system is mandatory. The catheter and drainage tube must never be disconnected except when irrigation is necessary to relieve obstruction. Strict aseptic technique is employed under these circumstances.
	4.	Urine for culture should be obtained by aspirating the catheter with a 21-gauge needle after the catheter is prepared with povidone-iodine.
	5.	Maintain downhill, unobstructed flow, with the collection bag always below the level of the bladder and emptied at frequent intervals.
	6.	Replace indwelling catheters when obstruction or concretions are demonstrated.
	7.	Separate catheterized patients whenever possible; in particular, a patient with a sterile bladder catheter system should always be kept separate from patients with infected urine, and strict hand-washing procedures should be observed by staff caring for these patients.

Modified from Kaye D, Santoro J: Urinary tract infection. In Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases. New York, John Wiley & Sons, 1979. Copyright 1979 John Wiley & Sons. Reprinted by permission of John Wiley & Sons, Inc.

Treatment of catheter-associated UTI requires good clinical judgment. In any patient symptomatic from the infection (e.g., exhibiting fever, chills, dyspnea, and hypotension), immediate therapy with effective antibiotics is indicated, with use of the same antimicrobial strategies described earlier for other forms of complicated UTI. In an asymptomatic patient, no therapy is indicated. Patients with long-term indwelling catheters rarely become symptomatic unless the catheter is obstructed or is eroding through the bladder mucosa. In those patients who do become symptomatic, antibiotics should be given and close attention should be directed to changing the catheter or changing the type of urinary drainage.

Candidal Infection of the Urinary Tract

Clear-cut guidelines for the treatment of candidal infection of the urinary tract are not available, particularly because there are no criteria that are generally accepted to distinguish between colonization and infection.^[429] Until more information is available, the following approach is the one that we currently advocate:

	1.	In patients with catheter-associated candidal UTI, removal of the preceding catheter, insertion of a three-way catheter, and infusion of an amphotericin rinse for a period of 3 to 5 days appear to have a greater than 50% success rate in eradicating this infection. Success is increased if such contributing factors as hyperglycemia, corticosteroid use, and antibacterial therapy can be eliminated.^[430]
	2.	In patients with candiduria without an indwelling catheter, insertion of a catheter for an amphotericin rinse appears to introduce another hazard, the risk of bacteriuria. Our preference is to treat such patients with fluconazole, 200 to 400 mg/day for 10 to 14 days. Oral fluconazole therapy is at least as effective as amphotericin rinses in the manage-ment of candiduria.^{[430] [431] [432]} In a population of organ transplant patients, such an approach has been successful in more than 75% of patients with candiduria.^{[433] [434] [435]}
	3.	Any patient with candiduria who is to undergo instrumentation of the urinary tract requires systemic therapy with amphotericin or fluconazole to prevent the consequences of transient candidemia.

SPECIAL FORMS OF PYELONEPHRITIS

Renal Tuberculosis

Approximately 10% of the new cases of tuberculosis reported annually are extrapulmonary, with the genitourinary tract being the most common site of extrapulmonary tuberculosis.^{[15] [436] [437] [438]} Unfortunately, many cases of renal tuberculosis remain clinically silent for years while irreversible renal destruction takes place. Thus, unexplained “sterile” pyuria or hematuria should prompt the clinician to undertake an evaluation for renal tuberculosis.^[15]

Genitourinary tuberculosis usually results from “silent” bacillemia accompanying pulmonary tuberculosis. However, active lesions in the kidney may not become manifest clinically for many years, often at a time when little evidence of active pulmonary disease exists. If routine screening of urine specimens for tubercle bacilli is undertaken in a group of patients hospitalized specifically for active pulmonary infection, a number of silent urinary infections is detected.^[15] In the general population, symptoms referable to the urinary tract rather than the lung are those most likely to cause the patient with renal tuberculosis to visit the physician. In one series describing 41 cases of genitourinary tuberculosis observed from 1962 through 1974,^[436] concomitant pulmonary findings were present in only 66% of newly diagnosed cases of genitourinary tuberculosis. In the same series, dysuria (34%), hematuria (27%), flank pain (10%), and pyuria (5%) were the most frequent presenting symptoms for active urinary tuberculosis. Constitutional symptoms occurred in only 14% of cases, and no symptoms attributable to tuberculosis could be elicited in 20% of patients. An abnormal urinalysis was found in well over half these cases. A positive skin test result (purified protein derivative) was present in 95% of cases, and urine cultures grew Mycobacterium tuberculosis in 90%. Excretory urograms were abnormal in 93% of patients examined. Thus, genitourinary tuberculosis should not be a difficult diagnosis to make if patients with localizing urinary symptoms plus abnormal urinalyses are screened for tuberculosis after routine urine cultures have been found to be negative. The pathologic changes—granulomatous inflammation and caseous necrosis—often (but not always) begin in the medulla and papilla, causing papillary necrosis, but soon involve the cortex and occasionally the perirenal tissues. Coalescence of the lesions sometimes leads to large caseous cavities.

Radiographic examinations are rarely pathognomonic for renal tuberculosis, but the intravenous urogram and CT scan may be helpful in the differential diagnosis of tuberculosis from other infectious and granulomatous entities. The gross strictures, cavities, and calcifications of advanced renal tuberculosis are distinctive.^[15]

Recommendations for the treatment of genitourinary tuberculosis are as follows^[15]:

	1.	Uncomplicated urinary tract tuberculosis, likely to be due to drug-sensitive organisms, is well treated with an initial 2 months of daily rifampin, isoniazid, and pyrazinamide followed by 4 months of daily rifampin and isoniazid. Such a regimen is particularly useful in women. In men, in whom concern regarding sequestered foci within the prostate is an issue, we prefer to continue such a program for an additional 3 to 6 months. If pyrazinamide is not tolerated, rifampin and isoniazid therapy for 9 months is recommended for women, with a preference for an additional 3 to 6 months in men.
	2.	There is little published experience with these relatively short regimens in patients with caseating destruction of the kidneys or in men with overt genital disease. In such instances, we would prefer to prolong the isoniazid and rifampin components so that a minimum of 12 to 18 months of therapy with at least two bactericidal agents is delivered.
	3.	Anyone with possible drug-resistant tuberculosis should have therapy instituted with isoniazid, rifampin, and pyrazinamide to ensure the use of at least two bactericidal agents, plus one of the following: ethambutol, ofloxacin, or streptomycin. Once drug sensitivity results are available, the regimen can be modified accordingly. If two bactericidal agents can be employed, we prefer a minimum of 12 months of therapy in patients with drug-resistant disease. If only one bactericidal agent plus ethambutol is possible, a minimum of 24 months of therapy is recommended.
	4.	Preliminary experience with the treatment of tuberculosis in the setting of AIDS suggests that 9 to 12 months of therapy may be adequate, particularly with the initial 2 months of isoniazid, rifampin, and pyrazinamide being part of this regimen. However, the possibility of relapse in this population of immunocompromised patients must be considered. In selected patients with progressive AIDS, longer courses of therapy or reinstitution of therapy should be considered.
	5.	In patients who cannot tolerate at least two of the three primary bactericidal agents because of side effects, one bactericidal agent plus a second agent such as ethambutol should be used for a period of 24 months.

Additional issues that should be addressed include the following: Antimicrobial sensitivity testing should be carried out on all primary isolates (owing to the increase in drug-resistant tuberculosis in more recent years); proof of cure must be documented by culture; and follow-up urograms or ultrasound examinations must be performed to rule out the development of obstructive uropathy as a consequence of the healing process. Such a development would obligate surgical correction to salvage renal function.^[15]

Xanthogranulomatous Pyelonephritis

Xanthogranulomatous pyelonephritis is a form of chronic bacterial pyelonephritis characterized by the destruction of renal parenchyma and the presence of granulomas, absce-sses, and collections of lipid-filled macrophages (foam cells).^{[439] [440] [441] [442] [443] [444]}

Although the disease remains uncommon, accounting for 6 in 1000 surgically proven cases of chronic pyelonephritis, it has apparently increased in frequency in more recent years.^[439] It occurs at any age, from 11 months to 89 years, but is most common in adults in the 5th through the 7th decades. Women are affected more often than men (2:1), and except in a rare patient with bilateral disease, the lesions affect only one kidney. Most patients present with renal pain, recurrent UTI, fever (of undetermined nature), malaise, anorexia, weight loss, and constipation. Duration of treatment before diagnosis is between 3 months and 9 years. Seventy-three percent of patients have a history of previous calculous disease, obstructive uropathy, or diabetes mellitus, and 38% have undergone urologic procedures. A renal mass is present in 60% of cases and hypertension in about 40%.^{[443] [445]}

In gross appearance, the kidney is usually enlarged, and the capsule and perirenal tissue are often thickened and adherent. The process may be localized to one tumor mass involving one pole of the kidney or may be diffuse and multifocal. On section, the pelvis and calices are dilated and contain either purulent fluid or calculi (often staghorn calculi) or both. The renal parenchyma, particularly surrounding the dilated calices, is replaced by orange-yellow, soft inflammatory tissue, often with surrounding small abscesses. The tumor can be mistaken grossly for renal cell carcinoma, but the presence of calculi, obstruction, abscesses, and purulent material and the localization of yellow tissue adjacent to the pelvis and calices points to an inflammatory disorder ( Fig. 34-14 ). However, there have been reports of coexistent renal cell carcinoma in the same or contralateral kidney, as well as a transitional cell carcinoma of the renal pelvis.^{[446] [447] [448] [449] [450] [451]}



FIGURE 34-14 Xanthogranulomatous pyelonephritis, localized form. The orange-yellow granulomatous mass surrounds a black calculus (arrow) in a caliceal diverticulum. Note resemblance to renal cell carcinoma.

On microscopic examination, the orange-yellow areas are made up of inflammatory tissue consisting of an admixture of large foamy macrophages, smaller macrophages with granular cytoplasm, neutrophils, lymphocytes, plasma cells, and fibroblasts. Neutrophils and necrotic debris are particularly abundant surrounding the pelvic mucosa. An occasional foreign body giant cell may be present. The cytoplasm of the foamy macrophages and particularly of the small granular monocytes stains strongly with PAS.^[443]

The radiographic picture is varied. The heterogeneous pattern is due to diverse combinations of localized or diffuse lesions; the radiologic appearance depends on the presence of obstruction, calculi, or other anomalies. On excretory urograms, a stone-bearing, nonfunctioning kidney is present in about 80% of cases. Caliceal deformity and irregularity are also common, particularly in the diffuse type. The localized lesions appear as cystic or cavitary masses that show no “puddling” of contrast medium. On angiograms, most xanthogranulomatous renal masses are hypovascular or avascular. There is spreading of intrarenal arteries without peripheral arborization, but usually there are no pathologic vessels; however, some cases have shown increased vascularity. Furthermore, the avascular solitary mass of xanthogranulomatous pyelonephritis cannot be definitively distinguished from necrotic avascular adenocarcinoma by angiography alone. CT is helpful in the diagnosis and particularly in identifying extension of the inflammation to the perirenal fat. MRI may also aid in the diagnosis.^{[449] [450] [451] [452]}

The diagnosis of xanthogranulomatous pyelonephritis should be considered in patients with a history of chronic infection and certain radiologic features. The radiologic findings include unilateral renal enlargement; a nonfunctioning kidney on intravenous urogram; the presence of renal calculi, ureteral calculi, or both; angiographic demonstration of an avascular mass or masses with stretched attenuated intrarenal vessels, prominent capsular periureteric vessels, and an irregular impaired nephrogram with prominent avascular areas; and suggestive changes by CT or MRI. With these features, some 40% of cases can be diagnosed or suspected preoperatively.^[452]

Bacterial cultures of the urine are almost invariably positive. P. mirabilis and E. coli are the organisms that are most commonly cultured.^[453] Series reporting a high frequency of E. coli also showed a low frequency of staghorn calculi. Methicillin-resistant S. aureus can also cause the condition.^[454]

The pathogenesis of xanthogranulomatous pyelonephritis is unclear, although it seems certain that the condition is caused by bacterial infection and accentuated by urinary obstruction. Similar cells with PAS reaction-positive granules have been produced by Proteus, E. coli, and staphylococcal infection in rats. Electron microscopy shows that the foamy macrophages initially contain bacteria and subsequently contain numerous phagolysosomes filled with myelin figures and amorphous material.^[455] The presence of these phagolysosomes has suggested that there may be a lysosomal defect of macrophages that interferes with the digestion of bacterial products.^[456]

Most kidneys with xanthogranulomatous pyelonephritis are removed surgically, largely because a correct preoperative diagnosis is made infrequently, but studies suggest that diagnosis by a combination of clinical and radiologic features is possible in 40% of cases. In the focal disease, unnecessary radical surgery may be prevented in the poor-risk patient. Recurrences in the other kidney have not been reported after surgery.^{[455] [456] [457] [458]} The disease has also been reported in transplant recipients.

