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PURPOSE: The highest incidence of urinary tract infection in females occurs in elderly women. This study was done to determine whether this is due to the declining immune response that occurs during advancing age, or the menopausal state in the aged. MATERIALS AND METHODS: Adult female monkeys (average age 19 years) were studied, half being subjected to bilateral oophorectomy to produce the menopause. In addition, old females (average age 29 years) already at menopause were studied before and after hormonal replacement with estradiol and progesterone. Bacterial adherence to vaginal cells was studied prior to and after urethral infection with E. coli. Plasma estradiol and progesterone levels were done, as well as white blood counts, plasma cytokine assays and serum antibody titers. RESULTS: Bacteriuria was not prolonged, nor was there a significant difference in bacterial adherence to vaginal cells due to menopause. Interleukin-1 levels were depressed after surgical menopause but not as much as found in the old menopausal females and this low level was not corrected by hormonal replacement. The initial interleukin-2 levels were higher after spontaneous menopause, but the increasing plasma levels seen in cycling animals after infection did not occur in the aged menopausal females following infection even after hormone replacement. The antibody titers to the E. coli infection showed a trend to a lessened response to infection after menopause but were not significantly decreased. CONCLUSIONS: The deficient Il-1, Il-2 and antibody response following infection was not corrected by hormone replacement and thus appears to be due to aging rather than lack of female hormones. These facts may be explained by the T cell senescence known to occur in aged individuals.

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The authors studied plasma cytokine activity using cross reactive polyclonal antibodies to human cytokines in young and old female monkeys to determine if age had any effect on cytokine secretion, and compared hormonal effects as well. While interleukin 1 (IL-1) was not higher in aged cycling monkeys, it was after menopause. Menopause depressed IL-2 activity also. Variable results were seen with the other cytokines.

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PURPOSE: This is a study of the interaction of the tip protein of P-fimbriae E. coli, its specific urothelial adhesin, and urothelial receptors for the adhesin. This tip protein has several epitopes that adhere to different isoreceptors containing the urothelial alpha-gal-1-4 beta-gal disaccharide. Renal tubular cells of our monkey model contain the globoside isoreceptor, and thus ureteral inoculation of E. coli with the class II tip protein leads to pyelonephritis. The class III tip protein adheres to the Forssman antigen and causes cystitis in humans. MATERIALS AND METHODS: An E. coli strain, DS17 which originally caused pyelonephritis in a child, is P-fimbriated and contains a class II tip adhesin. A mutant was produced to contain a class III tip adhesin. Eight monkeys had a ureteral inoculation of E. coli DS17 and 4 monkeys with E. coli DS17-1. In addition, we studied in vitro adherence by these strains. RESULTS: We show that in vitro adherence by the tip protein of P-fimbriae to bladder cells of the monkey occurs by several mechanisms, adhering to specific receptors for the class II and III epitopes of the tip protein as well as by means of type 1 fimbriae. In addition, the PapE protein of the fibrillum of the P-fimbriae adheres to fibronectin. As always, electrostatic and hydrophobic interaction remain important contributions to adherence. E. coli DS17 caused pyelonephritis, but DS17-1 caused cystitis. Bacteriuria was prolonged by DS17 infection. CONCLUSION: The site of a urinary tract infection from P-fimbriated E. coli can be predicted by the epitope of the tip protein of P-fimbriae.

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A formalin-killed P-fimbriated Escherichia coli serotype O4 vaccine was evaluated for protective efficacy in monkeys in an experimental pyelonephritis model following urethral bacterial inoculation. The vaccination did not protect against initial colonization and there were no significant differences in the time of bacteriuria after experimental infection in the two groups of animals. The whole-cell vaccine offers a limited protection against renal dysfunction and scarring (p = 0.002) and less renal involvement (p = 0.04), results that are quite similar to those given by a synthetic O-antigen-specific saccharide-protein conjugate vaccine previously tested.

