Year : 2019 | Volume
: 13 | Issue : 1 | Page : 1--4
Urinary tract infection in renal transplant recipients: A clinical conundrum
Praveen Kumar Etta
Department of Nephrology, Dialysis and Renal Transplantation, Asian Institute of Nephrology and Urology, Hyderabad, Telangana, India
Dr. Praveen Kumar Etta
Department of Nephrology, Dialysis and Renal Transplantation, Asian Institute of Nephrology and Urology, Hyderabad, Telangana
|How to cite this article:|
Etta PK. Urinary tract infection in renal transplant recipients: A clinical conundrum.Indian J Transplant 2019;13:1-4
|How to cite this URL:|
Etta PK. Urinary tract infection in renal transplant recipients: A clinical conundrum. Indian J Transplant [serial online] 2019 [cited 2022 Aug 13 ];13:1-4
Available from: https://www.ijtonline.in/text.asp?2019/13/1/1/255186
Urinary tract (UT) infection is the most common infection noted among renal transplant (RT) recipients. It is associated with the development of acute rejection (AR), graft dysfunction or loss, and death. Bacteriuria can be divided into two categories: asymptomatic bacteriuria (ASB) and symptomatic UT infection (UTI). For the diagnosis of ASB, two consecutive positive tests are needed in women compared to one single-positive test in men. Uncomplicated UTI presents with local urinary symptoms such as dysuria, frequency, or urgency but no systemic symptoms such as fever or allograft pain. Complicated UTI presents with fever and either one of the following: allograft pain, chills, malaise, bacteremia, or biopsy consistent with pyelonephritis (PN). Since the transplanted kidney is not innervated, pain may not always be present in cases of PN. Few transplant physicians consider all forms of UTIs occurring in RT recipients (RTRs) as complicated UTIs because of the altered anatomy of the UT and the immunocompromised status.
Graft PN can be confused with AR. Fever and graft tenderness are usually suggestive of UTI, whereas graft dysfunction in the presence of proteinuria and hypertension usually suggests AR. In a study published in this issue by Koul et al., the authors noted that the common symptoms associated with the UTI were dysuria (71%) and fever (66%), and almost 17% of cases presented with shock; around 69% cases of UTI were community acquired and 31% were hospital acquired. Recurrent UTI (rUTI) is three or more episodes of UTI in 1 year or two or more episodes of UTI in a 6-month period. Emphysematous PN (EPN) is characterized by severe necrotizing infection which results in the formation of gas within the renal parenchyma, collecting system, or perinephric tissue.
Epidemiology and Risk Factors
The prevalence of UTIs in RTRs varied considerably due to differences in the definition, follow-up periods, geographical location, and prophylactic regimen. They are most often seen during the 1st year, especially first few months after RT. UTIs contribute to 35%–72% of all infections, and 30% of all hospitalizations for sepsis in RTR. Two recent studies from North and South India showed UTI prevalence of 32.86% and 41.9%, respectively, among RTR., According to Rubin's timetable and few papers from India, UTIs predominate in the 1st month due to healthcare-related causes such as urinary stents and catheters. One study comprising RTRs with bacteriuria found that ASB, uncomplicated UTI, and complicated UTI occurred in 44%, 32%, and 24% of cases, respectively; rUTI observed in 14% of cases. In contrast, a recent Indian study showed that rUTI was noted in 46.2% of all RTRs with UTI. EPN in RTRs is very rare. Till now, only about thirty cases of EPN-affecting renal allografts have been reported in literature globally.
Some of the important risk factors for UTI in RTR include female gender, elderly age, rUTI before RT, UT abnormality, vesicoureteral reflux (VUR), polycystic kidney disease (PKD), deceased donor, delayed graft function, frequent AR, new-onset diabetes after transplantation, coexisting viral infection, repeated urologic instrumentation, ureteral stent placement, prolonged catheterization, and hospital stay. The presence of a urological catheter gives an estimated daily risk of 2%–7% to develop bacteriuria; approximately 70% of the patients develop bacteriuria after 14 days of catheterization. The absence of a sphincter between the transplanted ureter and the native bladder increases the risk of VUR predisposing to PN. The use of immunosuppressive drugs also contributes to the risk for infection, including UTI. Risk factors for drug resistance include diabetes mellitus, rUTI, previous antibiotic exposure, and prophylaxis.
