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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 5  |  Page : 876-880
Urinary tract infections in the era of newer immunosuppressant agents : A tertiary care center study


Pondicherry Institute of Medical Sciences, Madras Medical Mission, Chennai, India

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Date of Web Publication31-Aug-2010
 

   Abstract 

We studied the incidence and the risk factors predisposing to post transplantation urinary tract infection (UTI) and the association with use of different immunosuppressive regimens. We performed a retrospective analysis of 152 recipients of renal transplantation over a period of two years. Seventy one (46.71%) patients had culture positive UTI, Escherichia coli (45.1%) being the commonest. Thirty four (22.39%) patients had acute rejection and 14.4% of those had suffered UTI in the early post transplant period. Immunosuppression included induction with various anti­bodies and maintenance on antirejection medications. Trimethoprim-sulphamethoxazole was given as prophylaxis throughout the period. The UTI was treated according to microbiological sensitivity. 2.8% died due to urosepsis. In our retrospective analysis renal transplant recipients under the age of 45, female gender and diabetics suffered more UTI. Combination therapy with micro-emulsion form of cyclosporine A, prednisolone and azathioprine developed more UTI (P= 0.0418).

How to cite this article:
Khanna P, Abraham G, Mohamed Ali AA, Miriam PE, Mathew M, Lalitha M K, Lesley N. Urinary tract infections in the era of newer immunosuppressant agents : A tertiary care center study. Saudi J Kidney Dis Transpl 2010;21:876-80

How to cite this URL:
Khanna P, Abraham G, Mohamed Ali AA, Miriam PE, Mathew M, Lalitha M K, Lesley N. Urinary tract infections in the era of newer immunosuppressant agents : A tertiary care center study. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2019 Jul 17];21:876-80. Available from: http://www.sjkdt.org/text.asp?2010/21/5/876/68884

   Introduction Top


Screening for Urinary Tract Infection (UTI) is undertaken regularly in the immediate post trans­plant period and at less often intervals there­after. Prophylaxis against Pneumocystis jerovicii pneumonia, listeriosis, nocardiosis and UTI is instituted since they are prone to infections in the early post transplant period. [1],[2] In the early post-transplantation period UTI account for 60% of gram negative bacteremia thereby increasing the morbidity and mortality. [3]

Regular urine cultures may detect asymptoma­tic and significant UTI. The typical causative micro-organisms are the enteric gram negative bacilli and enterococci. Risk factors are old age, [4] female gender [5] and agents such as mycopheno­late mofetil (MMF) and cyclosporine, ureteric stents, indwelling bladder catheters, [6] pre-opera­tive UTI and rejection episodes.

We undertook a study for the incidence and risk factors predisposing to post transplant UTI and its association with different immunosup­pressive regimen.


   Subjects and Methods Top


The retrospective study consisted of 152 patients (M=114, F=38) who had undergone renal trans­plantation between February 2005 and February 2007 in a tertiary care centre. All patients with documented UTI during the follow up were in­cluded in the study. Patients with inadequate medical record and inconclusive urine culture were excluded from the study and a total of 71 patients were therefore analyzed after exclusion. The usual practice at our center is to remove the urinary catheter by the fifth post operative day and by the tenth day in complicated cases. A double J ureteric stent was used in two patients for post operative ureteric leak after surgical reimplantation of ureter. Cefuroxime 1.5 g as single dose was used as perioperative antibiotic prophylaxis.

Triple immunosuppression with micro emulsion form of cyclosporine A (Neoral) 8 mg/kg in di­vided doses, prednisolone (0.5 mg/kg) and Myco­phenolate Mofetil (MMF), 1 g twice a day, was commonest, 29.6%. Other combinations of immu­nosuppression included, cyclosporine/predniso­lone/sodium salt of mycophenolic acid (NaMPA) 360 mg-720 mg twice a day in 25.4% and tac­rolimus (0.15 mg/kg/day in divided doses)/pred­nisolone/MMF in 15.5%. A few other patients were taking different combinations of azathio­prine 2.5 mg/kg, tacrolimus 0. 15 mg/kg/day in divided doses and sirolimus 2 mg-6 mg/day.

All patients with allograft dysfunction without evidence of obstruction thought to be due to rejection underwent an ultrasound guided allo­graft biopsy. The biopsy proven acute cellular and vascular rejection episodes were treated with injection methylprednisolone 0.5 g to 1 g i.v. boluses for three to five days and a change in baseline immunosuppressant regimen.

The patients received double strength trimetho­prim (TMX 160 mg)-sulphamethoxazole (SMX 800 mg) three times a week as prophylaxis against UTI and Pneumocystis jerovicii pneu­monia. The mid stream urine sample was sent for culture immediately prior to transplantation except in anuric patients. A urine sample taken from the indwelling catheter without disconnec­ting the transfer set, with a sterile syringe and needle, was sent on day three, five and eight in all recipients. A mid stream sterile urine sample was sent from patients after removal of urinary catheter. The bacterial growth of 10 5 CFU per mL was considered significant in mid stream urine sample and any growth from the catheter specimen was considered significant. We classi­fied infections as those occurring within 48 hours after surgery as early whereas those which developed after 48 hours of transplant surgery as late infections.


