Urinary Tract Infections

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Host Defense Mechanisms in the Pathogenesis of Urinary Tract Infection Robert E. Measley, Jr., MD, * and Matthew E. Levison, MDt

This article reviews the host factors involved in the pathogenesis of urinary tract infection (UTI). The types of organisms infecting the urinary tract, the origin of the uropathogens, routes of spread to the urinary tract, and factors influencing the rates of microbial growth at each anatomic locus in the urinary tract are discussed. Recent advances in our understanding of bacterial virulence factors, including mechanisms of bacterial adherence to mucosal surfaces, are discussed elsewhere in this issue. TYPES OF UROPATHOGENS The most frequent uropathogens are aerobic and facultative anaerobic gram-negative bacilli, primarily Escherichia coli and other Enterobacteriaceae, such as Proteus mirabilis, Klebsiella pneumoniae, Enterobacter sp., and, to a lesser extent, Pseudomonas aeruginosa. Indeed, only about six serotypes of E. coli cause about 85% of acute UTI. Gram-positive cocci, such as Enterococcus sp., are infrequent uropathogens. Staphylococcus aureus, Salmonella, Candida sp., and Mycobacterium tuberculosis are unusual uropathogens and are found in special clinical situations. ORIGIN OF THE UROPATHOGENS The most common uropathogens, the Enterobacteriaceae and Enterococcus sp., are normal constituents of the colonic flora. The colon has larger numbers of these organisms than any other site on the body, at about 106 From the Medical College of Pennsylvania, Philadelphia, Pennsylvania *Instructor in Medicine and formerly Fellow in Infectious Diseases tProfessor of Medicine and Chief, Division of Infectious Diseases

Medical Clinics of North America-Vo!' 75, No. 2, March 1991

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to 108/g of colon contents (or about 0.1% of total colonic flora). In fact, the very same serotype of E. coli infecting the urinary tract is found to be the predominant coliform in that patient's colonic flora. 23 Although infrequent members of the normal colonic flora, Pseudomonas and Salmonella are thought to originate in the intestinal tract in the special situations in which UTI follows colonic colonization by these organisms; S. aureus and the tubercle bacillus, not normal constituents of the colon, are thought to originate in a primary source of infection elsewhere in the body (e.g., S. aureus abscess or endocarditis or pulmonary tuberculosis, respectively). Candida, which is an occasional constituent of the intestinal flora, is thought to originate either in the intestinal tract in patients with indwelling bladder catheters (that provide ready access to the urinary tract) or in a primary source of infection elsewhere in the body (e. g., candidal intravenous catheter sepsis). ROUTES OF INFECTION Microorganisms can reach the urinary tract by way of the ascending, hematogenous, or lymphatic routes. There is considerable clinical and experimental evidence that the ascent of microorganisms within the urethra l2 , 14, 35 from external sources represents the most common pathway for UTI, especially for organisms of enteric origin, i. e" E, coli and other Enterobacteriaceae, This is the most logical explanation for the greater frequency of UTI in women and for the increased risk of infection following bladder catheterization or instrumentation, In women, the urethra is shorter and is more liable to contamination (during sexual activity, urethral massage, or even during urination) with colonic flora that reside on the perineal skin,4, 5, 28, 38 Indeed, in women prone to recurrent UTIs, the vaginal mucosal surfaces of the vaginal introitus are colonized with E. coli and enterococci, rather than the lactobacilli that normally constitute vaginal flora,82 In men, the greater length of the urethra and the antibacterial properties of prostatic secretions are effective barriers to invasion by this route,81 A single insertion of a catheter into the urinary bladder in ambulatory patients results in urinary infection 1% to 2% of the time. 28 Indwelling catheters with open drainage systems result in UTI in almost 100% of cases within 3 to 4 days, Use of closed drainage systems, which greatly delays the onset of infection, is strong evidence for the ascending route in patients with catheters. Bladder microorganisms may further ascend the ureters, even against the downward flow of urine, especially if facilitated by vesicoureteral reflux, to reach the renal pelvis, where they may penetrate the kidney via backflow into the renal collecting system or via lymphatics, In experimental animals, the ability to cause renal infection can be greatly enhanced in the presence of a water diuresis, which facilitates vesicoureteral reflux, following the injection of small numbers of E. coli into the bladder. 19 If one ureter is completely ligated, and then the bladder is injected, only the opposite kidney with an intact ureter becomes infected, The hydronephrotic kidney proximal to the ligation, which is highly