Malakoplakia

Malakoplakia is a rare, histologically distinct inflammatory reaction usually caused by enteric bacteria and affecting many organs but most commonly the urinary tract. In most cases, the condition is confined to the urinary bladder mucosa, where it appears as soft, yellow, slightly raised, often-confluent plaques 3 to 4 cm in diameter. It is most common in middle-aged women with chronic UTI. The microscopic picture is typical. Plaques are composed of closely packed, large macrophages with occasional lymphocytes and multinucleate giant cells. The macrophages have abundant, foamy, PAS reaction-positive cytoplasm; in addition, laminated mineralized concretions, known as Michaelis-Gutmann bodies, are typically present within macrophages and in the interstitial tissue. The Michaelis-Gutmann bodies measure 4 to 10 cm in diameter, stain strongly with PAS, and contain calcium ( Fig. 34-15 ). On electron microscopic studies, they show a typical crystalline structure with a central dense core, an intermediate halo, and a peripheral lamellated ring. Intracellular bacteria and giant phagolysosomes can be demonstrated within macrophages.^{[459] [460]}



FIGURE 34-15 Michaelis-Gutmann bodies of malakoplakia (arrow).

Identical lesions have been discovered in the prostate, ureteral and pelvic mucosa, bones, lungs, testes, gastrointestinal tract, skin, and kidneys. Renal malakoplakia occurs in the same clinical setting as xanthogranulomatous pyelonephritis—chronic infection and obstruction—and indeed, except for the presence of Michaelis-Gutmann bodies, there is considerable overlap in the gross histologic features of both conditions. E. coli is the most common organism cultured from urine. Clinical findings usually include flank pain and signs of active renal infection. Bilateral involvement has been reported, as has a clinical presentation simulating acute renal failure.^[461]

The pathogenesis of malakoplakia is unclear, but about half of the cases are associated with immunodeficiency or autoimmune disorders, including hypogammaglobulinemia, therapeutic immunosuppression, malignant neoplasms, chronic debilitating disorder, rheumatoid arthritis, and AIDS.^[459] One scenario is that the lesions result from a defect in macrophage function that blocks the lysosomal enzymatic degradation of engulfed bacteria and overloads the cytoplasm with undigested bacterial debris. Microtubule defects impairing the movement of lysosomes to phagocytic vacuoles and decreased lysosomal enzyme release within phagocytes have been postulated.^{[462] [463]} The Michaelis-Gutmann bodies are thought to result from the deposition of calcium phosphate and other minerals on these overloaded phagosomes.

Another histologic entity that overlaps with both malakoplakia and xanthogranulomatous pyelonephritis is so-called megalocytic interstitial nephritis; in this variant, the interstitial infiltrate is polymorphous with predominance of histiocytes containing crystalloid material.^[463]

References

1. Heptinstall RH: The enigma of chronic pyelonephritis. J Infect Dis 1969; 120:104.

2. Rubin RH, Shapiro ED, Andriole VT, et al: Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Clin Infect Dis 1992; 5:S216.

3. Hooton TM, Stamm WE: Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997; 11:551.

4. Vosti KL: Infections of the urinary tract in women. Medicine (Baltimore) 2002; 81:369.

5. Lifshitz E, Kramer L: Outpatient urine culture. Arch Intern Med 2000; 160:2537.

6. Stamm WE: Measurement of pyuria and its relation to bacteriuria. Am J Med 1983; 75:53.

7. Stamm WE: Diagnosis of coliform infection in acutely dysuric women. N Engl J Med 1982; 307:463.

8. Tambyah PA, Maki DG: The relationship between pyuria and infection in patients with indwelling urinary catheters. Arch Intern Med 2000; 160:673.

9. Foxman B, Brown P: Epidemiology of urinary tract infections. Transmission and risk factors, incidence and cost. Infect Dis Clin North Am 2003; 17:227.

10. Latham RH, Running K, Stamm WE: Urinary tract infections in young women caused by Staphylococcus saprophyticus.. JAMA 1983; 250:3063.

11. Pead L, Marshall R, Morris J: Staphylococcus saprophyticus as a urinary pathogen: A six-year perspective survey. BMJ 1985; 291:1157.

12. Marrie TJ, Kwan C, Noble MA, et al: Staphylococcus saprophyticus as a cause of urinary tract infections. J Clin Microbiol 1982; 16:427.

13. Cascio S, Colhoun E, Puri P: Bacterial colonization of the prepuce in boys with vesicoureteral reflux who receive antibiotic prophylaxis. J Pediatr 2001; 139:160.

14. Schoen EJ, Colby CJ, Ray GT: Newborn circumcision decreases incidence and costs of urinary infections during the first year of life. Pediatrics 2000; 105:441.

15. Pasternack MS, Rubin RH: Urinary tract tuberculosis. In: Schrier RW, Gottschalk CW, ed. Diseases of the Kidney, 7th ed. Philadelphia: Lippincott Williams and Wilkins; 2001:1017-1040.

16. Wu VC, Fang CC, Li WY, et al: Candida tropicalis-associated bilateral renal papillary necrosis and emphysematous pyelonephritis. Clin Nephrol 2004; 62:473.

17. Ang BSP, Telenti A, King B, et al: Candidemia from a urinary tract source: Microbiological aspects and clinical significance. Clin Infect Dis 1993; 17:662.

18. Scerpella EG, Alhalel R: An unusual cause of acute renal failure: Bilateral ureteral obstruction due to Candida tropicalis fungus balls. Clin Infect Dis 1994; 18:440.

19. Rubin RH: Infection in the organ transplant patient. In: Rubin RH, Young LS, ed. Clinical Approach to Infection in the Compromised Host, 4th ed. New York: Kluwer/Academic/Plenum; 2002:629.

20. Edwards Jr JE, Lehrer RI, Stiehm ER, et al: Severe candidal infections: Clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann Intern Med 1978; 89:91.

21. Rubin RH: Mycotic infections. In: Dale DC, ed. The Scientific American Textbook of Medicine, New York: Scientific American; 2000:1-5.

22. Randall Jr RE, Story WK, Toone EC, et al: Cryptococcal pyelonephritis. N Engl J Med 1968; 279:60.

23. Kim SS, Hicks J, Goldstein SL: Adenovirus pyelonephritis in a pediatric renal transplant patient. Pediatr Nephrol 2003; 18:457.

24. Walter EA, Bowden RA: Infection in the bone marrow transplant recipient. Infect Dis Clin North Am 1995; 9:823.

25. Moreno E, Planells I, Prats G, et al: Comparative study of Eschericia coli virulence determinants in strains causing urinary tract bacteremia versus strains causing pyelonephritis and other sources of bacteremia. Diagn Microbiol Infect Dis 2005; 53:93.

26. Sobel JD: Pathogenesis of urinary tract infection: Role of host defenses. Infect Dis Clin North Am 1997; 11:531.

27. O'Hanley P, Lark P, Falkow S, Schoolnik G: Molecular basis of Escherichia coli colonization of the upper urinary tract in BALB/c mice. J Clin Invest 1985; 75:347.

28. Barnes RC, Diafuku R, Roddy RE, et al: Urinary tract infection in sexually active homosexual men. Lancet 1986; 1:171.

29. Johnson JR: Microbial virulence determinants and the pathogenesis of urinary tract infection. Infect Dis Clin North Am 2003; 17:261.

30. Svanborg C, Jodal U: Host-parasite interaction in urinary tract infection. In: Brumfitt W, Hamilton-Miller JMT, Bailey RR, ed. Urinary Tract Infections, London: Chapman & Hall; 1998:87.

31. Stapleton A, Stamm WE: Prevention of urinary tract infection. Infect Dis Clin North Am 1997; 11:719.

32. Hooten TM, Scholes D, Stapleton AE, et al: A perspective study of asymptomatic bacteriuria in sexually active women. N Engl J Med 2000; 343:1037.

33. Stapleton A, Nudelman E, Clausen H, et al: Binding of uropathogenic Escherichia coli R45 to glycolipids extracted from vaginal epithelial cells is dependent on histo-blood group secretor status. J Clin Invest 1992; 90:965.

34. Kinane DF, Blackwell CC, Brettle RF, et al: ABO blood group, secretor state and susceptibility to recurrent urinary tract infection in women. BMJ 1981; 285:7.

35. Lomberg H, Hellstrom M, Jodal U, Svangorg-Eden C: Secretor state and renal scarring in girls with recurrent pyelonephritis. FEMS Immunol Med Microbiol 1989; 47:371.

36. Scholes D, Hooten TM, Roberts PL, et al: Risk factors for recurrent urinary tract infection in young women. J Infect Dis 2000; 182:1177.

37. Hopkins WJ, Elkahawaji JE, Heisey DM, Ott CJ: Inheritance of susceptibility to induced Escherichia coli bladder and kidney infections in female C3H/HeJ mice. J Infect Dis 2003; 187:418.

38. Hooten TM: Pathogenesis of urinary tract infection: An update. J Antimicrob Chemother 2000; 46(Suppl A1):

39. Spach DH, Stapleton AE, Stamm WE: Lack of circumcision increases the risk of urinary tract infection in young men. JAMA 1992; 267:679.

40. Lipsky BA: Urinary tract infections in men: Epidemiology, pathophysiology, diagnosis, and treatment. Ann Intern Med 1989; 110:138.

41. Stamm WE, Hooton TM: Management of urinary tract infections in adults. N Engl J Med 1993; 329:1328.

42. Ulleryd P, Lincoln K, Scheutz F, Sandberg T: Virulence characteristics of Escherichia coli in relation to host response in men with symptomatic urinary tract infection. Clin Infect Dis 1994; 18:579.

43. Fair WR, Timothy MM, Churg HD: Antibacterial nature of prostatic fluid. Nature 1968; 218:444.

44. Foxman B, Manning SD, Tallman P, et al: Uropathogenic Escherichia coli are more likely than commensal strains to be shared between heterosexual sex partners. Am J Epidemiol 2002; 156:1133.

45. Ruiz J, Simon K, Horcajada JP, et al: Differences in virulence factors among clinical isolates of Escherichia coli causing cystitis and pyelonephritis in women and prostatitis in men. J Clin Microbiol 2002; 40:4445.

46. Kelsey MC, Mead MG, Gruneberg RN, Oriel JD: Relationship between sexual intercourse and urinary tract infection in women attending a clinic for sexually transmitted diseases. J Med Microbiol 1979; 12:511.

47. Nicolle LE, Harding GKM, Preiksaitis J, Ronald AR: The association of urinary tract infection with sexual intercourse. J Infect Dis 1982; 146:579.

48. Vosti KL: Recurrent urinary tract infections: Prevention by prophylactic antibiotics after sexual intercourse. JAMA 1975; 231:934.

49. Stamm WE: An epidemic of urinary tract infection?. N Engl J Med 2001; 345:1055.

50. Svanborg C, Bergsten G, Fischer H, et al: The “innate” host response protects and damages the infected urinary tract. Ann Med 2001; 33:563.

51. Gargan RA, Hamilton-Miller JMT, Brumfitt W: Effect of alkalinisation and increased fluid intake on bacterial phagocytosis and killing in urine. Eur J Clin Microbiol Infect Dis 1993; 12:534.