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We studied the cellular and humoral events which follow experimental acute pyelonephritis from P-fimbriated Escherichia coli to gain insight into the relationships among cells and specifically cytokines to determine how early events in untreated infection lead to renal damage. Cynomolgus (Macaca fascicularis) monkeys were studied after they were subjected to unilateral ureteral bacterial inoculation. We evaluated the blood for leukocytosis and studied lymphocyte subsets using flow cytometry and monoclonal antibodies to the subsets and serum, complement, cytokines and antibody titers. Interleukin-1, 2 and 6 and tumor necrosis factor (TNF) were assayed by enzyme-linked immunoadsorbent assay (ELISA), using monoclonal and polyclonal antibodies. Leukocytosis was marked and there were significant elevations in serum cytokines, interleukin-1 alpha, 2 and 6 with only small changes in the level of TNF. Interleukin-2 levels were sustained and may have upregulated the homing receptor for virgin lymphocytes. The studies illustrated the unique relationship between cytokines and lymphocytes and the response to bacterial infection, showing that the inflammatory response is regulated not only by cytokine activity but also by lymphocyte activation.

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Nonobstructive acute pyelonephritis in humans is most often caused by P-fimbriated Escherichia coli. P-fimbriae are heteropolymeric fibers carrying a Gal(alpha 1-4)Gal-specific PapG adhesin at its distal end. The pyelonephritic strain DS17 expresses P-fimbriae from a single gene cluster. A mutant strain, DS17-8, which expresses P-fimbriae tacking the PapG adhesin, was constructed by allelic replacement introducing a 1-bp deletion early in the papG gene. In cynomolgus monkeys, DS17 and DS17-8 were equally able to cause bladder infection, whereas only the wild-type strain DS17 could cause pyelonephritis as monitored by bacteriological, functional, and histopathological criteria. Since DS17, but not DS17-8, adheres to renal tissue, these data underscore the critical role of microbial adherence to host tissues in infectious disease and strongly suggest that the PapG tip adhesin of P-fimbriae is essential in the pathogenesis of human kidney infection.

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Rhesus monkeys were vaccinated with a synthetic Escherichia coli serotype O8 oligosaccharide-protein conjugate. Using our experimental pyelonephritis monkey model, we tested whether such immunization was protective against the renal damage from inflammation following experimental infection with a P-fimbriated O-antigenically homologous E. coli strain. The vaccination did not significantly alter the duration of bacteriuria or interfere with the infection. However, the vaccine was efficient in renal protection, as vaccinated animals showed significantly less intratubular infiltration of neutrophils (P < 0.02) and the degree of renal scarring was also significantly less in these animals (P > 0.005) than in the control animals. Total kidney involvement in the vaccinated animals was 16.9%, compared with 32.5% in the control animals (P = 0.07).

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Experimental acute pyelonephritis in monkeys led to death in some of the animals following renal E. coli inoculation. It was found that both the inflammatory response and cytokine activation were much more severe in these monkeys as compared with others that survived. IL-1 was decreased just before death, and there were early increases in IL-2 and IL-6 serum concentrations, but no significant increase in TNF values. The data suggest that death in sepsis is due in part to excessive cytokine release because of a decrease in the protective activity of IL-1.

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The adherence of P-fimbriated Escherichia coli to a receptor containing alpha-D-Gal-(1-4)-beta-D-Gal (Gal-Gal) on urothelial cells is an important pathogenic mechanism in the development of pyelonephritis. Antibodies (Ab1) that had been produced by immunization with Gal-Gal conjugated with bovine serum albumin were specifically purified and used to stimulate the production of anti-idiotypic antibodies (Ab2) in cynomolgus monkeys (Macaca fascicularis). While sera from all of the Ab2-producing monkeys contained antibodies reactive with Ab1 and P-fimbriae, not all of the sera inhibited P-fimbrial binding to the Gal-Gal receptor. On the basis of the inhibition of binding, Ab2-producing monkeys were divided into two groups, termed reactive and nonreactive. The reactive and nonreactive Ab2-producing monkeys, together with a group of control monkeys, were challenged with a renal inoculation with P-fimbriated Escherichia coli. Hematologic, immunologic, microbiologic, and pathologic data were compared among the three groups. The reactive monkeys, whose Ab2 in serum inhibited binding between P-fimbriae and the Gal-Gal receptor, were protected against renal damage compared with the control group. The nonreactive group shared some parameters with the reactive group but overall developed renal damage comparable to that of the controls.

