Profile, Risk Factors, and Outcomes of Asymptomatic Bacteriuria in Kidney Transplant Recipients with Normal Pretransplant Genitourinary Tract: A Single-Center Experience

Introduction

Infectious complications remain the major cause of morbidity and mortality among kidney transplant recipients (KTRs) in the developing world. Urinary tract infection (UTI) is the most common bacterial infection reported after transplant surgery,^1,2. Asymptomatic bacteriuria (ASB) is especially common in the first year after transplant, with an incidence varying from 4% to 51% depending on the definition used.³ During the early post-transplant period, ASB is often treated due to high level of immunosuppression and proximate use of indwelling bladder catheter and/or ureteral stent. In recent years, a number of randomized control trials^4–6 have been conducted on the benefit of treating ASB more than two months after kidney transplantation.⁷ None of these trials have come from a developing country to support or oppose this approach. In developing countries, community-acquired UTIs have shown increasing rates of extended-spectrum beta-lactamase (ESBL) organisms.^8–10 Screening and treatment of ASB involves concern over the selection of resistant strains and the financial burden, especially in resource-limited settings.⁵ Abnormal pretransplant urinary tract, a significant risk factor for progression to UTI,¹¹ has not been excluded in most of the studies. In this study, we looked at the profile, risk factors, and outcomes of ASB in KTRs, with special reference to its treatment and drug-resistant organisms.

Materials and Methods

Results

Seven hundred ninety-four patients underwent kidney transplant during the study period [Figure 1]. Out of them, 710 (77.5% males, mean age 35.6 years, 10.6% diabetic) met the inclusion criteria [Table 1]. Basiliximab was the most common induction agent (71.7%). Prednisolone, mycophenolate, and tacrolimus were the maintenance immunosuppressive agents administered in 94.2% of patients. Three hundred eighty-six bacteriuric episodes occurred in 181 patients (25.5%), with a median follow-up of 47 months (IQR 27, 77). The first episode of bacteriuria occurred at a median of 25 days (IQR 10, 134.5) after transplant. Eighty-one out of 181 patients had ASB and the rest had UTI as the first bacteriuric episode.

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Figure 1:

Outcome of patients with early ASB on follow-up. All values are denoted as N (%). ASB = Asymptomatic bacteriuria, UTI = Urinary tract infection, C = Cystitis, P = Pyelonephritis, U = Urosepsis.

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Effect of timing, drug resistance, and treatment on outcomes of ASB

The following subgroup analyses were done Based on the first bacteriuric episode, ASB episodes were divided into early and late ASB. Among the 56 patients with early ASB, 31 (55.4%) were treated [Figure 1]. However, among the 25 patients with late ASB, only 4 (16%) were treated [Figure 2]. MDR organisms were more common in patients with early ASB episode than in those with late ASB episode (69.6% vs. 32%, 95% CI = 1.76–13.45; P = 0.003). However, the death censored graft survival did not differ (P = 0.83) between early ASB episodes (estimate = 110.2 months, 95% CI = 100.2–120.2) and late ASB episodes (estimate = 118.2, 95% CI = 105.3–131.1). There was no statistically significant difference (P = 0.34) in death censored graft survival between MDR ASB organisms (estimate = 101.3 months, 95% CI = 83.9–118.5) and non-MDR ASB organisms (estimate = 120.7 months, 95% CI = 109.8–131.7).

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Figure 2:

Outcome of patients with late ASB on follow-up. All values are denoted as N (%). ASB = Asymptomatic bacteriuria, UTI = Urinary tract infection, C = Cystitis, P = Pyelonephritis.

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Treatment of ASB neither prevented a UTI event on follow-up (estimate = 86.3 months, 95% CI = 73.3–99.3 vs. estimate = 100.1 months, 95% CI = 84.9–115.3; P = 0.35) nor resulted in better graft survival (estimate = 107.1 months, 95% CI = 101.7–112.6 vs. estimate = 109.5 months, 95% CI = 95.5–123.5; P = 0.083) when compared to untreated ASB episodes. Figure 3 shows the time trend of treating ASB by year. The average cost of treating an episode of ASB was 160 USD. There was no difference in rate of resistant organisms isolated in subsequent urine cultures in the patients whose ASB were treated when compared to those with untreated ASB (54.3% vs. 43.5%; P = 0.375). Among patients who had untreated ASB episodes with MDR organisms, 68% of them spontaneously cleared the organisms on subsequent screening, which was similar to pan susceptible organisms (81%).

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Figure 3:

Time trend of treating ASB over the years. All values are denoted as N. ASB = Asymptomatic bacteriuria.