52. Wold AE, Mestecky J, Svanborg C: Agglutination of Escherichia coli by secretory IgA: A result of interaction between bacterial mannose-specific adhesins and immunoglobulin carbohydrate. Monogr Allergy 1988; 24:307.

53. Mannhardt W, Becker A, Putzer M, et al: Host defense within the urinary tract: I. Bacterial adhesion initiates a uroepithelial defense mechanism. Pediatr Nephrol 1996; 10:568.

54. Mannhardt W, Putzer M, Zepp F, Schulte-Wissermann H: Host defense within the urinary tract: II. Signal transducing events activate the uroepithelial defense. Pediatr Nephrol 1996; 10:573.

55. Jahnukainen T, Chen M, Celsi G: Mechanism of renal damage owing to infection. Pediatr Nephrol 2005; 20:1043.

56. Mabeck CE: Treatment of uncomplicated urinary tract infection in nonpregnant women. Postgrad Med 1972; 48:69.

57. Majd M, Rushton HG: Renal cortical scintigraphy in the diagnosis of acute pyelonephritis. Semin Nucl Med 1992; 22:97.

58. Rushton HG, Massoud M, Jantausch B, et al: Renal scarring following reflux and nonreflux pyelonephritis in children: Evaluation with 99m-technetium-dimercaptosuccinic acid scintigraphy. J Urol 1992; 147:1327.

59. Lin KY, Chiu NT, Chen MJ, et al: Acute pyelonephritis and sequelae of renal scar in pediatric first febrile urinary tract infection. Pediatr Nephrol 2003; 18:362.

60. Sweeney B, Cascio S, Velayudam M, Puri P: Reflux nephropathy in infancy: A comparison of infants presenting with and without urinary tract infection. J Urol 2001; 62:1090.

61. Rushton HG: Urinary tract infections in children. Epidemiology, evaluation, and management. Pediatr Clin North Am 1997; 44:1133.

62. Elder JS, Peters CA, Arant Jr BS, et al: Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846.

63. Kanematsu A, Yamamoto S, Yoshino K, et al: Renal scarring is associated with nonsecretion of blood type antigens in children with primary vesicoureteral reflux. J Urol 2005; 174:1594.

64. Blumenthal I: Vesicoureteric reflux and urinary tract infection in children. Postgrad Med J 2006; 82:31.

65. Choi YD, Yang WJ, Do SH, et al: Vesicoureteral reflux in adult women and uncomplicated acute pyelonephritis. Urology 2005; 66:55.

66. Giel DW, Noe HN, Williams MA: Ultrasound screening of asymptomatic siblings of children with vesicoureteral reflux: A long-term follow-up study. J Urol 2005; 174:1602.

67. Steele B, Robtaille P, DeMaria J, Grignon A: Follow-up evaluation of a prenatally recognized vesicoureteric reflux. J Pediatr 1989; 115:95.

68. Burge DM, Griffiths MD, Malone PS, Atwell JD: Fetal vesicoureteral reflux: Outcome following conservative postnatal management. J Urol 1992; 148:1743.

69. Tullus K, Winberg J: Urinary tract infections in children. In: Brumfitt W, Hamilton-Miller JMT, Bailey RR, ed. Urinary Tract Infections, London: Chapman & Hall; 1998:175.

70. Noe HN: The role of dysfunctional voiding in failure or complication of ureteral implantation for primary reflux. J Urol 1985; 134:1172.

71. Griffiths JD, Scholtmeiger RJ: Vesicoureteral reflux and lower urinary tract dysfunction: Evidence for 2 different reflux/dysfunction complexes. J Urol 1987; 137:240.

72. Hoberman A, Charron M, Hickey RW, et al: Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003; 348:195.

73. Parkhouse HF, Barratt TM, Dillon MJ, et al: Long-term outcome of boys with posterior urethral valves. Br J Urol 1988; 62:59.

74. Chand OH, Rhodes T, Poe SR, et al: Incidence and severity of vesicoureteral reflux in children related to age, race and diagnosis. J Urol 2003; 170:1548.

75. Dejter Jr SW, Gibbons MD: The fate of infant kidneys with fetal hydronephrosis but initially normal postnatal sonography. J Urol 1989; 142:661.

76. Elder JS: Commentary: Importance of antenatal diagnosis of vesicoureteral reflux. J Urol 1992; 148:1750.

77. Ring E, Petritsch P, Riccabona M, et al: Primary vesicoureteral reflux in infants with a dilated fetal urinary tract. Eur J Pediatr 1993; 152:523.

78. Zerin JM, Ritchey ML, Chang AC: Incidental vesicoureteral reflux in neonates with antenatally detected hydronephrosis and other renal abnormalities. Radiology 1993; 187:157.

79. Chertin B, Puri P: Familial vesicoureteral reflux. J Urol 2003; 169:1804.

80. Vesicoureteric reflux: All in the genes? Report of a meeting of physicians at the Hospital for Sick Children, Great Ormond Street, London (clinical conference). Lancet 1996; 348:725.

81. Buonomo C, Treves ST, Jones B, et al: Silent renal damage in symptom-free siblings of children with vesicoureteral reflux: Assessment with technetiun Tc 99m dimercaptosuccinic acid scintigraphy. J Pediatr 1993; 122:721.

82. Chapman CJ, Bailey RR, Janus ED: Vesicoureteral reflux: Segregation analysis. Am J Med Genet 1985; 20:577.

83. Smellie JM, Edwards D, Hunter N, et al: Vesico-ureteric reflux and renal scarring. Kidney Int 1975; 8:S65.

84. Shah KJ, Robins DG, White RHR: Renal scarring and vesicoureteric reflux. Arch Dis Child 1978; 53:210.

85. Chapman SG, Chantler G, Haycock GB, et al: Radionuclide cystography in vesicoureteric reflux. Arch Dis Child 1988; 63:650.

86. International Reflux Study Committee : Medical versus surgical treatment of primary vesicoureteral reflux: Prospective International Reflux Study in Children. J Urol 1981; 125:277.

87. Lerner GR, Fleischman LE, Perlmutter AD: Reflux nephropathy. Pediatr Clin North Am 1987; 34:747.

88. Smellie JM, Normand ICS: Bacteriuria, reflux and renal scarring. Arch Dis Child 1975; 50:581.

89. Smellie JM, Normand ICS: Reflux nephropathy in childhood. In: Hodson CJ, Kincaid-Smith P, ed. Reflux Nephropathy, New York: Masson; 1978:14.

90. Greenfield SP, Wan J: Vesicoureteral reflux: Practical aspects of evaluation and management. Pediatr Nephrol 1996; 10:789.

91. Wennerstrom M, Mansson S, Jodal U, Stokland E: Primary and acquired renal scarring in boys and girls with urinary tract infection. J Pediatr 2000; 136:30.

92. Smellie JM, Prescod NP, Shaw PJ, et al: Childhood reflux and urinary tract infection: A follow-up of 10-41 years in 226 adults. Pediatr Nephrol 1998; 12:729.

93. Smellie JM, Normand IC, Katz G: Children with urinary tract infection: Comparison of those with and without vesicoureteric reflux. Kidney Int 1981; 20:717.

94. Caione P, Ciofetta G, Collura G, et al: Renal damage in vesico-ureteric reflux. BJU Int 2004; 93:591.

95. Bergstrom T, Larson H, Lincoln K, Winberg J: Studies of urinary tract infection in infancy and childhood: 1280 patients with neonatal infection. J Pediatr 1972; 80:858.

96. Rolleston GL, Maling TMJ, Hodson CJ: Intrarenal reflux and the scarred kidney. Arch Dis Child 1974; 49:531.

97. Guarino N, Casamassima MG, Todine B, et al: Natural history of vesicoureteral reflux associated with kidney anomalies. Urology 2005; 65:1208.

98. Rose JS, Glassberg KI, Waterhouse K: Intrarenal reflux and its relationship to renal scarring. J Urol 1975; 113:400.

99. Ransley PF: Intrarenal reflux: Anatomical, dynamic and radiological studies (part I). Urol Res 1977; 5:61.

100. Ransley PG, Risdon RA: Renal papillary morphology in infants and young children. Urol Res 1977; 3:111.

101. Ransley PG, Risdon RA: The pathogenesis of reflux nephropathy. Contrib Nephrol 1979; 16:90.

102. Ransley PG, Risdon RA: The renal papilla, intrarenal reflux, and chronic pyelonephritis. In: Hodson CJ, Kincaid-Smith P, ed. Reflux Nephropathy, New York: Masson; 1979:126.

103. Tamminen TE, Kaprio EA: The relation of the shape of the renal papilla and of collecting duct openings to intrarenal reflux. Br J Urol 1977; 49:345.

104. Bailey RR: Long-term follow-up of infants with gross vesicoureteric reflux. Contrib Nephrol 1984; 39:146.

105. Ransley PG, Risdon RA, Godley ML: High-pressure sterile vesicoureteral reflux and renal scarring: An experimental study in the pig and minipig. Contrib Nephrol 1984; 39:320.

106. Heptinstall RH, Hodson CJ: Pathology of sterile reflux in the pig. Contrib Nephrol 1984; 39:344.

107. Jorgensen TM, Olsen S, Djurhuus JC, Norgaard JP: Renal morphology in experimental vesicoureteric reflux in pigs. Scand J Urol Nephrol 1984; 18:49.

108. (VUR + IRR) + UTI = CPN. Editorial. Lancet 1978; 2:301.

109. Bishop MC, Moss SW, Oliver O, et al: The significance of vesicoureteral reflux in non-pyelonephritic patients supported by long-term hemodialysis. Clin Nephrol 1977; 8:354.

110. Smellie JM, Edwards D, Normand ICS, Prescod N: Effect of VUR on renal growth in children with urinary tract infection. Arch Dis Child 1981; 56:593.

111. Smellie JM, Normand ICM, Katz G: Children with urinary infection: A comparison of those with and without VUR. Kidney Int 1981; 20:717.

112. Holland NH, Jackson EC, Kazee M, et al: Relation of urinary tract infection and vesicoureteral reflux to scars: Follow-up of thirty-eight patients. J Pediatr 1990; 116:S65.

113. Ransley PG, Risdon RA, Godley ML: Effects of vesicoureteric reflux on renal growth and function. Br J Urol 1987; 60:193.

114. Johnson JR: Microbial virulence determinants and the pathogenesis of urinary tract infection. Infect Dis Clin North Am 2003; 17:261.

115. Svanborg Eden C, Hausson S, Jodal U, et al: Host-parasite interaction in the urinary tract. J Infect Dis 1988; 157:421.

116. Cougant DA, Levin BR, Lidin-Javson G, et al: Genetic diversity and relationship among strains of Escherichia coli in the intestine and those causing urinary tract infections. Prog Allergy 1983; 33:203.

117. Svanborg-Eden C, Hausson S, Jodal Y, et al: Host-parasite interaction in the urinary tract. J Infect Dis 1988; 157:421.

118. Phillips T, Eykyn S, King A, et al: Epidemic multiresistant Escherichia coli infection in West Lambeth health district. Lancet 1988; 1:1038.

119. Tullus K, Korlin K, Svenson SB, et al: Epidemic outbreak of acute pyelonephritis caused by nosocomial spread of P fimbriated Escherichia coli in children. J Infect Dis 1984; 150:728.

120. Svanborg-Eden C, de Man P: Bacterial virulence in urinary tract infection. Infect Dis Clin North Am 1987; 1:731.

121. Kaijser B, Hanson LA, Jodal U, et al: Frequency of E. coli K antigens in urinary tract infections in children. Lancet 1977; 1:663.

122. Schoolnik GK, O'Hanley P, Lark D, et al: Uropathogenic Escherichia coli: Molecular mechanisms of adherence. Adv Exp Med Biol 1987; 224:53.

123. Sandberg T, Stenquist K, Svanborg-Eden C, et al: Host-parasite relationship in urinary tract infections during pregnancy. Prog Allergy 1983; 33:228.

