Predisposing Factors to the Development of Urinary Tract Infections in Renal Transplant Recipients and the Impact on the Long-Term Graft function

Abstract

Urinary tract infections (UTIs) represent the most common cause of bacterial infection in renal allograft recipients. The purpose of this study was to estimate the predisposing factors and the impact of UTIs in the long-term graft function. We studied 122 patients (75 males and 47 females), aged 44 ± 12 years. UTIs occurring during the first month, during the first year, and through the entire follow-up period were analyzed. Diabetes mellitus (DM), delayed graft function, acute rejection episodes, and urinary tract obstruction were evaluated as potential predisposing factors. UTI episodes (n = 316) were recorded in 74 of 122 patients (60.7%). The most common pathogen was Escherichia coli. Most patients (81%) who developed infection during the first month had a new episode in the first year. Hospitalization was necessary in 141 of the 316 UTI episodes whereas 87 were hospital acquired. A strong correlation between female gender and UTI occurrence was found (p = 0.01). Urinary tract obstruction was also related to the UTI occurrence during the first year after transplantation (p = 0.001). Patients’ age, DM, delayed graft function, and acute rejection episodes did not correlate with UTI. Long-term renal graft function was not found to be affected by UTI occurrence. UTIs are common infectious complications in renal transplant recipients and often relapse and require hospitalization. The long-term graft function is not affected by the occurrence of UTIs.

Keywords:

• Infectious diseases
• urinary tract infections (UTIs)
• renal transplantation
• obstructive uropathy
• acute rejection episodes

INTRODUCTION

Urinary tract infections (UTIs) represent the most common bacterial infection in renal transplant recipients.¹ Several studies have shown that the incidence of UTIs in renal transplant recipients is much higher than that observed in the general population.² The prevalence of UTIs in renal allograft recipients ranges between 6% and 86% among various studies.³ Several risk factors have been implicated in the development of posttransplant UTIs. Female gender, immunosuppressive medication, comorbidities such as diabetes mellitus (DM), and delayed graft function are the most important parameters involved. Furthermore, instrumentation of the urinary tract (bladder catheters and ureteral stents) and acute rejection episodes, necessitating amplification of immunosuppressive treatment, have also been identified as potential risk factors for the development of posttransplant UTIs.

The most common manifestation is that of lower UTI with urinary frequency and urgency due to cystitis. However, symptoms of more severe infection such as fever and tenderness of the renal allograft as well as sepsis due to acute pyelonephritis can also be observed. Early diagnosis and treatment are necessary to prevent the occurrence of life-threatening complications and graft loss.

In this study, we analyzed the incidence of UTIs, the types of pathogens and their antibiotic resistance, the potential risk factors, and the impact of UTIs in the long-term outcome of renal transplantation in a large number of renal allograft recipients with posttransplant UTIs over a long observation period.

MATERIALS AND METHODS

The medical records of all adult patients (n = 180) who received a kidney transplant in the Renal Transplantation Center of the University Hospital of Patras, Greece, over a 10-year period (from January 1998 to January 2008) were analyzed. Out of 180 patients, 122 [75 men (61.5%) and 47 women (38.5%)], aged 44 ± 12 (mean ± SD) years, were included in this study. The inclusion criteria were adequate follow-up period of more than 1 year postoperatively and consistency at scheduled visits. The clinical characteristics of all included patients are summarized in Table 1.

Table 1 Patients’ characteristics and immunosuppressive medications at transplantation.

Mean age in years (±SD)	43.8 ± 11.8
Gender (male/female)	75/47
Mean (±SD) follow-up period (months)	67.8 ± 30.5
Cause of ESRD	Number (n)
Glomerulonephritis	29
Polycystic kidney disease	13
Interstitial nephritis	8
Diabetic nephropathy	6
Hypertension	3
Unknown	50
Other cause	13
Immunosuppressive medications
Methylprednisolone	122
Mycophenolate mofetil	122
Cyclosporine	89
Tacrolimus	33

Note: ESRD, end-stage renal disease.

