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The interaction of urinary tract infection and renal insufficiency
International Journal of Antimicrobial Agents 28S (2006) S72–S77
The interaction of urinary tract infection and renal insufficiency Reinhard F¨unfst¨uck a,∗ , Undine Ott b , Kurt G. Naber c a
Department of Internal Medicine I, Sophien- and Hufeland-Klinikum Weimar, Weimar, Germany b Department of Internal Medicine III, Friedrich-Schiller-University, Jena, Germany c Department of Urology, St. Elisabeth Hospital, Straubing, Germany
Abstract Urinary tract infections (UTIs) are among the most common infections caused by microorganisms, and pyelonephritis is the most severe infection of the urogenital tract. The risk of developing chronic renal insufficiency due to a UTI without other risk factors is low. The pathogenicity and virulence of the infective microorganisms as well as the efficiency of local or systemic defence mechanisms determine the course and severity of the disease. Virulence properties (adhesins, toxins, capsule, iron uptake) are encoded by genomic structures and the determination of virulence is influenced by the host situation. In renal insufficiency, a variety of quite different substances (uraemic toxins, betaine, amino acids, creatinine, urea, glucose) influence the microbial environment. Defence factors (Tamm-Horsfall protein, defensin, phagocytic activity of granulocytes) and underlying anatomical lesions as well as pre-existing renal disease determine the severity of UTI and the prognosis of renal insufficiency. © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Urinary tract infection; Renal insufficiency; Microbial properties; Local defence
1. Introduction Urinary tract infections (UTIs) are one of the most common bacterial infectious diseases in humans. The US National Ambulatory Care Survey shows that every year more than 7 million patients suffer from a UTI in the USA [1]. More than 40% of nosocomial sepsis cases are caused by UTIs [2]. The manifestation and course of the disease are influenced by virulence factors of microorganisms on the one hand and defence mechanisms of the host on the other. A deterioration in renal function correlates with disturbances of various specific and nonspecific host defence reactions. In renal diseases is a changes in the composition of urine in oliguria, anuria, albuminuria and haematuria observed. The resultant changes in pH, osmolarity and urinary urea have their own effects in urinary tract infection. An accumulation of various uremic toxins inhibit the antimicrobiological activity of granulocytes, macrophages and other defense reaction. These conditions may support the development of UTI in patients with renal disease. ∗
Corresponding author. Tel.: +49 3643 571150; fax: +49 3643 571102. E-mail address: [email protected] (R. F¨unfst¨uck).
This review will discuss some aspects fo UTI in relationship to renal insufficiency. The potential impact of UTI on renal function when underlying renal impairment as well as aspects of renal insufficiency on the development of UTI will be discussed. In this connection results of microbiological investigations and special parts of deterioration of host defence in renal insufficiency will be demonstrated.
2. Epidemiological aspects Epidemiological studies in many European countries confirm that an increasing number of patients suffer from progressive deterioration of renal function. The European Renal Association—European Dialysis and Transplant Association registry shows that the incidence of renal replacement therapy for end-stage renal disease increased from 79.4 cases per million population (pmp) in 1990–1991 to 117.3 pmp in 1998–1999, i.e. an increase of 4.8% per year [3]. The incidence of end-stage renal disease due to diabetes mellitus, hypertension and renal vascular disease nearly doubled over 10 years. The German registry of the QuaSi-Niere GmbH
0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2006.05.004
R. F¨unfst¨uck et al. / International Journal of Antimicrobial Agents 28S (2006) S72–S77
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Fig. 1. Cases of renal insufficiency in the Germany dialysis population in 2003 [36].
shows the same trend (Fig. 1). To summarize, of all patients undergoing renal replacement therapy in Germany, 14% suffered from interstitial nephritis (this value includes the population with UTI). It is difficult to determine the specific role of UTI in the official renal data reports. It is well known that infection perpetuated by anatomical or functional abnormalities of the urinary tract causes renal scars and renal failure. Common predisposing factors are obstructive uropathy and calculus disease. The incidence of UTI varies according to the primary renal disease. Saitoh et al. studied 182 patients with chronic renal failure and observed that 13%, 41% and 67% had chronic glomerulonephritis, diabetic nephropathy and polycystic kidney disease, respectively [4]. Of the patients with chronic glomerulonephritis, no significant differences between male and female patients were seen in the rate of bacteriuria and acute or chronic infection. Pyuria was significantly more frequent in oliguric patients than those on haemodialysis. Renal transplant recipients develop UTI more commonly compared with the general population [5]. The rate of infection occurring after transplantation is unknown, but an association with increased mortality is obvious. Abbott et al. found a 17% cumulative incidence of UTI during the first 6 months after renal transplantation in men and women equally, and at 3 years it was 60% in women and 47% in men (P < 0.001) [6]. Late UTI was significantly associated with subsequent death using Cox regression analysis (P < 0.001), and the adjusted hazard ratio for graft loss was 1.85 [6]. The most commonly isolated microorganisms were Escherichia coli (1/3) and Enterococcus faecalis (1/5) [7]. Early removal of the urethral catheter is recommended to reduce the risk of UTI [8]. The lack of exact information on UTI in renal insufficiency may be explained by the wide variety of underlying diseases, unknown prior instrumentation of the bladder, differences in age and sex, and the possible exis-
tence of diabetes mellitus and other co-existing diseases, as well as the response to chemotherapy. Therefore, it is difficult to evaluate the incidence of UTI in renal insufficiency.