124. Svanborg-Eden C, Hagberg L, Hull R, et al: Bacterial virulence versus host resistance in the urinary tracts of mice. Infect Immun 1987; 55:1224.

125. Falkow S: Molecular Koch's postulates applied to microbial pathogenesis. Rev Infect Dis 1988; 10:5274.

126. Kao JS, Stucker DM, Warren JW, et al: Pathogenicity island sequences of pyelonephritogenic Escherichia coli CFT073 are associated with virulent uropathogenic strains. Infect Immun 1997; 65:2812.

127. Swanson DL, Bukanov NO, Berg DE, et al: Two pathogenicity islands in uropathogenic Escherichia coli J96: Cosmid cloning and sample sequencing. Infect Immun 1996; 64:3736.

128. Guyer DM, Kao JS, Mobley HLT: Genomic analysis of a pathogenicity island in uropathogenic Escherichia coli CFT073. Infect Immun 1998; 66:4471.

129. Lee CA: Pathogenicity islands and the evaluation of bacterial pathogens. Infect Agents Dis 1996; 5:1.

130. Oelschlager TA, Dobrindt U, Hecker J: Pathogenicity islands of uropathic Escherichia coli and the evolution of virulence. Int J Antimicrob Agents 2002; 19:517.

131. Orskov O, Ferencz A, Orskov F: Tamm-Horsfall protein or uromucoid is the normal urinary slime that binds type I fimbriated E. coli.. Lancet 1980; 1:887.

132. Svanborg C, de Man P, Sandberg T: Renal involvement in urinary tract infection. Kidney Int 1991; 39:541.

133. Topley N, Steadman R, Mackenzie R, et al: Type 1 fimbriate strains of Escherichia coli initiate renal parenchymal scarring. Kidney Int 1989; 36:609.

134. Svanborg-Eden C, Hagberg L, Hanson LA, et al: Bacterial adherence: A pathogenetic mechanism in urinary tract infections caused by Escherichia coli.. Prog Allergy 1983; 33:175.

135. Lindberg FP, Lund B, Normark S: Genes of pyelonephritogenic E. coli required for digalactoside-specific agglutination of human cells. EMBO J 1984; 3:1167.

136. Johnson JR, O'Bryan TT, Delavari P, et al: Clonal relationships and extended virulence genotypes among Escherichia coli isolated from women with a first or recurrent episode of cystitis. J Infect Dis 2001; 183:1508.

137. Rasko DA, Phillips JA, Li X, Mobley HL: Identification of DNA sequences from a second pathogenicity island from uropathogenic Escherichia coli CFT073. J Infect Dis 2001; 184:1041.

138. Nou X, Skinner B, Braaten B, et al: Regulation of pyelonephritis-associated pili phase-variation in Escherichia coli: Binding of the PapI and the Lrp regulatory proteins is controlled by DNA methylation. Mol Microbiol 1993; 7:545.

139. Warren JW, Mobley HLT, Donnenberg MS: Host-parasite interactions and host defense mechanisms. In: Schrier RW, ed. Diseases of the Kidney and Urinary Tract, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:903.

140. Blanco M, Blanco JE, Alonso MP, Blanco J: Virulence factors and O groups of Escherichia coli isolates from patients with acute pyelonephritis, cystitis and symptomatic bacteriuria. Eur J Epidemiol 1996; 12:191.

141. Svanborg-Eden C, Gotschlich EC, Korhonen TK, et al: Aspects of structure and function of pili on Escherichia coli.. Prog Allergy 1983; 33:189.

142. Svanborg-Eden C, Bjursten LM, Hull R, et al: Influence of adhesion in the interaction of Escherichia coli with human phagocytes. Infect Immun 1984; 44:407.

143. Otto G, Sandberg T, Marklund BI, et al: Virulence factors and pap genotype in Escherichia coli isolates from women with acute pyelonephritis, with or without bacteremia. Clin Infect Dis 1993; 17:448.

144. Lomberg H, Eden CS: Influence of P blood group phenotype on susceptibility to urinary tract infection. FEMS Microbiol Immunol 1989; 1:363.

145. Johnson JR, Jelacic S, Schoening LM, et al: The IrgA homologue adhesin is an Escherichia coli virulence factor in murine urinary tract infection. Infect Immun 2005; 73:865.

146. Labigne-Roussel A, Falkow S: Distribution and degree of heterogeneity of the afimbrial adhesion encoding operon (afa) among uropathogenic Escherichia coli isolates. Infect Immun 1988; 56:640.

147. Le Bouguenec C, Garcia MI, Ouin V, et al: Characterization of plasmid-borne afa-3 gene clusters encoding afimbrial adhesins expressed by Escherichia coli strains associated with intestinal or urinary tract infections. Infect Immun 1993; 61:5106.

148. Johnson JR: Virulence factors in Escherichia coli urinary tract infection. Clin Microbiol Rev 1991; 4:80.

149. Nowicki B, Truong L, Moulds J, Hull R: Presence of the Dr receptor in normal human tissues and the possible role in pathogenesis of ascending urinary tract infection. Am J Pathol 1988; 133:11.

150. Pham TQ, Goluszko P, Popov V, et al: Molecular cloning and characterization of Dr-II, a nonfimbrial adhesin-I-like adhesin isolated from gestational pyelonephritis-associated Escherichia coli that binds to decay-accelerating factor. Infect Immun 1997; 65:4309.

151. Goluszko P, Moseley SL, Truong LD, et al: Development of experimental model of chronic pyelonephritis with Escherichia coli O75-K5:H-bearing Dr fimbriae: Mutation in the dra region prevented tubulointerstitial nephritis. J Clin Invest 1997; 99:1662.

152. Goluszko P, Popov V, Selvarangan R, et al: Dr fimbriae operon of uropathogenic Escherichia coli mediate microtubule-dependent invasion to the HeLa epithelial cell line. J Infect Dis 1997; 176:158.

153. Yamamoto S, Nakata K, Yuri K, et al: Assessment of the significance of virulence factors of uropathogenic Escherichia coli in experimental urinary tract infection in mice. Microbiol Immunol 1996; 40:607.

154. Tseng CC, Wu JJ, Wang MC, et al: Host and bacterial virulence factors predisposing to emphysematous pyelonephritis. Am J Kidney Dis 2005; 46:432.

155. Manges AR, Dietrich PS, Riley LW: Multidrug-resistant Escherichia coli clonal groups causing community-acquired pyelonephritis. Clin Infect Dis 2004; 38:329.

156. Johnson JR, Kuskowski MA, Gajewski A, et al: Extended virulence genotpes and phylogenetic background of Escherichia coli isolates from patients with cystitis, pyelonephritis, or prostatitis. J Infect Dis 2005; 191:46.

157. Manges AR, Johnson JR, Foxman B, et al: Widespread distribution of urinary tract infections caused by a multidrug-resistant Escherichia coli clonoal group. N Engl J Med 2001; 345:1007.

158. Stamm WE: An epidemic of urinary tract infections?. N Engl J Med 2001; 345:1055.

159. Mills M, Meysick KC, O'Brien AD: Cytotoxic necrotizing factor type 1 of uropathogenic Escherichia coli kills cultured human uroepithelial 5637 cells by an apoptotic mechanism. Infect Immun 2000; 68:58698.

160. Svanborg C, Bergsten G, Fischer H, et al: The “innate” host response protects and damages the infected urinary tract. Ann Med 2001; 33:563.

161. Hedges S, Stenqvist K, Lidin-Janson G, et al: Comparison of urine and serum concentrations of interleukin-6 in women with acute pyelonephritis or asymptomatic bacteriuria. J Infect Dis 1992; 166:653.

162. Ishitoya S, Yamamoto S, Mitsumore K, et al: Non-secretor status is associated with female acute uncomplicated pyelonephritis. BJU Int 2002; 89:851.

163. Wullt B, Bergsten G, Fischer H, et al: The host response to urinary tract infection. Infect Dis Clin North Am 2003; 17:279.

164. Svanborg C, Frendeus B, Godaly G, et al: Toll-like receptor signaling and chemokine receptor expression influence the severity of urinary tract infection. J Infect Dis 2001; 183(suppl 1):561.

165. deMan P, Jodal U, Lincoln K, Svanborg-Eden C: Bacterial attachment and inflammation in the urinary tract. J Infect Dis 1988; 158:29.

166. Frendeus B, Wachtler C, Hedlung M, et al: Escherichia coli P fibriae utilize toll-like receptor 4 pathway for cell activation. Mol Microbiol 2001; 40:37.

167. Anders HJ, Banas B, Schlondorff D: Signaling danger: Toll-like receptors and their potential roles in kidney disease. J Am Soc Nephrol 2004; 15:854.

168. Smithson A, Sarvias MR, Barcelo A, et al: Expression of interleukin-B receptor (CXCR1 and CXCR2) in premenopausal women with recurrent UTI. Clin Diagn Lab Immunol 2005; 12:125.

169. Hang L, Frendeus B, Godaly G, Svanborg C: Interleukin 8 receptor knockout mice have subepithelial neutrophil entrapment and renal scarring following acute pyelonephritis. J Infect Dis 2002; 182:1738.

170. Olszyna DP, Lorquin S, Sewnath M, et al: CXC chemokine receptor 2 contributes to host defense in murine urinary tract infection. J Infect Dis 2001; 184:301.

171. Svanborg C, Hedlund M, Connell H, et al: Bacterial adherence and mucosal cytokine responses: Receptors and transmembrane signaling. Ann N Y Acad Sci 1996; 797:177.

172. Tsubio N, Yoskikai Y, Matsuo S, et al: Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J Immunol 2002; 169:2026.

173. Wolfs TG, Buurman WA, van Schadewijk A, et al: In vivo expression of toll-like receptor 2 and 4 by renal epithelial cells: INF-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol 2002; 168:1286.

174. Benson M, Jodal U, Agace W, et al: Interleukin (IL)-6 and IL-8 in children with febrile urinary tract infection and asymptomatic bacteriuria. J Infect Dis 1996; 174:1080.

175. Kimball P, Reid F: Tumor necrosis factor b gene polymorphisms associated with urinary tract infections after renal transplantation. Transplantation 2002; 73:1110.

176. Cotton SA, Gbadegesin RA, Williams S, et al: Role of TGF-beta1 in renal parenchymal scarring following childhood urinary tract infection. Kidney Int 2002; 61:61.

177. Godaly G, Bergsten G, Hang L, et al: Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection. J Leukocyte Biol 2001; 69:899.

178. Jantausch BA, O'Donnell R, Wiedermann BL: Urinary interleukin 6 and interleukin 8 in children with urinary infection. Pediatr Nephrol 2000; 15:236.

179. Khalil A, Tullus K, Bartfai T, et al: Renal cytokine responses in acute Escherichia coli pyelonephritis in IL-6 deficient mice. Clin Exp Immunol 2000; 122:200.

180. Hedges S, Agace W, Svensson M, et al: Uroepithelial cells are part of a mucosal cytokine network. Infect Immun 1994; 62:2315.

181. Khalil A, Tullus K, Bakhiet M, et al: Angiotensin II type 1 receptor antagonist (losartan) down-regulates transforming growth factor b in experimental acute pyelonephritis. J Urol 2000; 164:186.

182. Andreu A, Stapleton AE, Fennell C, et al: Urovirulence determinants in Escherichia coli strains causing prostatitis. J Infect Dis 1997; 176:464.

183. Terrai A, Yamamoto S, Mitsumori K, et al: Escherichia coli virulence factors and serotypes in acute bacterial prostatitis. Int J Urol 1997; 4:289.

184. Hull RA, Rudy DC, Wieser IE, Donovan WH: Virulence factors of Escherichia coli isolates from patients with symptomatic and asymptomatic bacteriuria and neuropathic bladders due to spinal cord and brain injuries. J Clin Microbiol 1998; 36:115.