All UTI episodes, verified by a positive urine culture showing more than 10⁵ cfu/mL bacteria, and the sensitivity of each pathogen to antibiotics were recorded. Urinalysis and urine culture were obtained from each patient at the scheduled follow-up visits and when clinical symptoms suggestive of UTI were present. UTIs that occurred during the first month, the first year, and the rest of the follow-up period were separately recorded. Patients were categorized in three groups: the first group included those with no UTI during follow-up, the second group included those with one to three– UTI episodes, and the third group included those with more than three episodes.

Potential predisposing factors for UTI occurrence such as DM, delayed graft function, acute rejection episodes, and urinary tract obstruction with consequent dilation of the pelvicalyceal system (PCS) were recorded. The development of community- or hospital-acquired UTI was also investigated.

The immunosuppressive regimen used in all patients included an IL-2 receptor blocker (basiliximab) as part of the induction therapy, methylprednisolone (500 mg intravenously on day 0 followed by gradually reduced doses to 16 mg per os on day 30), a calcineurin inhibitor (cyclosporine or tacrolimus) depending on their immunological risk for rejection, and mycophenolate mofetil (1.5–2 g/day).

The surgical team remained unchanged during the observation period. An internal J ureteral stent and a bladder catheter were placed during the operation in all patients. Bladder catheters were removed within 7–9 days postoperatively whereas ureteral stents were removed approximately after 6 weeks. All patients received a prophylactic antibiotic regimen of vancomycin (1–2 doses in total) and ciprofloxacin against surgical site infection from day 0 till the seventh postoperative day. At this dose vancomycin is minimally nephrotoxic but highly effective against Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus and S. epidermidis, whose isolate rates are high (50% and 80%, respectively) in our hospital registry. Ciprofloxacin, on the other hand, shows high efficacy against Gram-negative rods. In addition, trimethoprim–sulfamethoxazole (TMP/SMX) was given for 6 months after transplantation for prophylaxis against Pneumocystis carinii.

The long-term renal function was estimated by changes of mean serum creatinine values measured every month.

Statistical Analysis

The chi-square test was used to examine the relationship between potential predisposing factors and UTI incidence.

Table 2 Pathogens, number of UTI episodes, hospital-acquired UTIs, and hospital admissions.

Pathogen	UTIs (n)	Admissions	Hospital-acquired infections
Escherichia coli	162	53	28
Klebsiella spp.	54	25	17
Pseudomonas aeruginosa	33	26	14
Proteus spp.	16	4	1
Enterobacter spp.	11	9	6
Enterococcus spp.	36	20	17
Acinetobacter spp.	4	4	4
Total (n)	316	141	87

Note: UTI, urinary tract infection.

To examine the regularity of creatinine values at the end of the first month after transplantation as well as at the end of the first, second, third, fourth, and fifth year, we used the Kolmogorov–Smirnov (K–S) test. K–S test was also used to examine whether the number of hospitalizations followed normal distribution.

Table 3 Pathogens resistance to antibiotics (%).

	Escherichia coli	Klebsiella spp.	Pseudomonas aeruginosa	Proteus	Enterobacter spp.	Acinetobacter	Enterococcus
Ampicillin	70.4	100		56	100	100	42
Amoxicillin/clavoulanic	40	63		44	91	100	33
Cefuroxime	31.5	50		25	100		97
Ceftriaxone		16.7	97		91	100	100
Ceftazidime		14.8	18.2		91	75
Piperacillin/tazobactam			39.4
Cotrimoxazole	56.2	68.5		44		100	100
Ciprofloxacin	35.2	35.2	88	12.5	91	100	100
Gentamicin					9	50
Amikacin	7.4	18.5	73	6.25	55	50
Netilmicin	8	18.5	60.6	6.25
Imipenem	1.2		52	0	18	75
Aztreonam			33.3		73	100
Penicillin							69
Oxacillin							100
Vancomycin							11
Linezolid							0

Covariance ANCOVA analysis was used to compare the mean creatinine value at the end of the fifth year postoperatively between patients who did not develop any infection, those who experienced one to three, and those who experienced more than three UTIs during this time, after these values were adjusted to the creatinine values at the end of the first month postoperatively.