3. Microbiological aspects In 80–90% of all cases of UTI, E. coli is the causative agent [9]. The proportion of enterococci, Proteus, Pseudomonas, Enterobacter spp. and staphylococci is particularly high in patients with predisposing factors and those with hospital cross-infections. In renal disease, a variety of different bacterial strains are able to initiate an infection. These microorganisms are characterized by specific virulence properties. The ability to colonize the urothelium (fimbriae/pili), to cytotoxically damage cells and tissue (haemolysin-␣), as well as serum resistance, iron sequestering, hydroxamate production and the presence of K antigen are typical markers of uropathogenic bacteria [10,11]. The virulence properties of microorganisms may aggravate the disease. In patients with non-obstructive pyelonephritis, pathogenic E. coli strains express various virulence factors [12]. In cases of acute UTI, bacterial strains often present one or more urovirulent properties. These strains are able to attach to the cells of the epithelial boundary layer and to produce toxins. On the other hand, properties such as hydroxamate production or the presence of K1 antigen were found in microorganisms that persisted in the host without causing clinical symptoms. During the persistence in the urinary tract, uropathogenic E. coli also show marked changes in virulence, as shown by Ziegler et al. [13]. In particular, the loss of haemolysin expression was significant (Fig. 2). Virulence properties, including adhesins, toxins, capsule and iron uptake systems are encoded by chromosomal and extra-chromosomal genomic structures [14]. In which degree enviromental variations in renal insufficiency
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Fig. 2. Incidence of virulence properties of Escherichia coli strains in patients with chronic urinary tract infection. Results of a follow-up over 3 years [13].
activate or depress genomic structures of uropathogens is not defined. P-fimbriated E. coli preferentially attach to luminal sites in the renal tubulus and Dr-fimbrated E. coli attach to Bowman’s capsule for instance. It could be speculated about molecular variations of receptor molecules of uroepithelial cells depending on the uremic situation also. These phenomenous may influence the attachment of microorganisms to the cells of the boundary layer and inhibit the virulence of bacterial. Uropathogenic E. coli possess a whole complex of different genes associated with virulence. These genetic regions may be identified by multiplex polymerase chain reaction assay. The activity of these genes is responsible for the phenotypic virulence of infectious agents. Investigations of virulence-associated genomic clusters of uropathogenic E. coli from urine of patients with diabetes mellitus and patients after renal transplantation demonstrated differences in their genotypic characteristics (Table 1). For instance, organisms occurring in cases of defined immunodeficiency after renal transplantation shared a high-frequency gene cluster that determined the activity of haemolysins and colony necrotizing factors. These observations could explain the high risk of severe post-transplant UTI and also the adverse effects on graft function in transplant patients. Investigations by Kreft and Pagel on the virulence of E. coli contributing to acute renal failure demonstrated a high frequency of haemolysin formation in strains causing acute renal complications [15]. The activation of a specific genomic structure expressing virulence properties depends on the condition of the host organisms. Table 1 Virulence determinants of Escherichia coli strains in urine of patients with type 2 diabetes mellitus and patients after renal transplantation [37] E. coli genotype characteristic (%)
Renal transplantation Diabetes mellitus
papA
hlyA
Cnf1
Fim H
sfas
K5
K1
40 30
46.6 17.5
46.6 12.5
80.0 97.5
6.6 7.5
13.3 30.0
12.5 20.0
4. Aspects of host defences Host defence aspects can be defined as local or systemic. 4.1. Local defence Generally, urine acts as a good medium for enabling uropathogenic microorganisms to persist in the urinary tract [16]. The presence of glucose stimulates bacterial growth, but differences in growth rate may be observed depending on the level of urea and creatinine [17]. Creatinine hinders the persistence of bacteria in the urinary tract. In renal insufficiency, a variety of different substances in blood and urine as well as in the intra- and extracellular space influence the parasite–host interaction in renal insufficiency (Table 2). These molecules alter the environment and the expression of different virulence factors of microorganisms, as well as the activity of host-specific defence mechanisms. For instance, urea, creatinine and organic acids inhibit bacterial growth, Table 2 Substances influencing the host–parasite interaction in renal insufficiency Substance
Effect
• Urea
• Growth and persistence of microorganisms in urinary tract • Function and structure of organs (kidney, immune system, etc.) • Interaction between microorganisms and host
• Organic acids • Glucose • Amino acids • Methyl guanidine • Polyamines • Cadaverine • Putrescine • Phenols • Oxalic acid • Betaine • Proline • Glutamine • Defensin • Tamm-Horsfall protein
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of the kidney [23,24]. This peptide is believed to function in the antimicrobial defence of the urogenital tract, but its quantitative alteration and pathophysiological significance in infection are yet to be determined [25]. Disturbances of normal glomerular and tubular architecture in various kidney diseases may alter the physiological tubular function and the expression of -defensin-1. Currently it may be assumed that this defence mechanism is not available at all in chronic renal diseases. 4.2. Systemic defence
Fig. 3. Escherichia coli binding to Tamm-Horsfall glycoprotein in urine of a female patient with relapsing urinary tract infection (R. F¨unfst¨uck, 2005).