185. Bahrani FK, Johnson DE, Robbins D, Mobley HL: Proteus mirabilis flagella and MR/P fimbriae: Isolation, purification, N-terminal analysis, and serum antibody response following experimental urinary tract infection. Infect Immun 1991; 59:3574.

186. Bahrani FK, Mobley HL: Proteus mirabilis MR/P fimbriae: Molecular cloning, expression, and nucleotide sequence of the major fimbrial subunit gene. J Bacteriol 1993; 175:457.

187. Massad G, Lockatell CV, Johnson DE, Mobley HL: Proteus mirabilis fimbriae: Construction of an isogenic pmfA mutant and analysis of virulence in a CBA mouse model of ascending urinary tract infection. Infect Immun 1994; 6:536.

188. Allison C, Emody L, Coleman N, Hughes C: The role of swarm cell differentiation and multicellular migration in the uropathogenicity of Proteus mirabilis.. J Infect Dis 1994; 169:1155.

189. Li X, Zhao H, Geymonat L, et al: Proteus mirabilis mannose-resistant, Proteus-like fimbriae: MrpG is located at the fimbrial tip and is required for fimbrial assembly. Infect Immun 1997; 65:1327.

190. Zhao H, Li X, Johnson DE, et al: In vivo phase variation of MR/P fimbrial gene expression in Proteus mirabilis infecting the urinary tract. Mol Microbiol 1997; 23:1009.

191. Mobley HL, Belas R, Lockatell V, et al: Construction of a flagellum-negative mutant of Proteus mirabilis: Effect on internalization by human renal epithelial cells and virulence in a mouse model of ascending urinary tract infection. Infect Immun 1996; 64:5332.

192. Johnson DE, Russell RG, Lockatell CV, et al: Contribution of Proteus mirabilis urease to persistence, urolithiasis, and acute pyelonephritis in a mouse model of ascending urinary tract infection. Infect Immun 1993; 61:748.

193. Mobley HL, Chippendale GR: Hemagglutinin, urease, and hemolysin production by Proteus mirabilis from clinical sources. J Infect Dis 1990; 161:55.

194. Mobley HL, Chippendale GR, Swihart KG, Welch RA: Cytotoxicity of the HpmA hemolysin and urease of Proteus mirabilis and Proteus vulgaris against cultured human renal proximal tubular epithelial cells. Infect Immun 1991; 59:036.

195. Senior BW, Loomes LM, Kerr MA: The production and activity in vivo of Proteus mirabilis IgA protease in infections of the urinary tract. J Med Microbiol 1991; 35:03.

196. Platt R, Polk BF, Murdock B, et al: Risk factors for nosocomial urinary tract infection. Am J Epidemiol 1986; 14:977.

197. Patterson JE, Andriole VT: Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 1997; 11:735.

198. Harding GK, Zhanel GG, Nicolle LE, et al: Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. N Engl J Med 2002; 347:1576.

199. Goswami R, Bal CS, Tejaswi S, et al: Prevalence of urinary tract infection and renal scars in patients with diabetes mellitus. Diabetes Res Clin Pract 2001; 53:181.

200. Gilbert DN: Urinary tract infections in patients with chronic renal insufficiency. Clin J Am Soc Nephrol 2006; 6:327.

201. Meiland R, Geerlings SE, Hoepelman AI: Management of bacterial urinary tract infections in adult patients with diabetes mellitus. Drugs 2002; 62:1859.

202. Nicolle LF: Urinary tract infections in diabetes. Curr Opin Infect Dis 2005; 18:49.

203. McDermid KP, Watterson J, van Eiden SF: Emphysematous pyelonephritis: Case report and review of the literature. Diabetes Res Clin Pract 1999; 44:71.

204. Huang JJ, Tseng CC: Emphysematous pyelonephritis: Clinicoradiological classification, management, prognosis, and pathogenesis. Arch Intern Med 2000; 160:797.

205. Hildebrand TS, Nibbe L, Frei U, Schindler R: Bilateral emphysematous pyelonephritis caused by Candida infection. Am J Kidney Dis 1999; 33:E10.

206. Svanborg-Eden C, Kulhavy R, Marild S, et al: Urinary immunoglobulins in healthy individuals and children with acute pyelonephritis. Scand J Immunol 1985; 21:305.

207. Kantele A, Papunes R, Virtahen E, et al: Antibody secreting cells in acute urinary tract infection as indicators of local immunoresponse. J Infect Dis 1994; 169:1023.

208. O'Hanley P, Lark D, Falkow S, et al: Molecular basis of Escherichia coli colonization of the upper urinary tract in BALB/c mice: Gal-Gal pili immunization prevents Escherichia coli pyelonephritis in the BALB/c mouse model of human pyelonephritis. J Clin Invest 1985; 75:347.

209. Svanborg-Eden C, Svennerholm AM: Secretory IgA and IgG antibodies prevent adhesion of Escherichia coli to human urinary tract epithelial cells. Infect Immun 1997; 22:790.

210. Svanborg-Eden C, Briles D, Hagberg L, et al: Genetic factors in host resistance to urinary tract infection. Infection 1984; 12:118.

211. Glauser MP, Lyons JM, Braude AI: Prevention of chronic experimental pyelonephritis by suppression of acute suppuration. J Clin Invest 1978; 61:403.

212. Cotran RS, Galvanek EG: Immunopathology of human tubular interstitial diseases: Localization of immunoglobulins and Tamm-Horsfall protein. Contrib Nephrol 1979; 16:16.

213. McCluskey RT, Colvin RG: Immunologic aspects of renal, tubular and interstitial disease. Annu Rev Med 1978; 9:191.

214. Mayrer AR, Kashgarian M, Ruddle NH, et al: Tubulointerstitial nephritis and immunologic responses to Tamm-Horsfall protein in rabbits' challenged homologous urine or Tamm-Horsfall protein. J Immunol 1983; 18:634.

215. Cotran RS: Pathogenetic mechanisms in the progress of reflux nephropathy: The roles of glomerulosclerosis and extravasation of Tamm-Horsfall protein. In: Zurukzoglu W, Papadimitriou M, Pyrpasopoulous M, et al ed. Advances in Basic and Clinical Nephrology, Basel: S Karger; 1981:368.

216. Blomjous EM, Meijer CJLM: Pathology of urinary tract infections. In: Brumfitt W, Hamilton-Miller JMT, Bailey RR, ed. Urinary Tract Infections, London: Chapman & Hall; 1998:17.

217. Chrispin AR: Medullary necrosis in infancy. Br Med Bull 1972; 8:33.

218. Benz G, Willich E, Scharer K: Segmental renal hypoplasia in childhood. Pediatr Radiol 1976; 5:86.

219. Arant Jr BS, Sotelo-Avila C, Bernstein J: Segmental hypoplasia of the kidney (Ask-Upmark). J Pediatr 1979; 95:931.

220. Kincaid-Smith PS, Bastos MG, Becker GJ: Reflux nephropathy in the adult. Contrib Nephrol 1984; 39:94.

221. Bailey RR: Clinical presentations and diagnosis of vesicoureteric reflux and reflux nephropathy. In: Davison A, ed. Nephropathy II, Philadelphia: WB Saunders; 1988:835-843.

222. Bailey RR, Lynn KL: End-stage reflux nephropathy. Contrib Nephrol 1984; 39:10.

223. Hodson CJ: Reflux nephropathy: Scoring the damage. In: Hodson CJ, Kincaid-Smith P, ed. Reflux Nephropathy, New York: Masson; 1979:29.

224. Papanikolaou G, Arnold AJ, Howie AJ: Tamm-Horsfall protein in reflux nephropathy. Scand J Urol Nephrol 1995; 29:141.

225. Heptinstall RH: Pathology of the Kidney, Boston, Little, Brown, 1983.

226. Kincaid-Smith P: Glomerular lesions in atrophic PN and reflux nephropathy. Kidney Int 1975; 8:S81.

227. Kincaid-Smith P: Glomerular and vascular lesions in chronic atrophic PN and reflux nephropathy. Adv Nephrol 1975; 5:3.

228. Rushton HG, Majd M: Pyelonephritis in male infants: How important is the foreskin?. J Urol 1992; 148:733.

229. Spach DH, Stapleton AE, Stamm WE: Lack of circumcision increases the risk of urinary tract infection in young men. JAMA 1992; 67:679.

230. Serour F, Samra Z, Kushel Z, et al: Comparative periurethral bacteriology of uncircumcised and circumcised males. Genitourin Med 1997; 73:288.

231. Wijesinha SS, Atkins BL, Dudley NE, Tam PK: Does circumcision alter the periurethral bacterial flora?. Pediatr Surg Int 1998; 13:146.

232. Foxman B, Gillespie B, Koopman J, et al: Risk factors for second urinary tract infections among college women. Am J Epidemiol 2000; 151:1194.

233. Foxman B: Recurring urinary tract infection: incidence and risk factors. Am J Public Health 1990; 80:331.

234. Ikaheimo R, Siltonen A, Heiskanan T, et al: Recurrence of urinary tract infection in a primary care setting: Analysis of a 1-year follow-up of 179 women. Clin Infect Dis 1996; 22:91.

235. Sanford JP: Urinary tract symptoms and infections. Annu Rev Med 1976; 26:485.

236. Silverberg DS: City-wide screening for urinary abnormalities in school boys. Can Med Assoc J 1974; 111:410.

237. Cohen M: The first urinary tract infection in male children. Am J Dis Child 1976; 130:810.

238. Baines RC, Daifuku R, Roddy RE, Stamm WE: Urinary tract infection in sexually active homosexual men. Lancet 1986; 1:171.

239. Foxman B, Zhang L, Tallman P, et al: Transmission of uropathogens between sex partners. J Infect Dis 1997; 175:989.

240. Hallet RJ, Pead L, Maskell R: Urinary infection in boys. Lancet 1976; 2:1107.

241. Park J, Buono D, Smith DK, et al: Urinary tract infections in women with or at risk for human immunodeficiency virus infection. Am J Obstet Gynecol 2002; 187:581.

242. Freedman LR: Urinary tract infections in the elderly. N Engl J Med 1983; 309:1451.

243. Dontas AS, Kasviki-Charvati P, Papanayiotou PC, Marketos SG: Bacteriuria and survival in old age. N Engl J Med 1981; 304:939.

244. Nicolle LE: Urinary tract infection in geriatric and institutionalized patients. Curr Opin Urol 2002; 12:51.

245. Millar LK, Cox SM: Urinary tract infections complicating pregnancy. Infect Dis Clin North Am 1997; 11:13.

246. Patterson TF, Andriole VT: Detection, significance, and therapy of bacteriuria in pregnancy: Update in the managed health care era. Infect Dis Clin North Am 1997; 11:593.

247. Zinner SH, Kass EH: Long-term (10 to 14 years) follow-up of bacteriuria of pregnancy. N Engl J Med 1971; 285:820.

248. Martinell J, Jodal U, Lidin-Janson G: Pregnancies in women with and without renal scarring after urinary infections in childhood. BMJ 1990; 300:840.

249. Mittendorf R, Williams MA, Kass EH: Prevention of preterm delivery and low birth weight associated with asymptomatic bacteriuria. Clin Infect Dis 1992; 14:927.

250. Tullus K, Horlin K, Svenson SB, Kallenius G: Epidemic outbreaks of acute pyelonephritis caused by nosocomial spread of P fimbriated E. coli in children. J Infect Dis 1984; 150:728.

251. Hill JB, Sheffield JS, McIntire DD, Wendel Jr GD: Acute pyelonephritis in pregnancy. Obstet Gynecol 2005; 105:18.

252. Tullus K, Kallenius G: Epidemiological aspects of p-fimbriated E. coli: IV. Extraintestinal E. coli infections before the age of one year and their relation to fecal colonization with p-fimbriated E. coli.. Acta Paediatr Scand 1987; 76:463.

253. The prevention and management of urinary tract infections among people with spinal cord injuries. National Institute on Disability and Rehabilitation Research Consensus Statement. J Am Paraplegia Soc 1992; 15:194.