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Previous clinical studies of catheters with hydrophilic coating have, in some instances, shown a delay in the onset of significant bacteriuria, while others reported no such effect. To attempt to determine reasons for these differences we decided to study bacterial adherence of bacteria obtained from nosocomial urinary tract infections associated with catheters. Almost all strains adhered to the silicone catheter and none of them adhered to the catheter with the hydrophilic surface whether incubated in urine or serum. When incubated in urine, all strains adhered to the red rubber catheters. Adherence was variable to the Teflon and elastomer surfaces.

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Extracorporeal shock wave lithotripsy (SWL) is becoming popular in the management of lower ureteral calculi; however, the quantity of data on its potential gonadotoxic effects are limited. Eight nonhuman primates had baseline measurements of testicular volume, semen analysis, serum testosterone and FSH assays, and DNA flow cytometric analysis of testicular aspirates. The anesthetized primates were lowered into a Dornier XL-1 lithotripter and at a 20 kV power setting had various numbers of shocks (0, 500, 1500) directed at each testis. Sequential studies were done at 6-week intervals for 9 months. The control group showed no significant change in any measure. Semen analysis, testosterone, and FSH results were variable and without statistically significant differences. There were changes in the DNA histograms, with the tetraploid (4N) group of cells being the most sensitive. All changes caused by SWL application returned to baseline by 9 months. Data from this primate study document no apparent long-term male gonadotoxicity from SWL, but the authors suggest measures to protect the testis during clinical use.

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Patients with prostatitis have been found to have decreased prostatic fluid zinc (PF Zn). It is unclear whether changes of prostatitis are due to an inherent lack of Zn in some patients or whether the changes, including reduced PF Zn, are due to the infectious process itself. Six nonhuman primates were infected with 1 x 10(5) E. coli JR340, a clinical isolate known to cause prostatitis in the monkey. After infection, seminal fluid for culture and zinc assay was obtained by electroejaculation. Zinc was measured by colorimetric analysis. Blood counts, quantitative renal scans and urine cultures were also monitored. The animals were followed for 4 weeks and then sacrificed. The histopathology showed resolving prostatitis and fibrosis. Zinc levels dropped with acute infection, and variably recovered as the infection cleared. Controls showed slight variability with respect to PF Zn. It appears that PF Zn decreases as a result of the infectious process.

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While acute pyelonephritis is known to elicit an antibody response, it is also known that a patient who has had pyelonephritis once is susceptible to recurrent renal infection. Using our experimental model of pyelonephritis in the monkey, we tested whether antibiotic therapy of the acute disease would affect the antibody response. We found that it did, because antibiotic therapy beginning 72 h after bacterial inoculation attenuated the antibody response so that rechallenge 3 months later produced acute pyelonephritis and prolonged bacteriuria. The animals with untreated infection had an antibody response that lasted a sufficient period of time to prevent acute pyelonephritis after renal challenge. We have confirmed that antibody titers against P fimbriae are protective, and to a degree, this protective effect may be abrogated by antibiotic therapy.

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Since the advent of extracorporeal shock wave lithotripsy (ESWL) concern has surfaced as to the long-term risk of the development of hypertension, as well as risk to the developing kidney. To study this concern 8 infant and 3 adult rhesus monkeys (Macaca mulatta) underwent treatment with the XL1 experimental lithotriptor to 1 kidney varying the amount of voltage and shocks. Followup consisted of measurement of renin levels and quantitative renal scans, using 131iodine hippurate to calculate effective renal plasma flow. In the infants a slight change was noted in the absolute effective renal plasma flow of the treated kidney versus the untreated side but it was not statistically different. When indexed to body surface area in the growing animal, there was a statistically significant decrease in renal function. However, peripheral renin levels were markedly elevated in the infants at 3 weeks, and they gradually declined during the 6-month period, although levels remained elevated over baseline. The adults also had central renin levels drawn from the renal vein on the treated side, and there was a close correlation with the peripheral levels, which peaked at 3 weeks and returned to normal. Thus, it seems that at least in the short term renin production is increased in infants more than adults. This finding may be an indicator as to renal damage and is a possible explanation for hypertension occurring after ESWL.