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susceptible to hematogenous infection, remains uninfected. This experimental demonstration proves convincingly that infection can spread by ascending via an intact ureter, and not necessarily via the bloodstream. 95 Clinically, hematogenous infection of the urinary tract is restricted to a few relatively uncommon uropathogens, such as S. aureus, Candida sp., Salmonella, and M. tuberculosis, which cause primary infection elsewhere in the body. In the experimental animal, S. aureus, Enterococcus sp., and Candida sp. readily cause renal infection following intravenous injection. IR , 25.45 However, renal infection fails to occur following intravenous injection in the experimental animal of even large inocula of Enterobacteriaceae, such as E. coli, and P. aeruginosa,22 which are cleared efficiently from the bloodstream by the reticuloendothelial system. After intravenous injection, only a small number of organisms seed the kidney, which then rapidly are cleared by local defense mechanisms, unless the kidney is made more vulnerable by the presence of either extra- or intrarenal obstruction to urine flow (e.g., renal cautery, ureteral ligation)24 or diabetes mellitus. 4l Larger intravenous inocula are rapidly fatal as a result of endotoxemia. 22 However, renal infection occurs if injection oflarge inocula is made directly into the renal artery, which delivers to the kidney a large number of E. coli that overcomes renal defense mechanisms. 70 Candida albicans readily causes clinical and experimental UTI by the hematogenous route, but it is an infrequent cause of ascending infection, unless a chronic indwelling urinary bladder catheter is present. 42 The resistance to ascending infection is likely due to poor adherence of Candida to normal bladder mucosa. 42 Neither diuresis, diabetes mellitus, nor vaginal candidiasis experimentally promotes ascending infection. However, prior E. coli UTI enhances adherence of Candida to bladder mucosa and promotes ascending Candida infection.42 Spread of infection to the urinary tract via lymphatics remains speculative. 53 HOST DEFENSES IN THE URINARY TRACT

Following spread of microorganisms to the urinary tract, the outcome depends on bacterial virulence factors and on host defenses in the urine, bladder, ureters, and kidneys. Urine Under some circumstances, urine may be inhibitory, or even bactericidal, against small inocula of uropathogens. 36 The most important inhibitory factors in urine are high osmolality, urea concentration, and organic acid concentration and low pH. Oligosaccharides and uromucoid, now known to be identical to Tamm-Horsfall protein, are found in normal urine and may competitively inhibit attachment of E. coli to the mucosal surface of the urinary tract by aggregating the bacteria in the urine, 31, 5R The increased risk of urinary infection in the elderly has been attributed in part to the lower urinary excretion rates of Tamm-Horsfall protein found in the elderly,77 Finally, antibody known to be released into urine in patients with