whereas amino acids and glucose promote it. The accumulation of toxic uraemic substances such as methyl guanidine, polyamines, putrescine, phenols and oxalic acid do not promote the expression of virulence factors and persistence of microorganisms in the urinary tract. These toxins cause various deteriorations of organs and organ systems in the host including host defence mechanisms [18]. It is still unknown to what degree local defence processes are impaired in renal insufficiency. Tamm-Horsfall protein, defensin or secretory immunoglobulin A (IgA) act as protective agents against uropathogenic microorganisms. Urinary Tamm-Horsfall protein carries high mannose and NeuAc ␣-2,3-Gal sequences. These may be considered ligands for type 1 and type S fimbriated E. coli [19]. There is evidence that type 1 fimbriated E. coli strains represent the predominant phenotype of isolates from patients with UTI. These microorganisms bind to uroplakin Ia and Ib, the most abundant integral membrane glycoproteins of the luminal surface in urothelial cells. Pak et al. [20] showed that Tamm-Horsfall protein binds type 1 fimbriated E. coli in vitro and efficiently competes with uroplakin Ia and Ib in binding to these pathogens. These mechanisms can eliminate bacteria by urine flow from the urinary tract. They support the concept that Tamm-Horsfall protein represents a protective agent against colonization of the urinary tract by pathogens. Fig. 3 shows E. coli binding to uromucoid in the urine of a patient with relapsing UTI. Tamm-Horsfall protein has been localized in the thick ascending limb of the loop of Henley and in the distal convoluted tubule [20]. This glycoprotein is present in variable amounts in renal stones. Data on its role in stone formation and in renal insufficiency are contradictory [21] but its immunological role seems to be better determined. This molecule and its fragments stimulate tumour necrosis factor (TNF)-␣ and tissue factor expression [22]. Human -defensin-1 seems to play another part in the local defence reaction. In situ hybridization has detected the defensin messenger ribonucleic acid in the epithelium of the loop of Henley, the distal tubules and the collecting ducts
Vanholder [26] and Ringior [27] and their colleagues demonstrated that the activity of the hexose monophosphate shunt in phagocytosis-related respiratory burst is disturbed in chronic renal failure. Certain cells ingest foreign material by phagocytosis enclosing it within a cytoplasmic vacuole, which is subsequently destroyed. The importance of phagocytosis in the host defence has become increasingly apparent. Phagocytes do not only have the capacity to kill and destroy bacteria, they also produce cytokines and activate other cells of the immune system such as T- and B-lymphocytes. In renal insufficiency they also produce an elevated parathyroid hormone level, thus increasing cytosolic calcium in granulocytes and other cells. The chronic overloading of cells with calcium ions is responsible for a significant decrease in intracellular adenosine triphosphate, which consequently restricts phagocytosis. Further disturbances of granulocyte activity such as impairment of migration behaviour, chemotaxis and degranulation, or the blockade of glucose uptake, are correlated with the degree of renal insufficiency. According to Vanholder, renal insufficiency can be understood as a prototype of an acquired immune deficiency. 4.3. Consequences for bacterial attachment Colonization of the urinary tract by uropathogenic microorganisms, bacterial adherence to the urothelial borderline layer, cell destruction and the process of invasion of infective agents are accompanied by inflammatory reactions [28,29]. Fig. 4 shows the attachment of E. coli on urothelial cells of a female patient with relapsing UTI. These processes include the release of various cytokines as well as the activation of granulocytes, macrophages, monocytes and other immunoregulatory cells [30]. The release of cytokines by epithelial cells due to stimulation by E. coli is shown in Fig. 5. Many cytokines are pleiotropic, causing a great number of different actions. Interleukin (IL)-1, TNF-␣, IL-6 and IL-8 have been shown to be the major proinflammatory cytokines. They are the key inducers of many of the symptoms and signs accompanying inflammatory disease, and they induce events such as acute renal failure or septic shock. The release of cytokines and growth factors may also be important for stimulating proliferation. This could explain the development of interstitial cystitis or interstitial nephritis and renal scar formation [31].