254. Montgomerie JZ: Infections in patients with spinal cord injuries. Clin Infect Dis 1997; 25:1285.

255. Tolkoff-Rubin NE, Rubin RH: Urinary tract infection in the immunocompromised host: Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am 1997; 11:707.

256. Abbott KC, Swanson SJ, Richter ER, et al: Late urinary tract infection after renal transplantation in the United States. Am J Kidney Dis 2004; 44:353.

257. Giral M, Pascuariello G, Karsum G, et al: Acute graft pyelonephritis and long-term kidney allograft outcome. Kidney Int 2002; 61:1880.

258. Murray T, Goldberg MJ: Chronic interstitial nephritis: Etiologic factors. Ann Intern Med 1975; 82:453.

259. Freedman LR, Andriole V: The long-term follow-up of women with urinary tract infections. In: Villarreal H, ed. Proceedings of the 5th International Congress of Nephrology, Basel: S. Karger; 1972:230.

260. Freeman RB, Smith WM, Richardson JA, et al: Long-term therapy for chronic bacteriuria in men: US Public Health Service Cooperative Study. Ann Intern Med 1975; 83:133.

261. Berg UB: Long-term follow-up of renal morphology and function in children with recurrent pyelonephritis. J Urol 1992; 148:1715.

262. Hannerz L, Celsi G, Eklof AC, et al: Ascending pyelonephritis in young rats retards kidney growth. Kidney Int 1989; 35:1133.

263. Hansson S, Martinell J, Stokland E, Jodal U: The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1997; 11:499.

264. Tullus K, Winberg J: Urinary tract infections in childhood. In: Brumfitt W, Hamilton-Miller JMT, Bailey RR, ed. Urinary Tract Infections, London: Chapman & Hall; 1998:175.

265. Edwards D, Normand ICS, Prescott N, Smellie JM: Disappearance of reflux during long-term prophylaxis of urinary tract infection in children. BMJ 1977; 2:285.

266. Lenaghan D, Whitaber JG, Jemsen F, Stephens FD: The natural history of reflux and long-term effects of reflux on the kidney. J Urol 1976; 115:728.

267. Becker GJ, Kincaid-Smith P: Reflux nephropathy: The glomerular lesion and progression of renal failure. Pediatr Nephrol 1993; 7:365.

268. Coppo R, Porcellini MG, Gianoglio B, et al: Glomerular permselectivity to macromolecules in reflux nephropathy: Microalbuminuria during acute hyperfiltration due to amino acid infusion. Clin Nephrol 1993; 40:299.

269. Jacobson SH, Eklof O, Eriksson CG, et al: Development of hypertension and uraemia after pyelonephritis in childhood: 27-year follow-up. BMJ 1989; 299:703.

270. Mittendorf R, Lain KY, Williams MA, Walker CK: Preeclampsia: A nested, case-control study of risk factors and their interactions. J Reprod Med 1996; 41:491.

271. Kincaid-Smith P: Bacteriuria and urinary infection in pregnancy. Clin Obstet Gynecol 1968; 11:533.

272. Harris RE, Thomas VL, Shelokov A: Asymptomatic bacteriuria in pregnancy: Antibody-coated bacteria, renal function, and intrauterine growth retardation. Am J Obstet Gynecol 1976; 126:20.

273. McGrady GA, Daling JR, Peterson DR: Maternal urinary tract infection and adverse fetal outcomes. Am J Epidemiol 1985; 121:377.

274. Naeye RL: Cause of the excessive rates of perinatal mortality and prematurity in pregnancies complicated by maternal urinary tract infections. N Engl J Med 1979; 300:819.

275. Gilstrap III LC, Whalley PJ: Asymptomatic bacteriuria during pregnancy. In: Brumfitt W, Hamilton-Miller JMT, Bailey RR, ed. Urinary Tract Infections, London: Chapman & Hall; 1998:199.

276. Zinner SH: Bacteriuria and babies revisited. N Engl J Med 1979; 300:853.

277. Gilstrap LC, Leveno KJ, Cunningham FG, et al: Renal infection and pregnancy outcome. Am J Obstet Gynecol 1981; 141:709.

278. McGladdery SL, Aparicio S, Verrier-Jones K, et al: Outcome of pregnancy in an Oxford-Cardiff cohort of women with previous bacteriuria. Q J Med 1992; 83:533.

279. Platt R, Polk BF, Murdock B, Rosner B: Mortality associated nosocomial urinary tract infection. N Engl J Med 1982; 307:637.

280. Nordenstam GR, Brandberg CA, Oden AS, et al: Bacteriuria and mortality in an elderly population. N Engl J Med 1986; 314:1152.

281. Nicolle LE, Mayhew WJ, Bryan L: Prospective randomized comparison of therapy and no therapy for asymptomatic bacteriuria in institutionalized elderly women. Am J Med 1987; 83:27.

282. Nicolle LE, Henderson E, Bjornsen J, et al: The association of bacteriuria with resident characteristics and survival in elderly institutionalized men. Ann Intern Med 1987; 106:682.

283. Abrutyn E, Mossey J, Berlin JA, et al: Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women?. Ann Intern Med 1994; 120:827.

284. Nicolle LE: Asymptomatic bacteriuria in the elderly. Infect Dis Clin North Am 1997; 11:647.

285. Johnson JR, Stamm WE: Diagnosis and treatment of acute urinary tract infections. Infect Dis Clin North Am 1987; 1:773.

286. Stamm WE, Running K, McKevitt M, et al: Treatment of acute urethral syndrome. N Engl J Med 1981; 304:956.

287. Hoberman A, Chao HP, Keller DM, et al: Prevalence of urinary tract infection in febrile infants. J Pediatr 1993; 123:17.

288. Kreiger JN, Ross SO, Simonsen JM: Urinary tract infections in healthy university men. J Urol 1993; 149:1046.

289. Smith JW, Jones SR, Reed WP, et al: Recurrent urinary tract infection in men: Characteristics and response to therapy. Ann Intern Med 1979; 91:544.

290. Scholes D, Hooton TM, Roberts PL, et al: Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med 2005; 142:20.

291. Hoberman A, Wald ER: Urinary tract infections in young febrile children. Pediatr Infect Dis J 1997; 16:11.

292. Rushton HG: Urinary tract infections in children: Epidemiology, evaluation, and management. Pediatr Clin North Am 1997; 44:1133.

293. Rushton HG, Majd M, Jantausch B, et al: Renal scarring following reflux and nonreflux pyelonephritis in children: Evaluation with 99mtechnetium-dimercaptosuccinic acid scintigraphy. J Urol 1992; 147:1372.

294. Rushton HG, Majd M: Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: A review of experimental and clinical studies. J Urol 1992; 148:1726.

295. Jakobsson B, Nolstedt L, Svensson L, et al: 99mTechnetium-dimercaptosuccinic acid scan in the diagnosis of acute pyelonephritis in children: Relation to clinical and radiological findings. Pediatr Nephrol 1992; 6:328.

296. Shanon A, Feldman W, McDonald P, et al: Evaluation of renal scars by technetium-labeled dimercaptosuccinic acid scan, intravenous urography, and ultrasonography: A comparative study. J Pediatr 1992; 120:399.

297. Eggli DF, Tulchinsky M: Scintigraphic evaluation of pediatric urinary tract infection. Semin Nucl Med 1993; 23:199.

298. Benador D, Benador N, Slosman DO, et al: Cortical scintigraphy in the evaluation of renal parenchymal changes in children with pyelonephritis. J Pediatr 1994; 124:17.

299. Kovanlikaya A, Okkay N, Cakmakci H, et al: Comparison of MRI and renal cortical scintigraphy findings in childhood acute pyelonephritis: Preliminary experience. Eur J Radiol 2004; 49:76.

300. Teh HS, Jin Gan JS, Foo-Cheong NG: Magnetic resonance cystography: Novel imaging technique for evaluation of vesicoureteral reflux. Urology 2005; 65:793.

301. Greenfield SP, Ng M, Wan J: Experience with vesicoureteral reflux in children: Clinical characteristics. J Urol 1997; 158:574.

302. Vernon SJ, Coulthard MG, Lambert HJ, et al: New renal scarring in children who at age 3 and 4 years had had normal scans with dimercaptosuccinic acid: Follow-up study. BMJ 1997; 315:905.

303. Benador D, Benador N, Slosman D, et al: Are younger children at highest risk of renal sequelae after pyelonephritis?. Lancet 1997; 349:17.

304. Martinell J, Claesson I, Lidin-Janson G, Jodal U: Urinary infection, reflux and renal scarring in females continuously followed for 13-38 years. Pediatr Nephrol 1995; 9:131.

305. Bengtsson U: Long-term pattern in chronic pyelonephritis. Contrib Nephrol 1979; 16:31.

306. Holland NH, Kotchen T, Bhathena D: Hypertension in children with chronic pyelonephritis. Kidney Int 1975; 8:S243.

307. Holland NH: Reflux nephropathy and hypertension. In: Hodson CJ, Kincaid-Smith P, ed. Reflux Nephropathy, New York: Masson; 1979:257.

308. Martinell J, Lidin-Janson G, Jagenburg R, et al: Girls prone to urinary infections followed into adulthood: Indices of renal disease. Pediatr Nephrol 1996; 10:139.

309. Goonasekera CED, Shah V, Wade AM, et al: 15-Year follow-up of renin and blood pressure in reflux nephropathy. Lancet 1996; 347:640.

310. Kohler J, Tencer J, Thysell H, Forsberg L: Vesicoureteral reflux diagnosed in adulthood: Incidence of urinary tract infections, hypertension, proteinuria, back pain and renal calculi. Nephrol Dial Transplant 1997; 12:2580.

311. Savage JM, Koh CT, Shah V, et al: Five-year prospective study of plasma renin activity and blood pressure in patients with corresponding reflux nephropathy. Arch Dis Child 1987; 62:678.

312. Torres DE, Velosa JA, Holley KE, et al: The progression of vesico-ureteral reflux nephropathy. Ann Int Med 1980; 92:766.

313. Woods HF, Walls J: Nephrotic syndrome in vesicoureteral reflux. BMJ 1976; 2:917.

314. Kincaid-Smith P: Clinical implications of reflux in the adult. In: Zurukzoglu W, Papadimitriou M, Pyrpasopoulous M, et al ed. Advances in Basic and Clinical Nephrology, Basel: S Karger; 1981:359.

315. Karlen J, Linne T, Wikstad I, Aperia A: Incidence of microalbuminuria in children with pyelonephritic scarring. Pediatr Nephrol 1996; 10:705.

316. Hostetter RH, Olson JL, Rennke HG, et al: Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. Am J Physiol 1981; 241:F85.

317. Olson JL, Hostetter TH, Rennke HG, et al: Altered charge and size-selective properties of the glomerular wall: A response to reduced renal mass. Kidney Int 1982; 22:112.

318. Bailey RR, Swainson CP, Lynn KL, Burry AF: Glomerular lesions in the “normal” kidney in patients with unilateral reflux nephropathy. Contrib Nephrol 1984; 39:126.

319. Verrier Jones K, Asscher W, Verrier Jones R, et al: Renal functional changes in schoolgirls with covert asymptomatic bacteriuria. Contrib Nephrol 1984; 39:152.

320. Khatib ML, Becker GJ, Kincaid-Smith P: Morphometric aspects of reflux nephropathy. Kidney Int 1987; 32:261.

321. Bartlett RC, O'Neill D, McLaughlin JC: Detection of bacteriuria by leukocyte esterase, nitrate, and the automicrobic system. Am J Clin Pathol 1984; 82:683.

322. Pollack HM: Laboratory techniques for detection of urinary tract infection and assessment of value. Am J Med 1983; 75:79.

323. Sanderson PJ: Laboratory methods. In: Brumfitt W, Hamilton-Miller JMT, Bailey RR, ed. Urinary Tract Infection, London: Chapman & Hall; 1998:1.

324. Lejeune B, Baron R, Guillois B, Mayeux D: Evaluation of a screening test for detecting urinary tract infection in newborns and infants. J Clin Pathol 1991; 44:1029.