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renal disease has been shown to inhibit adherence to uroepithelial cells in vitro.32. 65. 85 Modification of the chemical composition of the urine in certain clinical conditions or with medication can alter ability of urine to support the growth of microorganisms. For example, glucose in diabetic urine enhances the growth of uropathogens, such as E. coli41 and C. albicans. 64 Women, especially during pregnancy, have a urinary pH more suitable for the growth of E. coli than men have. When the pH of the urine is about 5, the urine is inhibitory as a result of conversion of naturally occurring weak organic acids to the unionized form that has antibacterial activity. Changes in the environment in the urine may have an opposite effect on host defenses in other areas of the urinary tract. For example, acidification stimulates renal production of ammonia, which inactivates the fourth component of complement, an essential factor for efficient phagocytosis in renal tissues. Indeed, the undamaged kidneys of experimental animals receiving acidifying agents were susceptible to hematogenous E. coli infection. 21 Thus, acidification, which may enhance urinary defenses, simultaneously diminishes renal defenses. Conversely, water diuresis, which may diminish urinary defenses by diluting urinary antibacterial substances, simultaneously enhances renal defenses by a number of different mechanisms. For example, water diuresis abolishes the normally high renal medullary osmolality, which interferes with the action of complement and the migration of phagocytes into the renal parenchyma. 2 Water diuresis also increases medullary blood flow, which enhances delivery of phagocytic cells and antibacterial substances to the renal tissues. 1 In addition, water diuresis also bolsters bladder defenses by increasing bladder emptying. Nevertheless, the delicate balance between host defenses in various portions of the urinary tract and microbial multiplication can be altered by water diuresis in favor of renal infection by enhancing vesicoureteral reflux or by diluting the antibacterial substances in the urine. 19 Recently, a number of urinary "osmoprotective" substances, mainly betaine, choline, proline, and glutamine, which protect distal tubular epithelium from locally high osmolar gradients, may simultaneously protect microorganisms from osmotic forces. 6 • 7 Vaginal Introitus The vaginal mucosa is normally colonized by lactobacilli, despite close proximity and probable frequent contamination with large numbers of enteric organisms. However, women at risk of UTI have been noted to have enteric organisms colonizing the mucosal surfaces of the vaginal introitus. 63. 80. 82 This has been attributed to increased receptivity of vaginal and uroepithelial cells for attachment of E. coli in these patientsY' 33. 71. 72, 86 The increased receptivity is perhaps controlled by genetic factors,85 as reflected by prevalence of certain HLA types 73 or blood group substances 43 among those with UTI. Blood group substances that appear on the surfaces of uroepithelial cells may either function as receptors for attachment of bacterial surface structures or block attachment to less prominent receptors, For example, nonsecretors of blood group substances AB and B have the highest risk for UTI in comparison to secretors or those with other blood

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groups. 13, 39 It is hypothesized that the epithelial cell surfaces of secretors are associated with A, B, and H blood group oligosaccharides that may obscure the less prominent receptors for bacterial adherence, thereby preventing attachment of bacteria. 75 Recent studies have suggested that use of diaphragms and spermicide may correlate with increased risk for UTI. This was associated with increased vaginal colonization with E. coli and other enteric flora, perhaps as a consequence of the antibacterial effects of the spermicide that disrupts normal vaginal flora. 16, 83

Bladder In addition to the antibacterial activity of urine, the bladder has several defense mechanisms capable of clearing bacteria that have reached the bladder. 11, 56, 57, 74 Although the mechanical removal of bladder microorganisms by dilution with fresh urine, followed by complete emptying of the bladder, removes the bulk of contaminated urine, micturition leaves behind a film of contaminated urine on the surface of the bladder mucosa that should be sufficient to maintain colonization. 54 However, several animal studies have demonstrated the effectiveness of antibacterial properties of the bladder mucosa in clearing surface contamination. 9, 54, 95 The exact mechanism of the mucosal antibacterial activity remains to be elucidated, 87 In addition, the surface mucin coating of the bladder mucosa undoubtedly plays a role in preventing bacterial attachment and subsequent colonization because its removal with acetic acid enhances bacterial colonization. 59-62 Ureter U reteral peristalsis facilitates flow of urine from the kidney to the bladder. Diminished ureteral peristalsis undoubtedly contributes to the increased susceptibility to UTI during pregnancy, Studies have identified a heat-sensitive calcium ionophore produced by some uropathogens that inhibits ureteral peristalsis. 89, 91 The efficiency of bladder emptying is maintained by competent vesicoureteral valve action, which prevents contaminated bladder urine from going up the ureters during voiding and allows only fresh urine to flow into the bladder when voiding is complete. Although even under normal conditions microorganisms can ascend against the flow of urine, vesicoureteral reflux is gross passage of bladder urine up the ureters on voiding. Reflux impairs the efficiency of bladder emptying by producing a residual ureteral urine. Reflux occurs in children as a congenital developmental anomaly. In children, if reflux is severe, it may exert sufficient hydrostatic pressure on the renal pelvis to impair renal growth, even in the presence of sterile urine. In the presence of infected urine, reflux can rapidly destroy the kidney. In those children without greatly dilated ureters and large amounts of residual urine, if infection is prevented by suppressive antimicrobial therapy, the reflux tends to lessen with age. Reflux is found in patients with lower urinary tract obstruction. It is also transiently present in adults with UTI and disappears once the infection is treated. As with reflux, extrarenal obstruction, due to stones, extrinsic compression of the ureters, congenital urinary tract anatomic anomalies, pros-