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Discussion

Screening and treatment of ASB is based on the risk of it progressing to graft pyelonephritis and subsequently affecting graft survival.^12,13 Overall, the incidence of ASB reported in literature—varying due to time period of screening, duration of follow-up, frequency of testing, and geographical location—is 4%–51%.^4,14–17 The low prevalence of ASB (3.4%) reported by Coussement et al.³ is probably because of the exclusion of early ASB episodes (first two months). A study by Sharma et al.¹⁸ with a smaller sample size and shorter duration of follow-up reported the incidence of ASB to be 41.79%. Table 4^3-6,14-26 summarizes the previously published studies on ASB in KTRs. Observational cohort studies done in a developing country like India are minimal.

Risk factors for development of ASB include female gender, chronic glomerulonephritis, pretransplant diabetes mellitus, Double J stenting, older age, and second transplant.^3,14,16,20 In our cohort, female gender, history of UTI before kidney transplant, and delayed graft function were independently associated with ASB. E. coli and Klebsiella were the common pathogens causing ASB in our study, as reported in the literature.^3,15,20

Significant antimicrobial resistance (42.2% ESBL-positive and 3.9% carbapenem-resistant) was noted among our community-acquired uropathogens too.⁹ Similar to a study from Poland two-third of ASB episodes presented early, which indicates that most of the ASB are hospital-acquired as the pre-transplant urine cultures were sterile.¹⁶ Despite MDR organisms being isolated mainly in the early ASB episodes, death censored graft survival did not differ between early and late ASB episodes.

A UTI event after an ASB episode, reported from a Cleveland clinic, was similar to our cohort (28.4%).²⁴ Jayanth et al.,²⁷ from our center, reported increased rates of pyelonephritis and epididymo-orchitis in patients with pretransplant abnormal lower urinary tract. Hence, those patients were excluded from our study. Pre- and post-transplant risk factors did not predict the development of UTI after an ASB episode [Table 3]. The role of bacterial functional virulence factors and metabolism in the development of UTI after an ASB episode has not been assessed in our study.²⁸ Even the presence of pyuria in urinalysis led to inappropriate treatment and serious consequences, and it did not predict the risk of progression to UTI.²⁹ UTI event after an ASB episode did not affect the graft and patient survival in our cohort, as reported in the literature.^14,18 However, it might be worth looking at the outcomes of ASB with MDR organisms prospectively.

Current consensus or guidelines on treatment of early ASB episodes and its impact on patient and graft outcomes are limited. In this cohort, nearly half of the early ASB episodes were treated but did not show any difference in development of UTI events or decline in delta eGFR at five years. Bohn et al.²⁴ reported that ASB episodes were treated in 74.6% of the patients, with there being no added benefit. Unwarranted treatment of ASB episodes may lead to increased risk of MDR organisms and increased economic burden in developing countries.^30,31 Kotagiri et al.²³ reported that treatment of ASB led to statistically lesser episodes of UTI when compared to those untreated. However, this was a retrospective study with no standardized protocol for treatment of ASB. Green et al.¹⁵ reported that treatment of ASB led to a higher risk of hospitalization for UTI or more than 25% reduction in eGFR. Reported randomized control trials did not show any benefit with a screen-and-treat strategy for ASB two months after transplantation.^4–6 Origüen et al.⁴ reported no benefits in treating ASB more than two months after kidney transplantation. However, only half of the patients assigned to the treatment group strictly fulfilled the planned treatment protocol for every episode of ASB. Sabé et al.⁵ too reported no added benefit in the treatment of ASB with added risk of antibiotic resistance. Published guidelines and studies on ASB do not provide clear guidance on management of early ASB episodes. The merits of our study are larger sample size and longer follow-up (median follow-up of 47 months); its limitation was its retrospective design. The study also highlights the profile, outcomes, and impact of treating the first ASB episode in KTRs with a normal pretransplant genitourinary tract from predominant live related donors. This contrasts with the published literature which included predominant deceased donors. The benefits of treating an early ASB could be studied from a multicenter randomized control trial with an adequately powered sample size.

Conclusion

ASB is common among KTRs in the first three months since the transplant . E. coli was the most common pathogen, with significant ESBL-positive or carbapenem-resistant organisms detected. The screen-and-treat strategy can be avoided as there is no additional benefit in graft survival or reduction in UTI events. With the current literature available, the screening for ASB could be limited to the first three months and treatment can be given only if there is progression to a UTI event. The financial implications of screening for ASB and the emergence of antibiotic resistance add to the burden on the healthcare system in a resource-limited setting.