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Fig. 4. Attachment of Escherichia coli to urothelial cells of a female patient with relapsing urinary tract infection R. F¨unfst¨uck.
The current knowledge on the pathogenesis of UTI shows that inflammatory response proceeds in three main steps. Firstly, the bacteria stimulate urothelial cells to produce inflammatory mediators. Secondly, chemokines and interleukins direct inflammatory cells to the site of infection. Thirdly, the quality of the inflammatory response determines bacterial clearance or tissue damage. These processes may be followed by deterioration in renal function. In addition, a pre-existing renal insufficiency may become worse.
5. Prognosis of UTI In renal insufficiency, local and systemic defence mechanisms of the host are altered. The attachment of uropathogenic microorganisms to urothelial cells and the internalization and invasion of bacteria obviously initiate a complex process in the host. The release of different cytokines and mediator molecules, as well as the activity of
immunoregulatory cells, influence interstitial reactions in the lower urinary tract and in the kidneys. In general, a lower UTI will not be progressive or lead to renal failure or death. The prognosis for individuals with recurrent or relapsing infections is excellent. These patients have low morbidity and essentially no mortality related to their urinary tract problem. The frequency of renal diseases resulting from pyelonephritis is exceedingly low. Smith estimated that the rate is less than 1 per 5000 persons with bacteriuria per year [32]. Of patients with acute pyelonephritis, 3–4% develop renal function deterioration [33]. The rate of end-stage renal disease in children caused by UTI in the absence of concomitant underlying abnormalities was analysed by Sreenarasimhaiah and Hellerstein [34]. UTI was an important contributing factor in only 1 of 102 children who developed end-stage renal disease because of acquired renal injury. In a long-term observation study over a period of 20 years, Jacobson et al. looked at children suffering from UTI within the first 5 years of life [35]. In cases with unilateral or bilateral renal scars, a significantly higher rate of hypertension and reduction of glomerular filtration rate was observed. An acute infection can influence the course of a pre-existing renal disease and enhance the development of renal failure in cases of existing damage of renal parenchyma or anatomical alteration of the urinary tract, and with impairment of host defence mechanisms by lack of secretory IgA, TammHorsfall glycoprotein or other defence factors. Pyelonephritis is the severest type of UTI and the development of a septic disease is life threatening. The risk of chronic renal disease and renal insufficiency caused by pyelonephritis is low. Underlying lesions including vesicoureteral reflux, analgesic abuse, nephrolithiasis or obstruction of the urinary tract would have to be observed. Acute bacterial infection can dramatically influence the progression of chronic renal disease on the one hand and on the other hand chronic renal failure can alter the severity of an infection. With the availability of effective diagnostic procedures and antimicrobial chemotherapy, it should be possible
Fig. 5. Release of cytokines by epithelial cells due to Escherichia coli HB 101 (K12, rough form) (F¨unfst¨uck, R., 2001). IL, interleukin; PDGF, platelet-derived growth factor; TNF, tumour necrosis factor [30].
R. F¨unfst¨uck et al. / International Journal of Antimicrobial Agents 28S (2006) S72–S77
to diagnose an infectious disease of the urinary tract early and thus prevent deterioration in renal function.
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[18] Vanholder R. Uremic toxins. Adv Nephrol Necker Hosp 1997;26:143–63. [19] Serafini-Cessi F, Malagolini N, Cavallone D. Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 2003;42:658–76. [20] Zimmerhackl LB, Rostasy K, Weigele G, et al. Tamm-Horsfall protein as a marker of tubular maturation. Pediatr Nephrol 1996;10:448–52. [21] Kokot F, Dulawa J. Tamm-Horsfall protein updated. Nephron 2000;85:97–102. [22] S¨aemann MD, Weichhart T, Zeyda M, et al. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. J Clin Invest 2005;115:468–75. [23] Valore EV, Park CH, Quayle AJ, Wiles KR, McCray Jr PB, Ganz T. Human beta-defensin-1: an antimicrobial peptide of urogenital tissue. J Clin Invest 1998;101:1633–42. [24] Schnapp D, Reid CJ, Harris A. Localization of expression of human beta defensin-1 in the pancreas and kidney. J Pathol 1998;186:99–103. [25] Hiratsuka T, Nakazato M, Ihi T, et al. Structural analysis of human beta-defensin-1 and its significance in urinary tract infection. Nephron 2000;85:34–40. [26] Vanholder R, Ringoir S, Dhondt A, Hakim R. Phagocytosis in uremic and hemodialysis patients: a prospective and cross section study. Kidney Int 1991;39:320–7. [27] Ringoir S, Vanholder R. Phagocytic function in the uremic patient. Contrib Nephrol 1992;100:15–24. [28] Svanborg C, Bergsten G, Fischer H, et al. The ‘innate’ host response protects and damages the infected urinary tract. Ann Med 2001;33:563–70. [29] Wullt B, Bergsten G, Connell H, et al. P-fimbriae trigger mucosal responses to Escherichia coli in the human urinary tract. Cell Microbiol 2001;3:255–64. [30] F¨unfst¨uck R, Franke S, Hellberg M, et al. Secretion of cytokines by uroepithelial cells stimulated by Escherichia coli and Citrobacter spp. Int J Antimicrob Agents 2001;17:253–8. [31] Sommer M, Eismann U, Deuther-Conrad W, et al. Time course of cytokine mRNA expression in kidney of rats with unilateral ureteral obstruction. Nephron 2000;84:49–57. [32] Smith JW. Prognosis of pyelonephritis: promise or progress. Am J Med Sci 1989;297:53–62. [33] Baily R. Management issue in recent nephropathy. In: Proceedings of the 11th Asian Coll Nephrol. 1997. p. 98–907. [34] Sreenarasimhaiah S, Hellerstein S. Urinary tract infections per se do not cause end-stage kidney disease. Pediatr Nephrol 1998;12:210–3. [35] Jacobson SH, Eklof O, Lins LE, Wikstad I, Winberg J. Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood—a 27-year follow-up. Pediatr Nephrol 1992;6:19–24. [36] Frei U, Schober-Halstenberg H-J. Nierenersatztherapie in Deutschland. bericht 2004 Quasi-Niere. Quasi-Niere GmbH 2004. [37] F¨unfst¨uck R. Kidney disease and UTI. 9th Intern Symp on UTI/STD: Management of UTI in spec Pts. 24th Intern Cong of Chemotherapy. Book of Abst p 63.
The interaction of urinary tract infection and renal insufficiency Reinhard F¨unfst¨uck a,∗ , Undine Ott b , Kurt G. Naber c a
Department of Internal Medicine I, Sophien- and Hufeland-Klinikum Weimar, Weimar, Germany b Department of Internal Medicine III, Friedrich-Schiller-University, Jena, Germany c Department of Urology, St. Elisabeth Hospital, Straubing, Germany
Abstract Urinary tract infections (UTIs) are among the most common infections caused by microorganisms, and pyelonephritis is the most severe infection of the urogenital tract. The risk of developing chronic renal insufficiency due to a UTI without other risk factors is low. The pathogenicity and virulence of the infective microorganisms as well as the efficiency of local or systemic defence mechanisms determine the course and severity of the disease. Virulence properties (adhesins, toxins, capsule, iron uptake) are encoded by genomic structures and the determination of virulence is influenced by the host situation. In renal insufficiency, a variety of quite different substances (uraemic toxins, betaine, amino acids, creatinine, urea, glucose) influence the microbial environment. Defence factors (Tamm-Horsfall protein, defensin, phagocytic activity of granulocytes) and underlying anatomical lesions as well as pre-existing renal disease determine the severity of UTI and the prognosis of renal insufficiency. © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Urinary tract infection; Renal insufficiency; Microbial properties; Local defence
1. Introduction Urinary tract infections (UTIs) are one of the most common bacterial infectious diseases in humans. The US National Ambulatory Care Survey shows that every year more than 7 million patients suffer from a UTI in the USA [1]. More than 40% of nosocomial sepsis cases are caused by UTIs [2]. The manifestation and course of the disease are influenced by virulence factors of microorganisms on the one hand and defence mechanisms of the host on the other. A deterioration in renal function correlates with disturbances of various specific and nonspecific host defence reactions. In renal diseases is a changes in the composition of urine in oliguria, anuria, albuminuria and haematuria observed. The resultant changes in pH, osmolarity and urinary urea have their own effects in urinary tract infection. An accumulation of various uremic toxins inhibit the antimicrobiological activity of granulocytes, macrophages and other defense reaction. These conditions may support the development of UTI in patients with renal disease. ∗
Corresponding author. Tel.: +49 3643 571150; fax: +49 3643 571102. E-mail address: [email protected] (R. F¨unfst¨uck).
This review will discuss some aspects fo UTI in relationship to renal insufficiency. The potential impact of UTI on renal function when underlying renal impairment as well as aspects of renal insufficiency on the development of UTI will be discussed. In this connection results of microbiological investigations and special parts of deterioration of host defence in renal insufficiency will be demonstrated.