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tatic hypertrophy, or tumors, can exert destructive hydrostatic pressure on the kidney and prevent efficient emptying of the urinary outflow tract. Although obstruction itself does not increase contamination of urine with uropathogens from external sources, the presence of obstruction increases the risk of renal infection, either by the hematogenous route or following introduction of a uropathogen into the urinary tract by the ascending route. Intrarenal obstruction (such as caused by renal scars, especially in the medulla, nephrocalcinosis, uric acid nephropathy, and interstitial nephritis) also increases susceptibility of the kidney to infection. The mechanisms for increased renal susceptibility following obstruction are unknown but probably are related to intrarenal hydronephrosis and changes in intrarenal blood flow, especially in the medulla. 68 Kidney The renal cortex is much more resistant to infection than the medulla, for both gram-negative bacilli or gram-positive cocci that reach the kidney by either the hematogenous or ascending routes. Even following direct injection into renal tissues, 1O,000-fold more bacteria are needed to initiate renal infection in the cortex than the medulla. 20 High concentration of ammonia and high osmolality, the relative anoxic state, and relatively low blood flow in the renal medulla impede humoral and cellular defenses,67 as discussed previously. Immune Response The immune response appears to have a limited protective role in both renal and bladder infection. 32, 48, 55, 65, 66, 76, 88, 92 Both systemic and local antibody production occur in renal infection, with type-specific antibody detectable in the urine,30 even before antibody can be detected in serum. Urinary antibody may function by decreasing adherence of bacteria to uroepithelial cells. 88 Antiadherence antibodies have been found to be directed against several different antigens of E. coli, the 0, K, and type 1 and P fimbriae. 32, 65, 88 Other postulated roles of antibody include activation of the complement system by antibody-antigen complexes, which in turn recruit cellular defenses to restrict further bacterial proliferation. Antibody production also prevents reinfection by the same strain. Clinical studies have shown that 80% of recurrent infections are caused by different serotypes of E. coli. so, 82 This is true not only for renal infection, in which serum and urine antibody is routinely produced, but also for lower UTI, in which serum and urinary antibody is characteristically not produced. 82 The exact protective mechanisms are unknown. Animal experiments have confirmed that renal infection is unlikely to recur with the same strain. 32, 48 Immunization of the bladder against bacterial antigens confers protection against renal infection, and renal infection confers protection against bladder infection with the same strain. 3, 92 In addition to a protective role, the immune response may contribute to the severity or chronicity of the infection, For example, the titer of serum antibody detected against the lipid A component of gram-negative bacillary lipopolysaccharide (or endotoxin) has been shown to correlate with