The nonparametric Mann–Whitney test was applied to compare the mean number of hospitalizations between diabetic and nondiabetic patients as well as between genders.

All statistical tests were two-sided, and a p-value of less than 0.05 was considered to indicate statistical significance. All aforementioned tests were performed using the SPSS for Windows v.17 software.

RESULTS

Urinary Tract Infections

Out of 122 patients included in this study, 316 episodes of UTI occurred in 74 (60.7%) patients. Out of these 74 patients, 39 (52.7%) experienced one to three UTI episodes and 35 patients (47.3%) more than three.

The most common pathogen was Escherichia coli, isolated in 162 of 316 episodes (51.3%), followed by Klebsiella spp. in 54 (17%) (Table 2). Out of 316 UTI episodes, 141 needed hospitalization for intravenous administration of antibiotics because of clinically severe infection or resistance of the pathogen to orally administered antibiotics, whereas 87 episodes were hospital-acquired. The most common isolated pathogens of hospital-acquired UTIs were E. coli in 28 of the 87 cases (32.2%), Klebsiella spp. in 17 (19.5%), and Enterococcus spp. in 17 (19.5%).

The resistance rates of all isolated pathogens to antibiotics are presented in Table 3. The resistance rates of E. coli to TMP/SMX, ciprofloxacin, and imipenem were 56.2%, 35.2%, and 1.2%, respectively. The prevalence of infections caused by extended-spectrum β-lactamase (ESBL)-producing E. coli and Klebsiella sp. was 14.8% and 16.7%, respectively.

Time of Appearance and Recurrence of UTIs

During the immediate postoperative period (first month after transplantation), UTIs were recorded in 31 of 122 patients (25.4%). Between the second month and the end of first year of observation, UTIs were observed in 55 patients. Out of these, 24 (43.6%) had already an episode during the first month and 31 (56.4%) showed their first UTI between the 2nd and 12th month of follow-up. Between the first and second year after transplantation, UTIs were observed in 34 patients. Out of these, 17 (50%) had previous episodes and 17 (50%) showed their first UTI episode during this period. After the second year and up to the end of the observation period, UTIs occurred in 58 patients. Out of these, 44 (76%) had at least one previous episode, whereas for 14 patients (24%) this was the first UTI episode.

A significant correlation was found between the incidence of UTI during the first month postoperatively and the occurrence of a new UTI episode during the first year (χ² = 20.71, p < 0.001), the second year (χ² = 17.554, p = 0.001), and the following years of the observation period (χ² = 14.877, p = 0.001).

Risk Factors and Incidence of UTIs

PCS dilatation in the immediate postoperative period was observed in 31 of 122 (25.4%) patients included in this study, delayed graft function in 38 (31.1%), abnormal glucose tolerance in 10 (8.2%), and acute rejection episodes in 7 patients (5.7%).

A significant correlation was found between female gender and UTI occurrence in the first month (χ² = 6.7, p = 0.01), in the first year after transplantation (χ² = 8.53, p = 0.003), and during the following years of the observation period (χ² = 15.757, p = 0.001). No correlation of patients’ age with the incidence and time of UTI occurrence after transplantation was observed.

Although the presence of PCS dilatation in the immediate postoperative period was not significantly correlated with UTI occurrence during the first month (χ² = 2.225, p = 0.136), it was correlated with UTI incidence during the first year after transplantation (χ² = 11.248, p = 0.001). However, no significant correlation was observed between PCS dilatation and UTI occurrence during the following years of the observation period (χ² = 1.846, p = 0.174).

The presence of delayed graft function was not significantly correlated with UTI occurrence at any time of the observation period, first month (χ² = 3.806, p = 0.51), first year (χ² = 5.317, p = 0.21), and rest of the follow-up period (χ² = 0.134, p = 0.715). The presence of DM was also not correlated to UTI occurrence during the first month (χ² = 3.475, p = 0.121), during the first year (χ² = 2.732, p = 0.183), and after the first year of follow-up (χ² = 1.344, p = 0.246). Finally, the presence of acute rejection episodes was not related to the occurrence of UTI at any time after transplantation, first month (χ² = 0.39, p = 0.843), first year(χ² = 2.082, p = 0.149), and rest of the follow-up period (χ² = 1.699, p = 0.192).