The pathogenesis involves immune evasion, toxin production, iron acquisition, adherence, motility, and bacterial ascent. Various virulence structures of bacteria (e.g., P-fimbriae in Escherichia coli) are involved in urothelial adhesion and invasion. About 80% of E. coli isolates from patients with UTI belong to a subset of O-serotype including O1, O2, O4, O6, O7, O16, O18, and O75. Some strains of E. coli encode the proteins SisA and SisB, which suppress the host inflammatory response, produce hemolysin, which induces the formation of pores in the cell membrane, and aerobactin, a siderophore necessary for iron uptake in the iron-poor environment of the UT. Nonsecretors of histoblood group antigens are more likely to have rUTI. Some of the uropathogenic bacteria (e.g., E. coli, Klebsiella pneumoniae) can enter the cytosol and rapidly multiply, forming a biofilm-like assembly known as intracellular bacterial community (IBC). This is determined by its fimbrial adhesins called Type 1 pilus. These IBC bacteria become a reservoir that will periodically resurge and cause rUTI. Few bacteria (e.g., Proteus mirabilis and Corynebacterium urealyticum) produce urease, which leads to alkalinization of urine and predispose to formation of stones and persistence of infection.
Gram-negative organisms contribute up to 60%–90% of UTIs; important pathogens include E. coli (most common), Pseudomonas, Enterobacter, Klebsiella, and Proteus. Few recent Indian studies have observed that the most common organisms associated with the UTI as E. coli followed by Klebsiella. In the study by Koul et al., the authors noted a different microbiological spectrum with isolation of K. pneumonia in 32%, Pseudomonas aeruginosa in 18%, E. coli in 14%, Enterococcus faecalis in 13%, Acinetobacter in 10%, Staphylococcus aureus in 9%, and Enterobacter in 4% of cases; Candida glabrata was isolated in one patient. Gram-positive organisms (e.g., Enterococcus) account for few cases. Fungal (e.g., Candida), mycobacterial, and viral infections (cytomegalovirus, BK virus, and adenovirus [hemorrhagic cystitis]) can also occur.
Screening for Urinary Tract Infection
The role of routine screening and treating ASB to prevent symptomatic UTI in RTR is debatable. However, untreated UTI that occurs within 3 months of RT is associated with an increased risk of graft dysfunction and AR. The American Society of Transplantation Infectious Diseases Community of Practice advises not to treat ASB occurring more than 3 months after RT unless there is an increase in serum creatinine. Most centers recommend screening for ASB at 2, 4, 8, and 12 weeks after RT.
Prophylactic antibiotics are routinely administered after RT as the standard of care to prevent infections including UTI. A systematic review and meta-analysis of randomized controlled trials (RCTs) concluded that antibiotic prophylaxis during the first 6 months after RT was associated with a reduced risk of sepsis and bacteriuria. No significant reduction was found in all-cause mortality and graft loss. The optimal strategy, antibiotic regimen, and duration of prophylaxis are not known. Most centers continue antibiotic prophylaxis for at least 6 months to 1 year after RT. Cotrimoxazole trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly prescribed drug based on its experience in RTR, and it also prevents opportunistic infections, such as Pneumocystis carinii and Nocardia. Few studies have shown that using ciprofloxacin in addition to TMP-SMX further reduces the incidence of UTI compared to TMP-SMX alone. The risk modification is also an important step in preventing UTI. A recent RCT comparing early ureteral stent removal at 1 week to routine stent removal at 4 weeks found that early removal can reduce risk of UTI.
Urine dipstick (for leukocyte esterase and nitrites), microscopy, and cultures should be done before initiation of antibiotics. Positive blood cultures are seen in up to 20% of cases of PN. Infection with fastidious bacteria (e.g., C. urealyticum) and Mycobacterium tuberculosis can present with repeated negative urine cultures.