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Interstitial cystitis presents a diagnostic and therapeutic challenge. Although many etiologies, including autoimmunity, have been proposed its pathogenesis remains obscure. Tamm-Horsfall protein has been identified in the superficial urothelium of patients with interstitial cystitis demonstrating abnormal urothelial permeability. Eight patients with a clinical diagnosis of interstitial cystitis underwent cystoscopy and bladder biopsy. Characteristic cystoscopic findings were present, and each patient had chronic inflammation and mast cells by histopathological analysis. Preoperative anti-Tamm-Horsfall protein serum antibody (IgG) titers were determined by enzyme-linked immunosorbent assay (range 500 to 8,000, mean 2,750). A control group of 8 patients with a negative urological history also had titers of 0 to 500 (p = 0.02). The humoral response to Tamm-Horsfall protein in these patients suggests a role for Tamm-Horsfall protein in interstitial cystitis. Measurement of serum Tamm-Horsfall protein antibody may prove to be useful as a noninvasive diagnostic test in patients with this disease.

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Closed sterile catheter drainage has markedly reduced the incidence of nosocomial urinary tract infections. Infections that occur during closed drainage must ascend by colonizing the catheter or urethra. Our study compared adherence by different bacterial species to different catheter surfaces. We found no bacteria adhering to the hydrophilic catheter surface. Of the gram-negative bacteria Proteus mirabilis showed the greatest adherence to the other catheters and it, like most bacteria, showed the most marked adherence to the red rubber catheter.

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Bacterial prostatitis is a common cause of urinary tract infection in males, but little is known of its pathophysiology. To study this, we developed a nonhuman primate model using a wild-type clinical isolate of Escherichia coli. Primates have a prostatic anatomy that is similar to humans, which makes them ideal as an animal model of this disease. The monkeys had a urethral inoculation of this organism and were then followed with urine, blood, and semen cultures, white blood counts, and renal scans. They were sacrificed at from 10 days to 4 weeks, and their genitourinary tracts histologically examined. The prostatitis paralleled that reported in humans, and we conclude that the infection occurs by the ascending route. The organisms causing the infection in man do so in our primate model, and the histologic change is also the same. Thus, the primate model holds promise for studies to help us understand this disease.

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Previous studies show that chronic pyelonephritis and end stage renal disease may follow acute pyelonephritis in children and adolescents when improperly or inadequately treated. Our study shows that there is a significant decrease in renal function following untreated acute bacterial pyelonephritis due to nephron loss. The acute inflammatory response is responsible for much of the renal damage, although damage from renal ischemia is an additional significant factor. The present study used a combination of an antibiotic and a xanthine oxidase inhibitor (allopurinol) as compared to antibiotic therapy alone begun 72 hours after infection. Both were successful in eradicating the infection rapidly, but did not entirely prevent renal damage. Treatment prior to 72 hours thus is important. It appears that the combined treatment, designed to eradicate the bacteria as well as reduce the post-ischemic reperfusion damage and the phagocytic burst of phagocytosis is ideal, as this combined treatment was effective in preventing almost all renal damage and loss of renal function.

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Escherichia coli with both P and type 1 fimbriae caused vaginal colonization in the female green monkey, while only the P-fimbriated bacteria frequently caused ascending bladder infection. Bladder inoculation caused only short-lived bladder infection from type 1 fimbriated E. coli, but those with P-fimbriae caused acute pyelonephritis even in the absence of vesicoureteral reflux. Thus, type 1 fimbriae of E. coli, while causing vaginal colonization, did not often cause ascending infection in the non-compromised host as did P-fimbriated bacteria.

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