UTIs and Long-Term Renal Allograft Function

The long-term renal function, estimated by measurements of serum creatinine values every month, showed no significant changes between patients with (n1) and without (n2) UTIs during the first month after transplantation (Mann–Whitney U = 1385, n1 = 91, n2 = 31, p = 0.952). Similarly, no significant changes in the renal function at 5 years of follow-up were observed between patients who showed no UTI, those who had one to three episodes, and those with more than three episodes (F = 2.04, p = 0.138).

DISCUSSION

Pathogens

UTIs represent a serious cause of morbidity after renal transplantation, accounting for approximately 40–50% of all infectious complications in renal allograft recipients.¹ UTIs are caused by a broad spectrum of pathogens including both Gram-negative and Gram-positive bacteria, as well as fungi.^3,4 E. coli, which is the most common pathogen of UTI in the general population,⁵ is also the most common cause of UTI in renal transplant recipients with a frequency ranging from 29% to 71% in various studies.^6,7 Furthermore, rare pathogens, such as Corynebacterium urealyticum,⁸ various mycobacteria, and BK virus⁷ have also been reported. In this study, E. coli was also the most frequent cause isolated in 51.3% of all cases and in 32.2% of hospital-acquired UTIs.

However, pathogens resistant to commonly used antibiotics, such as Acinetobacter, Enterobacter spp., Enterococcus spp., and Pseudomonas aeruginosa, were responsible for the majority of hospital-acquired UTIs (47%). This finding is worrying, as these patients need to be hospitalized for longer periods of time and need to receive potentially nephrotoxic antibiotics against multiresistant pathogens. Therefore, appropriate measures for prevention are necessary, to reduce the rate of hospital-acquired UTIs during at least the immediate posttransplantation period. Such measures may include the rapid removal of bladder catheter and ureteral J-stents^9,10 and the avoidance of routine use of antibiotics, unless there are specific symptoms and signs of infection.¹¹ However, the administration of prophylactic dose of antibiotics before the operation¹² and the administration of TMP/SMX, as prophylaxis against infection from P. carinii after transplantation, are necessary.

Pathogens’ Sensitivities

The resistance of E. coli, the most frequent pathogen causing UTI, to basic antibiotics such as TMP/SMX and ciprofloxacin ranges from 35% to 82%.^12,13 In our study, the resistance rates of E. coli against TMP/SMX and ciprofloxacin were 56.2% and 35.2%, respectively. It is noteworthy that 14.8% of isolated strains of E. coli were ESBL, whereas 1.2% were resistant to imipenem. The resistance rates of P. aeruginosa to ciprofloxacin and ceftazidime are reported to be 100% and 20%, respectively.¹⁴ We noticed that 88% of cases were resistant to ciprofloxacin, 18.2% to ceftazidime, and 52% to imipenem. Enterococcus faecalis has been reported to reach resistance rate of 83.3% against ampicillin and 30.8% against vancomycin.¹⁴ In our study, the resistance rates against these antibiotics were 42% and 11%, respectively. Interestingly, Acinetobacter showed a high resistance rate to imipenem (75%) and aztreonam (100%) in our study.

Time of UTIs Occurrence and Correlations with Risk Factors

The cumulative incidence of UTI after renal transplantation varies widely among studies and ranges from 6% to 86%.^15,16 The incidence of UTIs in our study was 60.7%. According to some studies, UTIs occur more frequently during the immediate postoperative period,^3,12 whereas others state that UTIs are more frequently observed after the first 6 months.¹³ We noticed that UTIs occurred in a large number of patients during the first month and first year after transplantation. However, a significant association was found between the occurrence of UTI during the first month and its recurrence during the following year and during the whole observation period.