Historically, all cases of ASB were treated universally. Recent evidence, however, indicates that treatment of ASB may not be necessary. ASB is associated with increased risk for symptomatic UTI, but treatment does not reduce the frequency of symptomatic UTI or recurrent ASB. One retrospective study concluded that evolution to symptomatic UTI was similar between treated and untreated ASB. Persistent ASB occurred in 46% treated episodes, with selection of resistant pathogen in 78% cases. Spontaneous bacterial clearance occurred in 59% untreated episodes. Another retrospective study showed that the risk of developing symptomatic UTI and hospitalization was significantly higher in the treated group. A recent single-center RCT concluded that the treatment of ASB made no difference in the incidence of any of the outcomes in 2-year follow-up.
Symptomatic Urinary Tract Infection
Empirical therapy is based on severity of UTI, local resistance pattern, previous infection, and antibiotic exposure. Fluoroquinolones have good oral bioavailability and achieve high concentrations in the UT, hence they are most preferred. Once susceptibility data are available; the most narrow-spectrum antibiotic should be used. The optimal duration of treatment is not known. It is generally recommended to treat complicated UTI with 14–21 days of therapy. A prolonged therapy up to 4–6 weeks may be required in special cases such as infected cysts in PKD.
The bacterial resistance to antibiotics is an evolving problem. Oral drugs such as nitrofurantoin, fosfomycin, and minocycline are effective against many of these resistant bacteria. Carbapenems are still preferred for infections due to extended-spectrum beta-lactamase (ESBL)-producing bacteria; less severe infections can be treated with cephamycins, cefepime, and β-lactam-β-lactamase inhibitors (e.g., piperacillin-tazobactam). UTI caused by carbapenem-resistant (CR) Enterobacteriaceae may require the use of fosfomycin, doxycycline, and nephrotoxic antibiotics (e.g. aminoglycosides and polymyxins). In a recent Indian study, about 46.6% and 33.3% of the UTI isolates were found to be ESBL producers and CR, respectively; CR was observed in 62.5% of E. coli isolates overall and 100% of E. coli in the 1st month of RT. Another recent Indian study showed that multidrug resistance was highest in K. pneumoniae (100%). A widespread bacterial resistance was also observed in a study by Koul et al. Recent case reports have noticed the emergence of novel-resistant bacilli like K. pneumoniae New Delhi metallo-beta-lactamase-1 strain in RTR as they are resistant to almost all antibiotics, including carbapenems. In patients with symptomatic UTI, removal (preferred) or replacement of UT instruments such as urethral catheters and urologic stents is recommended.
Management and Prevention of Recurrent Urinary Tract Infection
The management of patients with rUTI is challenging as the patients are repeatedly exposed to antibiotics, which can predispose them to infection by resistant organisms. Few authors recommend treatment with 4–6 weeks of antibiotics. Given the challenges and impact of rUTI, aggressive approach to evaluate for resolvable sources of recurrence and suppressive therapies should be considered.
The evaluation includes identifying any anatomical or functional abnormalities in the UT, postvoid residual volume, or persistent focus of infection like prostatitis/cyst infection using various imaging modalities directed to transplanted and native kidneys, ureters, and bladder; few may require micturating cystourethrogram, urodynamic studies, and cystoscopy.
Except for few studies, prevention of rUTI has not been well investigated specifically in RTR. Many of the currently used therapies such as behavioral modification and antibiotic prophylaxis tend to have some overlap with that of nontransplant population. Some of the behavioral factors include advising liberal fluid intake, frequent voiding, postcoital voiding, wiping from front to back with toilet tissue, and avoiding spermicides. In the cases of chronic colonization of the UT, long-term management includes bacterial suppression, which aims to reduce rather than eliminate bacteria to levels below the threshold for symptomatic infection.