2. Epidemiological aspects Epidemiological studies in many European countries confirm that an increasing number of patients suffer from progressive deterioration of renal function. The European Renal Association—European Dialysis and Transplant Association registry shows that the incidence of renal replacement therapy for end-stage renal disease increased from 79.4 cases per million population (pmp) in 1990–1991 to 117.3 pmp in 1998–1999, i.e. an increase of 4.8% per year [3]. The incidence of end-stage renal disease due to diabetes mellitus, hypertension and renal vascular disease nearly doubled over 10 years. The German registry of the QuaSi-Niere GmbH
0924-8579/$ – see front matter © 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2006.05.004
R. F¨unfst¨uck et al. / International Journal of Antimicrobial Agents 28S (2006) S72–S77
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Fig. 1. Cases of renal insufficiency in the Germany dialysis population in 2003 [36].
shows the same trend (Fig. 1). To summarize, of all patients undergoing renal replacement therapy in Germany, 14% suffered from interstitial nephritis (this value includes the population with UTI). It is difficult to determine the specific role of UTI in the official renal data reports. It is well known that infection perpetuated by anatomical or functional abnormalities of the urinary tract causes renal scars and renal failure. Common predisposing factors are obstructive uropathy and calculus disease. The incidence of UTI varies according to the primary renal disease. Saitoh et al. studied 182 patients with chronic renal failure and observed that 13%, 41% and 67% had chronic glomerulonephritis, diabetic nephropathy and polycystic kidney disease, respectively [4]. Of the patients with chronic glomerulonephritis, no significant differences between male and female patients were seen in the rate of bacteriuria and acute or chronic infection. Pyuria was significantly more frequent in oliguric patients than those on haemodialysis. Renal transplant recipients develop UTI more commonly compared with the general population [5]. The rate of infection occurring after transplantation is unknown, but an association with increased mortality is obvious. Abbott et al. found a 17% cumulative incidence of UTI during the first 6 months after renal transplantation in men and women equally, and at 3 years it was 60% in women and 47% in men (P < 0.001) [6]. Late UTI was significantly associated with subsequent death using Cox regression analysis (P < 0.001), and the adjusted hazard ratio for graft loss was 1.85 [6]. The most commonly isolated microorganisms were Escherichia coli (1/3) and Enterococcus faecalis (1/5) [7]. Early removal of the urethral catheter is recommended to reduce the risk of UTI [8]. The lack of exact information on UTI in renal insufficiency may be explained by the wide variety of underlying diseases, unknown prior instrumentation of the bladder, differences in age and sex, and the possible exis-
tence of diabetes mellitus and other co-existing diseases, as well as the response to chemotherapy. Therefore, it is difficult to evaluate the incidence of UTI in renal insufficiency.
3. Microbiological aspects In 80–90% of all cases of UTI, E. coli is the causative agent [9]. The proportion of enterococci, Proteus, Pseudomonas, Enterobacter spp. and staphylococci is particularly high in patients with predisposing factors and those with hospital cross-infections. In renal disease, a variety of different bacterial strains are able to initiate an infection. These microorganisms are characterized by specific virulence properties. The ability to colonize the urothelium (fimbriae/pili), to cytotoxically damage cells and tissue (haemolysin-␣), as well as serum resistance, iron sequestering, hydroxamate production and the presence of K antigen are typical markers of uropathogenic bacteria [10,11]. The virulence properties of microorganisms may aggravate the disease. In patients with non-obstructive pyelonephritis, pathogenic E. coli strains express various virulence factors [12]. In cases of acute UTI, bacterial strains often present one or more urovirulent properties. These strains are able to attach to the cells of the epithelial boundary layer and to produce toxins. On the other hand, properties such as hydroxamate production or the presence of K1 antigen were found in microorganisms that persisted in the host without causing clinical symptoms. During the persistence in the urinary tract, uropathogenic E. coli also show marked changes in virulence, as shown by Ziegler et al. [13]. In particular, the loss of haemolysin expression was significant (Fig. 2). Virulence properties, including adhesins, toxins, capsule and iron uptake systems are encoded by chromosomal and extra-chromosomal genomic structures [14]. In which degree enviromental variations in renal insufficiency
S74
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Fig. 2. Incidence of virulence properties of Escherichia coli strains in patients with chronic urinary tract infection. Results of a follow-up over 3 years [13].