325. Evans PJ, Leaker BR, McNabb WR, Lewis RR: Accuracy of reagent strip testing for urinary tract infection in the elderly. J R Soc Med 1991; 84:598.

326. Lachs MS, Nachamkin I, Edelstein PH, et al: Spectrum bias in the evaluation of diagnostic tests: Lessons from the rapid dipstick test for urinary tract infection. Ann Intern Med 1992; 117:135.

327. Bachman JW, Heise RH, Naessens JM, Timmerman MG: A study of various tests to detect asymptomatic urinary tract infections in an obstetric population. JAMA 1993; 270:1971.

328. Kavanagh EC, Ryan S, Awan A, et al: Can MRI replace DMSA in the detection of renal parenchymal defects in children with urinary tract infection?. Pediatr Radiol 2005; 35:275.

329. Smellie JM, Rigden SP: Pitfalls in the investigation of children with urinary tract infection. Arch Dis Child 1995; 72:251.

330. Fairley KF, Carson NE, Gutch RC, et al: Site of infection in acute urinary tract infection in general practice. Lancet 1971; 2:615.

331. Clarke SE, Smellie JM, Prescod N, et al: Technetium-99m-DMSA studies in pediatric urinary infection. J Nucl Med 1996; 37:823.

332. Stokland E, Hellstrom M, Jacobsson B, et al: Renal damage one year after first urinary tract infection: Role of dimercaptosuccinic acid scintigraphy. J Pediatr 1996; 129:815.

333. Lavocat MP, Granjon D, Allard D, et al: Imaging of pyelonephritis. Pediatr Radiol 1997; 27:159.

334. Craig JC, Knight JF, Sureshkumar P, et al: Vesicoureteric reflux and timing of micturating cystourethrography after urinary tract infection. Arch Dis Child 1997; 76:275.

335. Fair WR, McClennan BL, Jost RG: Are excretory urograms necessary in evaluating women with urinary tract infection?. J Urol 1979; 121:313.

336. Engel G, Schaeffer AJ, Grayback JT, Wendel EF: The role of excretory urography and cystoscopy in the evaluation and management of women with recurrent urinary tract infection. J Urol 1980; 123:190.

337. Fowler Jr JE, Pulaski ET: Excretory urography, cystography and cystoscopy in the evaluation of women with urinary tract infection: A prospective study. N Engl J Med 1981; 304:462.

338. Delange EE, Jones B: Unnecessary intravenous urography in young women with recurrent urinary tract infections. Clin Radiol 1983; 34:551.

339. Sandberg T, Stokland E, Brolin I, et al: Selective use of excretory urography in women with acute pyelonephritis. J Urol 1989; 141:1290.

340. Nickel JC, Wilson J, Morales A, Heaton J: Value of urologic investigation in a targeted group of women with recurrent urinary tract infections. Can J Surg 1991; 34:591.

341. Warren JW, Abrutyn E, Hebel JR, et al: Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999; 29:745.

342. Johnson JR, Manges AR, O'Bryan TT, Riley LW: A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet 2002; 359:2249.

343. Raz R, Chazen B, Kenner Y, et al: Empiric use of trimethoprim-sulfamethoxazole in the treatment of women with uncomplicated urinary tract infections in a geographic area with a high prevalence of TMP-SMX-resistant uropathogens. Clin Infect Dis 2002; 34:1165.

344. Karlowsky JA, Kelly LJ, Thornsberry C, et al: Trends in antimicrobial resistance among urinary tract infection isolates of Escherichia coli from female outpatients in the United States. Antimicrob Agents Chemother 2002; 46:2540.

345. Gupta K, Stamm WE: Outcomes associated with trimethoprim/sulphamethoxazole (TMP/SMX) therapy in TMP/SMX resistant community-acquired urinary tract infection. Int J Antimicrob Agents 2002; 19:554.

346. Gupta K, Sahm DF, Mayfield D, Stamm WE: Antimicrobial resistance among uropathogens that cause community acquired urinary tract infections in women: A nationwide analysis. Clin Infect Dis 2001; 33:89.

347. Hooton TM, Besser R, Foxman B, et al: Acute uncomplicated cystitis in an era of increasing antibiotic resistance: A proposed approach to empirical therapy. Clin Infect Dis 2004; 39:75.

348. Gupta K, Scholes D, Stamm WE: Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA 1999; 281:736.

349. Sannes MR, Kiskowski MA, Johnson JR: Geographical distribution of antimicrobial resistance among Escherichia coli causing acute uncomplicated pyelonephritis in the United States. FEMS Immunol Med Microbiol 2004; 42:213.

350. Hooton TM: The current management strategies for community-acquired urinary tract infections. Infect Dis Clin North Am 2003; 17:303.

351. Hooton TM: Fluoroquinolones and resistance in the treatment of uncomplicated urinary tract infections. Int J Antimicrobial Agents 2003; 22(suppl 2):65.

352. Hooton TM, Scholes D, Hughes JP, et al: A prospective study of risk factors for symptomatic urinary tract infections in young women. N Engl J Med 1996; 335:468.

353. Bent S, Nallamothu BK, Simel DL, et al: Does this woman have an acute uncomplicated urinary tract infection?. JAMA 2002; 287:2701.

354. Nicolle LE, Ronald AR: Recurrent urinary tract infections in adult women: Diagnosis and treatment. Infect Dis Clin North Am 1987; 1:793.

355. Tolkoff-Rubin NE, Wilson ME, Zuromskis P, et al: Single-dose amoxicillin therapy of acute uncomplicated urinary tract infection in women. Antimicrob Agents Chemother 1984; 25:626.

356. Harbord RB, Gruneborg RN: Treatment of urinary tract infection with a single dose of amoxicillin, co-trimoxazole, or trimethoprim. BMJ 1981; 303:409.

357. Johnson JR, Stamm WE: Diagnosis and treatment of acute urinary tract infections. Infect Dis Clin North Am 1987; 1:773.

358. Johnson JR, Stamm WE: Urinary tract infections in women: Diagnosis and treatment. Ann Intern Med 1989; 111:906.

359. Inter-Nordic Urinary Tract Infection Study Group : Double-blind comparison of 3-day versus 7-day treatment with norfloxacin in symptomatic urinary tract infections. Scand J Infect Dis 1988; 20:619.

360. Hooton TM, Johnson C, Winter C, et al: Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women. Antimicrob Agents Chemother 1991; 35:1479.

361. Norrby SR: Short-term treatment of uncomplicated lower urinary tract infections in women. Rev Infect Dis 1990; 12:458.

362. Hooton TM, Stamm WE: Management of acute uncomplicated urinary tract infection in adults. Med Clin North Am 1991; 75:339.

363. Wilson ML, Gaido L: Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis 2004; 38:1150.

364. Holmber L, Boman G, Bottinger LE, et al: Adverse reactions to nitrofurantoin: Analysis of 921 reports. Am J Med 1980; 69:733.

365. Tolkoff-Rubin NE, Rubin RH: Ciprofloxacin in the management of urinary tract infection. Urology 1988; 31:359.

366. Stapleton A, Latham RH, Johnson C, Stamm WE: Postcoital antimicrobial prophylaxis for recurrent urinary tract infection: A randomized, double-blind, placebo-controlled trial. JAMA 1990; 264:703.

367. Wong ES, McKevitt M, Running K, et al: Management of recurrent urinary tract infections with patient-administered single-dose therapy. Ann Intern Med 1985; 102:302.

368. Gupta K, Hooton TM, Roberts PL, Stamm WE: Patient-initiated treatment of uncomplicated recurrent urinary tract infections in young women. Ann Intern Med 2001; 135:9.

369. Stathers L: A randomized trial to evaluate effectiveness and cost-effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infections in women. Can J Urol 2002; 9:1558.

370. Kontiokari T, Sundquist K, Nuutinen M, et al: Randomized trial of cranberry-lingonberry juice and lactobacillus drink for the prevention of urinary tract infection in women. BMJ 2001; 322:1571.

371. Howell AB: Cranberry proanthocyanidins and the maintenance of urinary tract health. Crit Rev Food Sci Nutr 2002; 42:273.

372. Liu Y, Black MA, Caron L, Camesano TA: Role of cranberry juice on molecular-scale surface characteristics and adhesion behavior of Escherichia coli.. Biotechnol Bioeng 2006; 93:297.

373. Sobel JD, Muller G: Pathogenesis of bacteriuria in elderly women: The role of Escherichia coli adherence to vaginal epithelial cells. J Gerontol 1984; 39:682.

374. Molander U, Milson I, Ekelund P, et al: Effect of oral oestriol on vaginal flora and cytology and urogenital symptoms in the postmenopause. Maturitas 1990; 12:113.

375. Raz R, Stamm WE: A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753.

376. Parsons CL, Schmitd JD: Control of recurrent lower urinary tract infection in postmenopausal women. J Urol 1982; 12:1224.

377. Brandberg A, Mellstrom D, Samside G: Low-dose oral estriol treatment in elderly women with urogenital infections. Acta Obstet Gynecol Scand Suppl 1987; 140:33.

378. Jackson SL, Boyko EJ, Scholes D, et al: Predictors of urinary tract infections after menopause: A prospective study. Am J Med 2004; 117:903.

379. Avorn J, Monane M, Gurwitz JH, et al: Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994; 271:751.

380. Zafriri D, Ofek I, Adar R, et al: Inhibitory activity of cranberry juice on adherence of type 1 and P fimbriated Escherichia coli to eukaryotic cells. Antimicrob Agents Chemother 1989; 33:92.

381. Ofek I, Goldhar J, Zafriri D, et al: Anti-Escherichia adhesin activity of cranberry and blueberry juices. N Engl J Med 1991; 324:1599.

382. Abrutyn E, Berlin J, Mossey J, et al: Does treatment of asymptomatic bacteriuria in older ambulatory women reduce subsequent symptoms of urinary tract infection?. J Am Geriatr Soc 1996; 44:293.

383. Zinner SH: Management of urinary tract infections in pregnancy: A review with comments on single-dose therapy. Infection 1992; 20(suppl 4):S280.

384. Sanchez-Ramos L, McAlpine KJ, Adair CD, et al: Pyelonephritis in pregnancy: Once-a-day ceftriaxone versus multiple doses of cefazolin. A randomized, double-blind trial. Am J Obstet Gynecol 1995; 172:129.

385. Millar LK, Wing DA, Paul RH, Grimes DA: Outpatient treatment of pyelonephritis in pregnancy: A randomized controlled trial. Obstet Gynecol 1995; 86:560.

386. Pfau A, Sacks TG: Effective prophylaxis for recurrent urinary tract infections during pregnancy. Clin Infect Dis 1992; 14:810.

387. Sandberg T, Brorson JE: Efficacy of long-term antimicrobial prophylaxis after acute pyelonephritis in pregnancy. Scand J Infect Dis 1991; 23:221.

388. American College of Obstetricians and Gynecologists : Antimicrobial Therapy for Obstetric Patients, Washington, DC: ACOG Educational Bulletin; 1998:245.

389. Wong ES, Stamm WE: Sexual acquisition of urinary tract infection in a man. JAMA 1983; 250:3087.

390. Hoepelman AI, van Buren M, van den Broek J, Borleffs JC: Bacteriuria in men infected with HIV-1 is related to their immune status (CD4+ cell count). AIDS 1992; 6:179.

391. Tolkoff-Rubin NE, Rubin RH: Urinary tract infection in the immunocompromised host: Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am 1997; 11:707.

392. Krieger JN: Prostatitis revisited: New definitions, new approaches. Infect Dis Clin North Am 2003; 17:395.

393. Meares Jr EM: Acute and chronic prostatitis: Diagnosis and treatment. Infect Dis Clin North Am 1987; 1:855.

394. Gleckman R, Crowley M, Natsios GA: Therapy of recurrent invasive urinary tract infections of men. N Engl J Med 1979; 301:878.

395. Pewitt EB, Schaeffer AJ: Urinary tract infection in urology, including acute and chronic prostatitis. Infect Dis Clin North Am 1997; 11:623.