A meta-analysis of RCTs concluded that continuous antibiotic prophylaxis for 6–12 months reduced the rates of rUTI in nonpregnant women; postcoital prophylaxis could be offered to women who have UTIs associated with sexual intercourse. Antimicrobial agents are often used as an alternative to antibiotics for the prevention of rUTI. Methenamine decomposes in the acidic environment of bladder to form formaldehyde and ammonia. A recent meta-analysis concluded that methenamine hippurate may be effective for preventing UTI in patients without UT abnormalities. Cranberry juice has been shown to reduce the adherence of E. coli to uroepithelial cells; L-methionine acidifies the urine and is also thought to decrease bacterial adherence. One retrospective study showed that cranberry juice and L-methionine successfully reduce the incidence of rUTI in RTR. A meta-analysis of postmenopausal women concluded that vaginal estrogens reduced the number of UTIs compared to placebo. Another study found that a low vaginal pH produced by Lactobacillus colonization may reduce rUTI women. Glycosaminoglycans such as hyaluronic acid and chondroitin sulfate are thought to promote a healthy mucopolysaccharide film coating on the urothelium and have also been used to reduce the incidence of rUTI in postmenopausal women. In liver transplant recipients, one RCT suggested that the use of pre- and probiotics reduces the incidence of bacterial infections including UTI. Some other experimental therapies are under evaluation. Small compounds called pilicides are found to inhibit formation of IBC; FimH inhibitors or mannosides have been shown to be effective in murine models by targeting the pilus tip adhesin FimH. Antibacterial vaccines targeting adhesins, virulence factors, and iron receptors are under development.
ASB may be considered a risk factor for symptomatic UTI. A retrospective study showed that between 2–5 and >5 ASB episodes were independent risk factors associated with PN, whereas >5 episodes were also a risk factor associated with AR. Despite the treatment, the incidence of PN was much higher in the group of patients with ASB. The impact of UTI on the allograft function, graft loss, and mortality is not uniformly reported. Few studies including a more recent study found that UTI was associated with an increase in mortality, rejection, and graft loss., EPN-affecting renal allograft is associated with greater risk of graft loss. A recently published study identified 30 cases, of which 16 cases required allograft nephrectomy, 8 cases were treated by the combination of percutaneous drainage and antibiotics, and only 6 cases received antibiotics alone; a total of 5 patients died.
Fungal Urinary Tract Infection
Candida species are the most common fungal cause of UTI in RTR. Most cases of candiduria are asymptomatic, occurring in about 11% of RTR. Candiduria can uncommonly have serious consequences and may cause ascending infection, candidemia, and obstructive fungal balls. One study concluded that treatment of candiduria was not associated with improved clinical outcomes in RTR. At present, treatment of asymptomatic candiduria is not recommended unless the patient is undergoing urologic procedure or is neutropenic. Symptomatic candiduria may be treated with fluconazole, intravenous amphotericin B, or flucytosine. Voriconazole, echinocandins, and lipid formulations of amphotericin achieve low concentrations in the UT which reduces their usefulness for the treatment of UTI, but they may achieve sufficient concentration in the kidney tissue, thus may be useful to treat PN.
ASB and UTI are very common among RTR and remain a major cause of morbidity and mortality. The current data do not show a beneficial effect of treating ASB. UTI should be treated with a narrowest spectrum antibiotic to minimize the emergence of resistance. rUTI should be evaluated for reversible causes and managed with suppressive strategies. Future studies should focus on optimal prevention and treatment strategies.
|1||Parasuraman R, Julian K; AST Infectious Diseases Community of Practice. Urinary tract infections in solid organ transplantation. Am J Transplant 2013;13 Suppl 4:327-36.|
|2||Koul AN, Rather AR, Wani IA, Wani MS, Fomda BA. Noisy orchestra - Renal transplant and urinary tract infections. Indian J Transplant 2018;12:243-6.|
|3||Etta PK, Rao MV. Emphysematous pyelonephritis in a renal allograft. Indian J Transplant 2018;12:59-61.|