activate or depress genomic structures of uropathogens is not defined. P-fimbriated E. coli preferentially attach to luminal sites in the renal tubulus and Dr-fimbrated E. coli attach to Bowman’s capsule for instance. It could be speculated about molecular variations of receptor molecules of uroepithelial cells depending on the uremic situation also. These phenomenous may influence the attachment of microorganisms to the cells of the boundary layer and inhibit the virulence of bacterial. Uropathogenic E. coli possess a whole complex of different genes associated with virulence. These genetic regions may be identified by multiplex polymerase chain reaction assay. The activity of these genes is responsible for the phenotypic virulence of infectious agents. Investigations of virulence-associated genomic clusters of uropathogenic E. coli from urine of patients with diabetes mellitus and patients after renal transplantation demonstrated differences in their genotypic characteristics (Table 1). For instance, organisms occurring in cases of defined immunodeficiency after renal transplantation shared a high-frequency gene cluster that determined the activity of haemolysins and colony necrotizing factors. These observations could explain the high risk of severe post-transplant UTI and also the adverse effects on graft function in transplant patients. Investigations by Kreft and Pagel on the virulence of E. coli contributing to acute renal failure demonstrated a high frequency of haemolysin formation in strains causing acute renal complications [15]. The activation of a specific genomic structure expressing virulence properties depends on the condition of the host organisms. Table 1 Virulence determinants of Escherichia coli strains in urine of patients with type 2 diabetes mellitus and patients after renal transplantation [37] E. coli genotype characteristic (%)
Renal transplantation Diabetes mellitus
papA
hlyA
Cnf1
Fim H
sfas
K5
K1
40 30
46.6 17.5
46.6 12.5
80.0 97.5
6.6 7.5
13.3 30.0
12.5 20.0
4. Aspects of host defences Host defence aspects can be defined as local or systemic. 4.1. Local defence Generally, urine acts as a good medium for enabling uropathogenic microorganisms to persist in the urinary tract [16]. The presence of glucose stimulates bacterial growth, but differences in growth rate may be observed depending on the level of urea and creatinine [17]. Creatinine hinders the persistence of bacteria in the urinary tract. In renal insufficiency, a variety of different substances in blood and urine as well as in the intra- and extracellular space influence the parasite–host interaction in renal insufficiency (Table 2). These molecules alter the environment and the expression of different virulence factors of microorganisms, as well as the activity of host-specific defence mechanisms. For instance, urea, creatinine and organic acids inhibit bacterial growth, Table 2 Substances influencing the host–parasite interaction in renal insufficiency Substance
Effect
• Urea
• Growth and persistence of microorganisms in urinary tract • Function and structure of organs (kidney, immune system, etc.) • Interaction between microorganisms and host
• Organic acids • Glucose • Amino acids • Methyl guanidine • Polyamines • Cadaverine • Putrescine • Phenols • Oxalic acid • Betaine • Proline • Glutamine • Defensin • Tamm-Horsfall protein
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of the kidney [23,24]. This peptide is believed to function in the antimicrobial defence of the urogenital tract, but its quantitative alteration and pathophysiological significance in infection are yet to be determined [25]. Disturbances of normal glomerular and tubular architecture in various kidney diseases may alter the physiological tubular function and the expression of -defensin-1. Currently it may be assumed that this defence mechanism is not available at all in chronic renal diseases. 4.2. Systemic defence
Fig. 3. Escherichia coli binding to Tamm-Horsfall glycoprotein in urine of a female patient with relapsing urinary tract infection (R. F¨unfst¨uck, 2005).
whereas amino acids and glucose promote it. The accumulation of toxic uraemic substances such as methyl guanidine, polyamines, putrescine, phenols and oxalic acid do not promote the expression of virulence factors and persistence of microorganisms in the urinary tract. These toxins cause various deteriorations of organs and organ systems in the host including host defence mechanisms [18]. It is still unknown to what degree local defence processes are impaired in renal insufficiency. Tamm-Horsfall protein, defensin or secretory immunoglobulin A (IgA) act as protective agents against uropathogenic microorganisms. Urinary Tamm-Horsfall protein carries high mannose and NeuAc ␣-2,3-Gal sequences. These may be considered ligands for type 1 and type S fimbriated E. coli [19]. There is evidence that type 1 fimbriated E. coli strains represent the predominant phenotype of isolates from patients with UTI. These microorganisms bind to uroplakin Ia and Ib, the most abundant integral membrane glycoproteins of the luminal surface in urothelial cells. Pak et al. [20] showed that Tamm-Horsfall protein binds type 1 fimbriated E. coli in vitro and efficiently competes with uroplakin Ia and Ib in binding to these pathogens. These mechanisms can eliminate bacteria by urine flow from the urinary tract. They support the concept that Tamm-Horsfall protein represents a protective agent against colonization of the urinary tract by pathogens. Fig. 3 shows E. coli binding to uromucoid in the urine of a patient with relapsing UTI. Tamm-Horsfall protein has been localized in the thick ascending limb of the loop of Henley and in the distal convoluted tubule [20]. This glycoprotein is present in variable amounts in renal stones. Data on its role in stone formation and in renal insufficiency are contradictory [21] but its immunological role seems to be better determined. This molecule and its fragments stimulate tumour necrosis factor (TNF)-␣ and tissue factor expression [22]. Human -defensin-1 seems to play another part in the local defence reaction. In situ hybridization has detected the defensin messenger ribonucleic acid in the epithelium of the loop of Henley, the distal tubules and the collecting ducts