   Statistical Analysis Top


Statistical analysis was performed using the SPSS software package, version 12.0. Compari­son was done with Student's t-test and chi­square test. Variables with P value of < 0.05 were considered statistically significant.


   Results Top


Among the 152 patients, 71 (46.71%) were diag­nosed with urinary tract infection. Baseline de­mography and clinical characteristics of the UTI study group (n=71) are given in [Table 1].
Table 1 :Immunosuppressant regimen used.

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The rate of infection was 57.89% in females and 42.89% in males: 53.5% of the infected pa­tients were below 45 years of age. Amongst those with urinary tract infection, 69 (97.18%) were hypertensive and 24 (33.8%) were diabe­tic. Among eight patients with pre-transplan­tation positive urine cultures, almost all six (75.5%) patients developed post operative UTI also.

The data showed that 97.2% had late onset of UTI. Thirty four out of 152 patients developed acute rejection, and 14.4% of these patients had suffered from post transplant UTI. Acute biopsy proven cellular rejection of Banff grade I and II was seen in 21 patients. The septicemia rate in these patients was 2.8% and the causative orga­nism was non-fermenting gram negative bacilli including Klebsiella species.

The causative organisms isolated in urine cul­ture is shown in [Figure 1].
Figure 1 :Organisms isolated from urine of renal allograft recipients in the post transplant period.

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Significant association (0.0418) of UTI was observed only for the combination of cyclospo­rine, prednisolone and azathioprine. Induction with basiliximab was associated with more UTI.

The antibiotics used for treatment of UTI as per the culture and sensitivity reports were ofloxacin, cefoperazone/sulbactam, nitrofuran­toin, meropenem and levofloxacin. The dura­tion of treatment was 7-21 days. Those who had recurrence of infection were given a second course of antibiotic therapy and were put on low dose nitrofurantoin prophylaxis of 100 to 200 mg at bedtime for 1-3 months. Mortality rate among the patients was 2.8%.


   Discussion Top


The prevention and treatment of infections re­mains an integral part of clinical management of renal transplant recipients. The pharmacothe­rapy for transplant recipient has two compo­nents: an immunosuppressant regimen to prevent and treat rejection and an antimicrobial cover to make it safe. [7] The right approach should be in­dividualization of the treatment regimen. Inter­play of the four major factors determines the risk of infection: presence of anatomical/techni­cal abnormalities, recent and remote environmen­tal exposures, the net state of immunosuppre­ssion and the effects of the Darwinian compe­tition. [8] Young women and men who are sexually active may have more episodes of UTI. [9] We found that recipients under 45 years of age and females are more susceptible to UTI.

There is an emerging trend for resistance to antimicrobial agents used for prophylaxis and treatment of UTI in developing countries. In our retrospective analysis, inspite of antimic­robial prophylaxis (TMP-SMX), 46.71% deve­loped UTI, a third of them were diabetics and 14.4% had biopsy proven rejection. As a sizable population of renal transplant recipients are dia­betic, the immunosuppressive agents, poor bla­dder function, incomplete voiding and impaired cytokine secretion may contribute to UTI in such patients Certain severe clinical presenta­tions such as emphysematous cystitis, pyelo­nephritis, perinephric abscess and papillary nec­rosis are virtually unique to diabetic patients. [10] Diabetes is also a risk factor for development of fungal UTI. Severe and recurrent UTI presen­ting in the latter period warrant further work up for abnormalities such as bladder dysfunction, prostatic hypertrophy, stricture of the lower end of ureter and stones. [11]

In our study the commonest etiological agent for UTI was E. coli in 45.1% followed by Sta­phylococcus epidermidis in 26.76%, Klebsiella species in 18.32% and co-infection with mul­tiple organism in a few patients. The pathoge­nicity of E. coli is increased in the urothelium as it expresses type 1 or P fimbriae. Other organisms maybe associated with renal, ureteral or bladder calculi, which act as infective foci.  Corynebacterium urealyticum Scientific Name Search fficult to iso­late, and is not sensitive to the conventional oral antibiotics, has been recognized as a potential new pathogen. [12]

Post transplantation UTI can result in graft dysfunction through free-radical production, in­flammatory cytokine response, CMV reactiva­tion and pyelonephritis induced scarring. On the other hand, acute rejection requiring an increase in the immunosuppressive medications may re­sult in poor inflammatory response against the bacteria thus predisposing to urinary tract infec­tions as seen in 14.4% of our study cohort.