Several factors have been associated with increased risk of UTI in renal transplant recipients. Female gender, prolonged period of hemodialysis before transplantation, history of UTI before transplantation, Vesicoureteral reflux, polycystic kidneys, DM, and prolonged bladder catheterization have been implicated in various studies with conflicting results.³ In this study, recipients’ age and gender as well as the presence of DM, delayed graft function, acute rejection episodes, and urinary obstruction with subsequent dilatation of PCS were analyzed as potential predisposing factors for UTIs.

Female gender is closely related with posttransplant UTI in some reports.^2,5,17 However, others have shown no relation.^15,18 The analysis of our data showed a significant correlation between female gender and UTI occurrence within the first month after transplantation and throughout the follow-up period. Conflicting results have been reported for the relation of recipient’s age and UTI occurrence. Similar to other reports,^2,17,19 no relation of recipients’ age with UTI occurrence (total number of UTI episodes and time of occurrence during the follow-up period) was confirmed in this study. However, an increased risk of UTIs, attributed to increased incidence of benign prostatic hypertrophy, bladder atrophy, impaired immune system, and poor hygiene, has been reported in elderly renal transplant recipients.^5,20

Although a history of DM has been reported to predispose to the development of UTI in renal transplant recipients,²¹ others do not support this issue.⁵ In this study, no relation of DM to UTI occurrence at any time over the follow-up period was found.

Obstructive uropathy due to surgical complications, vesicoureteral reflux, neurogenic bladder, or prostate hypertrophy manifested as urine stasis with consequent graft ureteral and pelvis dilation represents a potential risk factor for the development of UTI. In this study, a significant relationship between urinary tract obstruction and UTIs during the first year of follow-up was observed. This finding is consistent with the results of Lyerov´ā et al., who stated that However, no relation of urinary tract obstruction with UTIs occurring after the first year of renal transplantation was found. This is probably due to the surgical management of all renal allograft recipients who developed PCS dilation with ureteral re-implantation. Although the presence of vesicoureteral reflux seems to increase the risk of UTI occurrence,⁵ Jung et al. showed that this dysfunction does not appear to significantly affect UTI prevalence and renal function.¹⁸ However, in such cases ureteral re-implantation represents the treatment of choice.²³

Infections of the upper or lower urinary tract can trigger acute rejection episodes.^1,3,16 Furthermore, treatment of acute rejection needs more intense immune suppression leading to increased risk of infectious complications.³ Although several reports confirm the correlation between acute rejection and UTI,^15,16 others do not support this issue.^2,9 In this study, no relation between acute rejection episodes and occurrence of UTIs was observed.

UTIs and Long-Term Allograft Function

Although it is difficult to estimate the impact of UTIs on the long-term renal function of healthy subjects, a small proportion (3–4%) of patients with chronic renal disease who develop acute pyelonephritis show unfavorable long-term effects on renal function.²⁴ For renal transplant recipients, the data are again unclear. Although renal transplant patients who develop upper UTIs caused by E. coli bearing adherence factors are at increased risk for acute renal failure and graft scarring,²⁵ they do not exhibit worsening of long-term renal function.²⁶ According to Giral et al., if acute pyelonephritis occurs in the first trimester after transplantation, the graft survival is independently and negatively affected. However, when renal transplant patients are examined as a whole, graft survival is not affected by UTIs.²⁷ The latter seems to be confirmed by other researchers, who did not find differences in graft survival rates between patients without UTIs and those who have suffered either a single episode^15,22 or repeated episodes,¹⁶ although a reduction of renal function might be observed in patients with UTI episodes.¹⁶ Similar to these studies, the results of this analysis showed no significant influence of the occurrence of UTIs on the long-term renal function of transplanted patients.

CONCLUSIONS

A high proportion of renal transplant recipients show at least one episode of UTI. Patients who develop UTI within the first month after transplantation usually show more UTI episodes during the follow-up period. E. coli and Klebsiella spp. are the most frequent pathogens and often show resistance to commonly used antibiotics, leading to increased number of hospital admissions. Urinary tract obstruction is an important predisposing factor for UTIs in renal transplant patients and should be treated promptly and effectively.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.