Vanholder [26] and Ringior [27] and their colleagues demonstrated that the activity of the hexose monophosphate shunt in phagocytosis-related respiratory burst is disturbed in chronic renal failure. Certain cells ingest foreign material by phagocytosis enclosing it within a cytoplasmic vacuole, which is subsequently destroyed. The importance of phagocytosis in the host defence has become increasingly apparent. Phagocytes do not only have the capacity to kill and destroy bacteria, they also produce cytokines and activate other cells of the immune system such as T- and B-lymphocytes. In renal insufficiency they also produce an elevated parathyroid hormone level, thus increasing cytosolic calcium in granulocytes and other cells. The chronic overloading of cells with calcium ions is responsible for a significant decrease in intracellular adenosine triphosphate, which consequently restricts phagocytosis. Further disturbances of granulocyte activity such as impairment of migration behaviour, chemotaxis and degranulation, or the blockade of glucose uptake, are correlated with the degree of renal insufficiency. According to Vanholder, renal insufficiency can be understood as a prototype of an acquired immune deficiency. 4.3. Consequences for bacterial attachment Colonization of the urinary tract by uropathogenic microorganisms, bacterial adherence to the urothelial borderline layer, cell destruction and the process of invasion of infective agents are accompanied by inflammatory reactions [28,29]. Fig. 4 shows the attachment of E. coli on urothelial cells of a female patient with relapsing UTI. These processes include the release of various cytokines as well as the activation of granulocytes, macrophages, monocytes and other immunoregulatory cells [30]. The release of cytokines by epithelial cells due to stimulation by E. coli is shown in Fig. 5. Many cytokines are pleiotropic, causing a great number of different actions. Interleukin (IL)-1, TNF-␣, IL-6 and IL-8 have been shown to be the major proinflammatory cytokines. They are the key inducers of many of the symptoms and signs accompanying inflammatory disease, and they induce events such as acute renal failure or septic shock. The release of cytokines and growth factors may also be important for stimulating proliferation. This could explain the development of interstitial cystitis or interstitial nephritis and renal scar formation [31].
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Fig. 4. Attachment of Escherichia coli to urothelial cells of a female patient with relapsing urinary tract infection R. F¨unfst¨uck.
The current knowledge on the pathogenesis of UTI shows that inflammatory response proceeds in three main steps. Firstly, the bacteria stimulate urothelial cells to produce inflammatory mediators. Secondly, chemokines and interleukins direct inflammatory cells to the site of infection. Thirdly, the quality of the inflammatory response determines bacterial clearance or tissue damage. These processes may be followed by deterioration in renal function. In addition, a pre-existing renal insufficiency may become worse.
5. Prognosis of UTI In renal insufficiency, local and systemic defence mechanisms of the host are altered. The attachment of uropathogenic microorganisms to urothelial cells and the internalization and invasion of bacteria obviously initiate a complex process in the host. The release of different cytokines and mediator molecules, as well as the activity of
immunoregulatory cells, influence interstitial reactions in the lower urinary tract and in the kidneys. In general, a lower UTI will not be progressive or lead to renal failure or death. The prognosis for individuals with recurrent or relapsing infections is excellent. These patients have low morbidity and essentially no mortality related to their urinary tract problem. The frequency of renal diseases resulting from pyelonephritis is exceedingly low. Smith estimated that the rate is less than 1 per 5000 persons with bacteriuria per year [32]. Of patients with acute pyelonephritis, 3–4% develop renal function deterioration [33]. The rate of end-stage renal disease in children caused by UTI in the absence of concomitant underlying abnormalities was analysed by Sreenarasimhaiah and Hellerstein [34]. UTI was an important contributing factor in only 1 of 102 children who developed end-stage renal disease because of acquired renal injury. In a long-term observation study over a period of 20 years, Jacobson et al. looked at children suffering from UTI within the first 5 years of life [35]. In cases with unilateral or bilateral renal scars, a significantly higher rate of hypertension and reduction of glomerular filtration rate was observed. An acute infection can influence the course of a pre-existing renal disease and enhance the development of renal failure in cases of existing damage of renal parenchyma or anatomical alteration of the urinary tract, and with impairment of host defence mechanisms by lack of secretory IgA, TammHorsfall glycoprotein or other defence factors. Pyelonephritis is the severest type of UTI and the development of a septic disease is life threatening. The risk of chronic renal disease and renal insufficiency caused by pyelonephritis is low. Underlying lesions including vesicoureteral reflux, analgesic abuse, nephrolithiasis or obstruction of the urinary tract would have to be observed. Acute bacterial infection can dramatically influence the progression of chronic renal disease on the one hand and on the other hand chronic renal failure can alter the severity of an infection. With the availability of effective diagnostic procedures and antimicrobial chemotherapy, it should be possible
Fig. 5. Release of cytokines by epithelial cells due to Escherichia coli HB 101 (K12, rough form) (F¨unfst¨uck, R., 2001). IL, interleukin; PDGF, platelet-derived growth factor; TNF, tumour necrosis factor [30].
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to diagnose an infectious disease of the urinary tract early and thus prevent deterioration in renal function.
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