Immunosuppressive medications suppress the humoral immunity through B-cell inhibition and prevention of lymphocyte migration to the site of inflammation such as MMF and others have been incriminated in lowering the IgG levels. [13],[14],[15] In our cohort of patients with UTI, the combination of cyclosporine, prednisolone and azathioprine was associate with more epi­sodes of UTI (P= 0.0418). There are very few studies reporting the incidence and outcome of UTI in the era of modern immunosuppressant regimen in India. In a recent study from South India of 1022 renal allograft recipients, 16.5% developed acute graft pyelonephritis following renal transplantation. [16] They found placement of ureteric stent, urological malformations of native kidney, Cytomegalovirus disease, MMF based regimen and acute rejection episodes as determinants of acute graft pyelopnephritis. As we sparingly used stents, we did not see sig­nificant occurrence of pyelonephritis in our co­hort. It has been observed that instrumentation disrupts the glycosaminoglycans from the uro­thelial surface and facilitates introduction of pa­thogen into the biofilm on the catheter/stent. The bacterial aggregates may escape the im­mune system by being walled off into polysac­charide and uroplakin plaques covering the in­tracellular pods, giving rise to recurrent UTI. [17]

In our experience, urine culture should be ca­rried out at regular intervals especially in the early post transplant period for those at in­creased risk, females, young age, diabetics due to the use of potent immunosuppressant's and induction agents routinely used. This will help diagnosing the UTI earlier and mange properly thus preventing adverse outcome including acute rejection and graft scarring.

 
   References Top

1.Franz M, Horl WH. Common errors in diag­nosis and management of urinary tract infection. II: clinical management. Nephrol Dial Transplant 1999;14(11):2754-62.  Back to cited text no. 1      
2.Abbud-Filho M, Adams PL, Alberti J, et al. A Report of the Lisbon conference on the care of the kidney transplant recipient. Transplantation 2007;83(8-Suppl):S1-22.  Back to cited text no. 2      
3.Myerowitz RL, Medeiros AA, O'Brien TF. Bac­terial infection in renal homotransplant reci­pients. A study of fifty-three bacteremic epi­sodes. Am J Med 1972;53(3):308-14.  Back to cited text no. 3      
4.Meier-Kriesche HU, Ojo AO, Hanson JA, Kaplan B. Exponentially increased risk of in­fectious death in older renal transplant reci­pients. Kidney Int 2001;59(4):1539-43.  Back to cited text no. 4      
5.Maraha B, Bonten H, van Hooff H, Fiolet H, Buiting AG, Stobberingh EE. Infectious compli­cations and antibiotic use in renal transplant recipients during a 1-year follow-up. Clin Microbiol Infect 2001;7(11):619-25.  Back to cited text no. 5      
6.Anantharaman P, Abraham G, Shekar U, Moorthy A, Shroff S, Soundararajan P. Klebsiella endo­carditis in the early post-operative period after renal transplantation. Nephrol Dial Transplant 1998;13(10):2665-6.  Back to cited text no. 6      
7.Rubin RH, Ikonen T, Gummert JF, Morris RE. The therapeutic prescription for the organ trans­plant recipient: the linkage of immunosuppre­ssion and antimicrobial strategies Transpl Infect Dis 1999;1(1):29-39.  Back to cited text no. 7      
8.Rubin RH. Infection in the organ transplant recipient. In: Rubin RS, Young LS, eds. Clinical Approach to infection in the Compromised host (4 th edn.). New York: Kluwer Academic / Plenum, 2002:573-679.  Back to cited text no. 8      
9.Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for sympto­matic urinary tract infection in young women. N Engl J Med 1996;335(7):468-74.  Back to cited text no. 9      
10.Jaik NP, Sujatha K, Mathew M, et al. Renal abscess. J Assoc Physician India 2006;54:241-3.  Back to cited text no. 10      
11.Rubin RH, Fang LS, Cosimi AB, et al. Useful­ness of the antibody-coated bacteria assay in the management of urinary tract infection in renal transplant patient. Transplantation 1979;27(1): 18-20  Back to cited text no. 11      
12.Nebreda-Mayoral T, Mufloz-Bellido JL, Garcia­RodrrIguez JA. Incidence and characteristics of urinary tract infections caused by Corynebac­terium urealyticum (Corynebacterium group D2). Eur J Clin Microbiol Infect Dis 1994;13 (7):600-4.  Back to cited text no. 12      
13.Allison AC, Kowalski WJ, Muller CJ, Waters RV, Eugui EM. Mycophenolic acid and brequinar, inhibitors of purine and pyrimidine synthesis, block the glycosylation of adhesion molecules. Transplant Proc 1993;25(3Suppl 2):67-70.  Back to cited text no. 13      
14.Yamani MH, Avery RK, Mawhorter SD, et al. Hypogammaglobulinemia following cardiac transplantation: a link between rejection and infection. J Heart Lung Transplant 2001;20(4): 425-30.  Back to cited text no. 14      
15.Keven K, Sahin M, Kutlay S, et al. Immuno­globulin deficiency in kidney allograft reci­pients: comparative effects of mycophenolate mofetil and azathioprine. Transpl Infect Dis 2003;5(4):181-6.  Back to cited text no. 15      
16.Kamath NS, John GT, Neelakantan N, Kiruba­karan MG, Jacob CK. Acute graft pyeloneph­ritis following renal transplantation. Transpl Infect Dis 2006;8(3):140-7.  Back to cited text no. 16      
17.de Souza RM, Olsburgh J. Urinary tract Infec­tion in the renal transplant patient. Nature Clin Pract Nephrol 2008;4(5):252-64.  Back to cited text no. 17      

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