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the severity of pyelonephritis and subsequent renal scarring. 47 In the experimental animal, T-cell infiltration occurs in the kidney and transiently in the bladder in ascending infection,29 and the prominence of the renal Tcell infiltrates correlates with the chronicity of the renal infection. The persistence of renal infection has been associated with enhanced suppressor T-cell activity. 51, 52 Treatment with cyclophosphamide and antibiotic paradoxically had greater antibacterial efficacy than antibiotic alone, presumably by enhancing cell-mediated immunity by modulation of suppressor T lymphocytes. 5o On the other hand, clinical experience with patients who have profound deficiency in T-Iymphocyte activity has failed to disclose any increased susceptibility to renal infection, despite a marked propensity to severe, multiple opportunistic infections. Chronicity of the inflammatory response in the renal parenchyma has been attributed to persistence of bacterial antigens and antibody-producing mononuclear cells, which can be demonstrated in the kidney of experimental animals long after disappearance of viable organisms. 10 Renal scarring has been related to the severity of the prior neutrophilic inflammatory response in the experimental animal. PREDISPOSING FACTORS FOR URINARY INFECTIONS Most women with UTIs have no known predisposing factor other than increased receptivity of uroepithelial cells for attachment of uropathogens, as mentioned previously, in some patients with recurrent infections. The Elderly Normal aging is associated with an increase in the frequency of UTI. About 10% to 20% of elderly living at home have bacteriuria. The rates increase to about 30% in the hospital setting and correlate with the degree of debility that results from the underlying diseases in these elderly patients. Over 65 years, the frequency of bacteriuria increases dramatically with age, especially in men, reaching near parity between the two sexes. 37 The many reasons for this age association in the rate of bacteriuria include (1) impaired bladder emptying as a result of immobility or underlying neuropathic diseases, (2) obstructive uropathy secondary to prostatic disease and the subsequent urologic instrumentation and surgery, (3) waning of bactericidal secretions from the prostate,46 and (4) increased perineal soiling in women. 37 Recent studies have failed to correlate an increased capacity for adherence of uropathogenic E. coli to urinary or vaginal epithelial cells with aging. 78, 79 However, Sobel et aF7 were able to show decreased Tamm-Horsfall protein (uromucoid) secretion in the urine of the elderly, which suggests that a decreased antiadherence effect may contribute to the higher frequency of bacteriuria in this group of patients. Diabetes Mellitus Controlled studies have demonstrated a two to four fold increased frequency of bacteriuria in diabetics compared to nondiabetics. 34 , 84, 96 Although most UTIs in diabetics are asymptomatic, they more often lead

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to severe complications, such as papillary necrosis, gas production (so-called emphysematous pyelonephritis), or perinephric abscess. In fact, up to 50% of patients with papillary necrosis 44 and 33% of those with perinephric abscess have diabetes. 90 Fungal UTls are also more common in diabetics, especially those with significant glycosuria. 49 In the experimental animal, hyperglycemia increases the susceptibility of the kidney to hematogenous E. coli infection, and the osmotic diuresis secondary to glycosuria predisposes to ascending E. coli infection.41 With Candida infection, fungus balls form more readily in the presence of glycosuria: they obstruct the urinary tract and result in rapid renal destruction. 64 Clinically, the mechanisms that predispose to UTI in diabetes include (1) autonomic neuropathy, which impairs bladder emptying15 and the subsequent urologic manipulation;93 (2) the high concentration of urinary glucose, which impairs phagocytosis;8 and (3) generalized vascular disease and nephrosclerosis, which may delay the protective inflammatory response and increase the possibility of papillary necrosis. Urinary Tract Calculi Calculi often obstruct urinary flow, but even without obstruction, calculi may serve as irritants to urinary tract mucosa, which promote bacterial adherence and colonization, and as a secluded focus of bacterial persistence. Stones that form in the presence of UTI owing to ureaseproducing microorganisms (known as struvite or triple phosphate stones) may account for 10% to 15% of urinary calculi. 40 Urease-producing microorganisms include Proteus mirabilis, Ureaplasma urealyticum,26 and strains of Klebsiella pneumoniae, Pseudomonas aeruginosa, Providencia sp., and Staphylococcus sp. Cure of infection with antimicrobial agents in the presence of calculi is difficult, if not impossible. Relapse of bacteriuria following therapy occurs as a result of release of bacteria from secluded foci deep within the stone; cure requires disruption or surgical removal of the stone. 69 Obstruction Clinical and experimental observations confirm that obstruction at any level in the urinary tract compromises defenses of the urinary tract against infection. In fact, obstruction may reactivate infection in healing renal tissues, and removal of ureteral obstruction may halt ongoing renal destructionY Intrarenal obstruction produced by renal scars, either due to prior infection or experimentally induced, especially when located in the medulla, increases susceptibility of the kidney to hematogenous infection. The increase in susceptibility is greatest around the old scars, where hydronephrosis is most severe. 68 Cortical scars do not appear to increase susceptibility to infection, presumably because minimal intrarenal obstruction is produced. As discussed previously, it is unclear exactly why obstruction has this effect. Early experiments showed that increased trapping of intravenously injected bacteria by the affected kidney did not explain the increased susceptibility of the obstructed kidney to hematogenous infection.

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Matthew E. Levison, MD Department of Infectious Diseases Medical College of Pennsylvania 3300 Henry Avenue Philadelphia, PA 19129