396. Avner ED, Ingelfinger JR, Herrin JT, et al: Single-dose amoxicillin therapy of uncomplicated pediatric urinary tract infections. J Pediatr 1983; 102:63.

397. Mofatt M, Embrec J, Grimm P, Law B: Short-course antibiotic therapy for urinary tract infections in children: A methodological review of the literature. Am J Dis Child 1988; 142:57.

398. Madrigal G, Odio CM, Mohs E, et al: Single-dose antibiotic therapy is not as effective as conventional regimens for management of acute urinary tract infections in children. Pediatr Infect Dis J 1988; 7:316.

399. Fine JS, Jacobsen MS: Single-dose versus conventional therapy of urinary tract infections in female adolescents. Pediatrics 1985; 75:916.

400. Durbin Jr WA, Peter G: Management of urinary tract infections in infants and children. Pediatr Infect Dis 1984; 3:564.

401. McCracken Jr GH: Options in antimicrobial management of urinary tract infections in infants and children. Pediatr Infect Dis J 1989; 8:552.

402. Smellie JM, Gruneberg RN, Leahey A, et al: Long-term low-dose co-trimoxazole in prophylaxis of childhood urinary tract infection: Clinical aspects. BMJ 1976; 2:203.

403. Belman AB, Skoog SJ: Nonsurgical approach to the management of vesicoureteral reflux in children. Pediatr Infect Dis J 1989; 8:556.

404. Loening-Baucke V: Urinary incontinence and urinary tract infection and their resolution with treatment of chronic constipation of childhood. Pediatrics 1997; 100:228.

405. Birmingham Reflux Study Group : Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: Five years' observation. BMJ 1987; 295:237.

406. Duckett JW, Walker RD, Weiss R: Surgical results: International Reflux Study in Children—United States branch. J Urol 1992; 148:1674.

407. Weiss R, Duckett J, Spitzer A: Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). The International Reflux Study in Children. J Urol 1992; 148:1667.

408. Tamminen-Mobius T, Brunier E, Ebel KD, et al: Cessation of vesicoureteral reflux for 5 years in infants and children allocated to medical treatment: The International Reflux Study in Children. J Urol 1992; 148:1662.

409. Hjalmas K, Lohr G, Tamminen-Mobius T, et al: Surgical results in the International Reflux Study in Children (Europe). J Urol 1992; 148:1657.

410. Olbing H, Claesson I, Ebel KD, et al: Renal scars and parenchymal thinning in children with vesicoureteral reflux: A 5-year report of the International Reflux Study in Children (European branch). J Urol 1992; 148:1653.

411. Jodal U, Koskimies O, Hanson E, et al: Infection pattern in children with vesicoureteral reflux randomly allocated to operation or long-term antibacterial prophylaxis. The International Reflux Study in Children. J Urol 1992; 148:1650.

412. Arant Jr BS: Medical management of mild and moderate vesicoureteral reflux: Follow-up studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study Group. J Urol 1992; 148:1683.

413. McLorie GA, McKenna PH, Jumper BM, et al: High-grade vesicoureteral reflux: Analysis of observational therapy. J Urol 1990; 144:537.

414. Smellie JM: Commentary: Management of children with severe vesicoureteral reflux. J Urol 1992; 148:1676.

415. Elder JS, Peters CA, Arant Jr BS, et al: Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997; 157:1846.

416. Tolkoff-Rubin NE, Weber D, Fang LST, et al: Single-dose therapy with trimethoprim-sulfamethoxazole for urinary tract infection in women. Rev Infect Dis 1982; 4:444.

417. Dow G, Rao P, Harding G, et al: A prospective, randomized trial of 3 or 14 days of ciprofloxacin treatment for acute urinary tract infection in patients with spinal cord injury. Clin Infect Dis 2004; 34:658.

418. Banovac K, Wade N, Gonzalez F, et al: Decreased incidence of urinary tract infections in patients with spinal cord injury: Effect of methenamine. J Am Paraplegia Soc 1991; 14:52.

419. Perrouin-Verbe B, Labat JJ, Richard I, et al: Clean intermittent catheterisation from the acute period in spinal cord injury patients: Long-term evaluation of urethral and genital tolerance. Paraplegia 1995; 33:619.

420. Larsen KDM, Chamberlin DA, Khonsari F, Ahlering TE: Retrospective analysis of urologic complications in male patients with spinal cord injury managed with and without indwelling urinary catheters. Urology 1997; 50:418.

421. Kreger BE, Craven DE, Carling PC, McCabe WR: Gram-negative bacteremia: III. Reassessment of etiology, epidemiology and ecology in 612 patients. Am J Med 1980; 68:332.

422. Warren JW: Catheter-associated urinary tract infections. Infect Dis Clin North Am 1997; 11:609.

423. Nickel JC, Gristina AG, Costerton JW: Electron microscopic study of an infected Foley catheter. Can J Surg 1985; 28:50.

424. Nickel JC, Ruseka I, Wright JB, Costerton JW: Tobramycin resistance of Pseudomonas aeruginosa cells growing as a biofilm on urinary catheter material. Antimicrob Agents Chemother 1985; 27:619.

425. Platt R, Polk BF, Murdock B, Rosner B: Risk factors for nosocomial urinary tract infection. Am J Epidemiol 1986; 124:977.

426. Johnson JR, Roberts PL, Olsen RJ, et al: Prevention of catheter-associated urinary tract infection with a silver oxide-coated urinary catheter. Clinical and microbiologic correlates. J Infect Dis 1990; 162:1145.

427. Fryjkybd B, Haeggman S, Burman LG: Transmission of urinary bacterial strains between patients with indwelling catheters: Nursing in the same room and in separate rooms compared. J Hosp Infect 1997; 36:147.

428. Matsumoto T, Sakumoto M, Takahashi K, Kumazawa J: Prevention of catheter-associated urinary tract infection by meatal disinfection. Dermatology 1997; 195(suppl 2):73.

429. Wong-Beringer A, Jacobs RA, Guglielmo BJ: Treatment of funguria. JAMA 1992; 267:2780.

430. Jacobs LG, Skidmore EA, Cardoso LA, Ziv F: Bladder irrigation with amphotericin B for treatment of fungal urinary tract infections. Clin Infect Dis 1994; 18:313.

431. Potasman I, Castin A, Moskovitz B, et al: Oral fluconazole for Candida urinary tract infection. Urol Int 1997; 59:252.

432. Jacobs LG, Skidmore EA, Freeman K, et al: Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients. Clin Infect Dis 1996; 22:30.

433. Hibberd PH, Rubin PH: Clinical aspects of fungal infection in organ transplant recipients. Clin Infect Dis 1994; 19(suppl 1):533.

434. Lundstrom T, Sobel J: Nosocomial candiduria: A review. Clin Infect Dis 2001; 32:1602.

435. Sobel JD, Kauffman CA, McKinsey D, et al: Candiduria: A randomized, double-blind study of treatment with fluconzaole and placebo. The National Institute of Allergy and Infectious Disease (NIAID) Mycosis Study Group. Clin Infect Dis 2000; 30:19.

436. Simon HB, Weinstein AJ, Pasternak MS, et al: Genitourinary tuberculosis: Clinical features in a general hospital population. Am J Med 1977; 63:410.

437. Garcia-Rodriguez JA, Garcia Sanchez JE, Munoz Bellido JL, et al: Genitourinary tuberculosis in Spain: Review of 81 cases. Clin Infect Dis 1994; 18:557.

438. Christiansen WJ: Genitourinary tuberculosis: Review of 102 cases. Medicine (Baltimore) 1974; 53:377.

439. Malek RS, Eza S, Elder JS: Xanthogranulomatous pyelonephritis: A critical analysis of 26 cases and of the literature. J Urol 1978; 119:589.

440. Parson MA, Harris SC, Longstaff AJ, Grainger RG: Xanthogranulomatous pyelonephritis: A pathological, clinical and etiological analysis of 87 cases. Diagn Histopathol 1983; 6:203.

441. Goodman M, Curry T, Russell T: Xanthogranulomatous pyelonephritis: A local disease with systemic manifestations. Report of 23 cases and review of the literature. Medicine (Baltimore) 1979; 58:171.

442. Braun G, Moussali L, Balamzar JL: Xanthogranulomatous pyelonephritis in children. J Urol 1985; 133:326.

443. Clapton WK, Boucat HA, Dewan PA, et al: Clinicopathological features of xanthogranulomatous pyelonephritis in infancy. Pathology 1993; 25:110.

444. Hammadeh MY, Nicholls G, Calder CJ, et al: Xanthogranulomatous pyelonephritis in childhood: Preoperative diagnosis is possible. Br J Urol 1994; 73:83.

445. Nataluk EA, McCullough DL, Scharling EO: Xanthogranulomatous pyelonephritis, the gatekeepers' dilemma: A contemporary look at an old problem. Urology 1995; 45:377.

446. Chuang CK, Lai MK, Chang TL, et al: Xanthogranulomatous pyelonephritis: Experience in 36 cases. J Urol 1992; 147:333.

447. Goldman SM, Hartman DS, Fishman EK, et al: CT of xanthogranulomatous pyelonephritis: radiologic-pathologic conditions. AJR Am J Roentgenol 1984; 142:963.

448. Kawashima A, LeRoy AJ: Radiologic evaluation of patients with renal infections. Infect Dis Clin North Am 2003; 17:433.

449. Lopez-Medina A, Ereno MJ, Fernandez-Canton G, Zuazo A: Focal xanthogranulomatous pyelonephritis simulating malignancy in children. Abdom Imaging 1995; 20:270.

450. Marteinsson VT, Due J, Aagenaes I: Focal xanthogranulomatous pyelonephritis presenting as renal tumour in children: Case report with a review of the literature. Scand J Urol Nephrol 1996; 30:235.

451. Val-Bernal JF, Castro F: Xanthogranulomatous pyelonephritis associated with transitional cell carcinoma of the renal pelvis. Urol Int 1996; 57:240.

452. Mulapulos GP, Patel SK, Pessis D: MR imaging of xanthogranulomatous PN. J Comput Assist Tomogr 1986; 10:154.

453. Oosterhof G, Delacre K: Xanthogranulomatous pyelonephritis. Urol Int 1986; 41:180.

454. Treadwall TL, Craven DC, Delfin H, et al: Xanthogranulomatous pyelonephritis caused by methicillin-resistant Staphylococcus aureus.. Am J Med 1984; 76:533.

455. Khalyl-Mawad J, Greco MA, Schinella RA: Ultrastructural demonstration of intracellular bacteria in xanthogranulomatous pyelonephritis. Hum Pathol 1982; 13:41.

456. Brown Jr PS, Dodson M, Weintrub PS: Xanthogranulomatous pyelonephritis: Report of nonsurgical management of a case and review of the literature. Clin Infect Dis 1996; 22:308.

457. Rodo J, Martin ME, Salarich J: Xanthogranulomatous pyelonephritis in children: Conservative management. Eur Urol 1996; 30:498.

458. Raziel A, Steinberg R, Kornreich L, et al: Xanthogranulomatous pyelonephritis mimicking malignant disease: Is preservation of the kidney possible?. Pediatr Surg Int 1997; 12:535.

459. Stanton MJ, Maxted W: Malakoplakia: A study of the literature and current concepts of pathogenesis, diagnosis, and treatment. J Urol 1981; 125:139.

460. McClurg FR, D'Agostino AN, Martin JH, Race GJ: Ultrastructural demonstration of intracellular bacteria in three cases of malakoplakia of the bladder. Am J Clin Pathol 1973; 60:780.

461. Bowers JH, Cathey WJ: Malakoplakia of the kidney with renal failure. Am J Clin Pathol 1971; 55:765.

462. Malfunctioning microtubules. Editorial. Lancet 1978; 1:697.

463. Abdou NI, NaPombejara C, Sagawa A, et al: Malakoplakia: Evidence for monocyte lysosomal abnormality correctable by cholinergic agonist in vitro and in vivo. N Engl J Med 1977; 297:1413.

Page

Contents

If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!