|4||Mukherjee D, Sharma S, Nair RK, Datt B, Arora D, Rao A, et al. Urinary tract infection in renal transplant recipients at a tertiary care center in India. Saudi J Kidney Dis Transpl 2018;29:361-8.|
|5||Mohan MV, Neeraja M, Sudhaharan S, Raju SB, Gangadhar T, Lakshmi V, et al. Risk factors for urinary tract infections in renal allograft recipients: Experience of a tertiary care center in Hyderabad, South India. Indian J Nephrol 2017;27:372-6.|
|6||Rubin RH. Infectious disease complications of renal transplantation. Kidney Int 1993;44:221-36.|
|7||Ariza-Heredia EJ, Beam EN, Lesnick TG, Cosio FG, Kremers WK, Razonable RR, et al. Impact of urinary tract infection on allograft function after kidney transplantation. Clin Transplant 2014;28:683-90.|
|8||Pickard R, Lam T, Maclennan G, Starr K, Kilonzo M, McPherson G, et al. Types of urethral catheter for reducing symptomatic urinary tract infections in hospitalised adults requiring short-term catheterisation: Multicentre randomised controlled trial and economic evaluation of antimicrobial- and antiseptic-impregnated urethral catheters (the CATHETER trial). Health Technol Assess 2012;16:1-97.|
|9||Rosen DA, Pinkner JS, Jones JM, Walker JN, Clegg S, Hultgren SJ. Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of FimK on type 1 pilus expression. Infect Immun 2008;76:3337-45.|
|10||Green H, Rahamimov R, Gafter U, Leibovitci L, Paul M. Antibiotic prophylaxis for urinary tract infections in renal transplant recipients: A systematic review and meta-analysis. Transpl Infect Dis 2011;13:441-7.|
|11||Khorvash F, Mortazavi M, Hakamifard A, Ataei B. Comparison of the effect of co-trimoxazole and co-trimoxazole plus ciprofloxacin in urinary tract infection prophylaxis in kidney transplant patients. Adv Biomed Res 2016;5:108.|
|12||Liu S, Luo G, Sun B, Lu J, Zu Q, Yang S, et al. Early removal of double-J stents decreases urinary tract infections in living donor renal transplantation: A prospective, randomized clinical trial. Transplant Proc 2017;49:297-302.|
|13||El Amari EB, Hadaya K, Bühler L, Berney T, Rohner P, Martin PY, et al. Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients. Nephrol Dial Transplant 2011;26:4109-14.|
|14||Green H, Rahamimov R, Goldberg E, Leibovici L, Gafter U, Bishara J, et al. Consequences of treated versus untreated asymptomatic bacteriuria in the first year following kidney transplantation: Retrospective observational study. Eur J Clin Microbiol Infect Dis 2013;32:127-31.|
|15||Origüen J, López-Medrano F, Fernández-Ruiz M, Polanco N, Gutiérrez E, González E, et al. Should asymptomatic bacteriuria be systematically treated in kidney transplant recipients? Results from a randomized controlled trial. Am J Transplant 2016;16:2943-53.|
|16||Wilkowski P, Ciszek M, Dobrzaniecka K, Sańko-Resmer J, Łabuś A, Grygiel K, et al. Successful treatment of urinary tract infection in kidney transplant recipients caused by multiresistant Klebsiella pneumoniae producing New Delhi metallo-beta-lactamase (NDM-1) with strains genotyping. Transplant Proc 2016;48:1576-9.|
|17||Albert X, Huertas I, Pereiró II, Sanfélix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non pregnant women. Cochrane Database Syst Rev 2004;(3):CD001209.|
|18||Lee BS, Bhuta T, Simpson JM, Craig JC. Methenamine hippurate for preventing urinary tract infections. Cochrane Database Syst Rev 2012;10:CD003265.|
|19||Pagonas N, Hörstrup J, Schmidt D, Benz P, Schindler R, Reinke P, et al. Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine. Transplant Proc 2012;44:3017-21.|
|20||Perrotta C, Aznar M, Mejia R, Albert X, Ng CW. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev 2008;(2):CD005131.|
|21||Reid G, Bruce AW. Low vaginal pH and urinary-tract infection. Lancet 1995;346:1704.|
|22||Torella M, Del Deo F, Grimaldi A, Iervolino SA, Pezzella M, Tammaro C, et al. Efficacy of an orally administered combination of hyaluronic acid, chondroitin sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2016;207:125-8.|
|23||Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation – A randomized, double-blind trial. Am J Transplant 2005;5:125-30.|
|24||Cusumano CK, Pinkner JS, Han Z, Greene SE, Ford BA, Crowley JR, et al. Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci Transl Med 2011;3:109ra115.|
|25||Fiorante S, López-Medrano F, Lizasoain M, Lalueza A, Juan RS, Andrés A, et al. Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients. Kidney Int 2010;78:774-81.|
|26||Safdar N, Slattery WR, Knasinski V, Gangnon RE, Li Z, Pirsch JD, et al. Predictors and outcomes of candiduria in renal transplant recipients. Clin Infect Dis 2005;40:1413-21.|