Urinary tract infections in kidney transplant patients admitted to hospital: A real-life experience

Abstract

BACKGROUND

Urinary tract infections (UTIs) in kidney transplant patients are a challenge.

AIM

To evaluate epidemiology, clinical status, therapeutic management, and clinical outcome of kidney transplant patients in a university hospital for UTI.

METHODS

We conducted a retrospective observational study, enrolling all kidney transplant patients hospitalized for UTI, with the objective to evaluate the epidemiology, clinical status, therapeutic management, and clinical outcome of kidney transplant patients.

RESULTS

From our real-life experience, infection with multidrug-resistant germs was confirmed as a risk factor for the severe evolution of the infection. At the same time, the re-evaluation of immunosuppressive therapy could be an important therapeutic strategy in the course of infection.

CONCLUSION

Prompt initiation of empiric antibiotic therapy upon initiation of microbiological investigations may reduce the risk of severe infection progression.

Key Words: Urinary tract infections; Kidney transplant; Multidrug-resistant germ; Solid organ transplant recipient; Empiric therapy

Core Tip: From our real-life experience, infection with multidrug-resistant germs was confirmed as a risk factor for the severe evolution of the infection. At the same time, the re-evaluation of immunosuppressive therapy may be an important therapeutic strategy in the course of infection. Prompt initiation of empiric antibiotic therapy upon initiation of microbiological investigations may reduce the risk of severe infection progression.

INTRODUCTION

Urinary tract infections (UTIs) are one of the main complications in patients who have received a kidney transplant[1,2]. It is estimated that 75% of kidney transplant recipients experience at least one episode of UTI[3,4], and approximately 27% experience recurring episodes[5]. Moreover, UTIs are a risk factor for unfavorable graft evolution, with a negative impact on kidney function over time[6-8]. Additionally, in recent years, the complexity of UTIs in kidney transplant patients has increased due to the frequent isolation of multidrug-resistant (MDR) bacteria[9]. More data are emerging regarding the increasing prevalence of extended-spectrum beta-lactamase (ESBL) strains and carbapenem-resistant Enterobacterales, not to mention the emerging presence of metallo-beta-lactamase-producing strains[10-13]. In particular, the detection of ESBL-producing Enterobacterales is becoming increasingly common in kidney transplant patients, leading to difficulties and a higher likelihood of empiric therapy being insufficient[10-13]. The role of these MDR microorganisms is becoming increasingly relevant in the context of UTIs in kidney transplant patients, both from an epidemiological perspective and in terms of therapeutic management, with an increased risk of mortality and graft loss for the patient[14-18].

These insights are crucial for the correct management of infection and highlight the importance of initiating a comprehensive and timely diagnostic process when a UTI is suspected in a kidney transplant patient. We aimed to evaluate the epidemiology, clinical status, therapeutic management, and clinical outcomes of kidney transplant patients hospitalized for UTI in a university hospital.

MATERIALS AND METHODS

We conducted a retrospective observational study, enrolling all kidney transplant patients hospitalized for UTI at A.O.U. Federico II in Naples from January to December 2023. We enrolled kidney transplant patients hospitalized for UTI who were naïve to antibiotic therapy prior to admission and before the initiation of diagnostic-microbiological investigations. Patients receiving secondary prophylaxis for UTI were excluded. All enrolled patients met the diagnosis of UTI according to the guidelines of the Infectious Diseases Society of America. UTIs were defined as the presence of bacteriuria with signs of infection, which may manifest with mild symptoms, such as inflammation of the lower urinary tract or acute graft pyelonephritis[14-16].

All patients underwent urine testing and culture before starting antibiotic therapy. Blood cultures were obtained prior to antibiotic administration in cases where body temperature ≥ 37.3 °C or chills were observed. Manual plate cultures were performed. After these diagnostic procedures, empiric antibiotic therapy with piperacillin/tazobactam, at a dose adjusted according to each patient’s baseline renal function, was initiated. This empiric therapy continued until the identification of the causative organism, at which point targeted antibiotic therapy was established. Clinical recovery was defined as clinical-laboratory response with the resolution of the clinical symptoms present at the time of hospitalization, along with normalization of C-reactive protein.

Additionally, we assessed the rate of severe infection progression during hospitalization and prolonged hospitalization. Severe progression of the infection was defined as patients who developed sepsis during hospitalization, determined based on the Sequential Organ Failure Assessment (SOFA) score criteria: a patient with an increase in SOFA score by ≥ 2 compared to baseline[17]. Prolonged hospitalization was defined as the need for the patient to remain hospitalized for more than 14 days. MDR was defined as antimicrobial resistance demonstrated by a microorganism species to at least one antimicrobial drug in three or more antimicrobial categories[18]. Manual plate cultures were conducted.

We considered previous events as dependent variables, and the following (defined a priori) as independent variables: Age > 60 years, presence of comorbidities (obesity, type 2 diabetes mellitus, cardiovascular disease), type of immunosuppression (triple vs dual immunosuppressive therapy), history of urinary tract bacterial colonization, recent episodes of UTI (in the last 6 months), MDR germ infection or colonization in the last 6 months, use of appropriate empiric therapy related to the timing between the onset of urinary symptoms and hospitalization (with a threshold of 3 days), and the timing between hospitalization and the start of empiric antibiotic therapy (with a threshold of 2 days).

Data are presented as mean and SD or median and IQR, depending on whether the distribution was Gaussian or non-Gaussian, respectively. For correlation analysis, Pearson or Spearman tests were used for Gaussian or non-Gaussian data distributions, respectively. Continuous variables were compared using Student’s t-test or Mann–Whitney U-test, depending on whether they followed parametric or non-parametric distributions. The P value for statistical significance was set at < 0.05 for all tests. A logistic regression model was employed to evaluate risk factors for severe infection progression and clinical recovery.

Regarding ethical considerations, the study was conducted in accordance with ethical principles derived from the Declaration of Helsinki and good clinical practice. The authors confirm that the ethical policies of the journal have been observed.

RESULTS

In 2023, approximately 700 kidney transplant patients were under follow-up at the A.O.U. Federico II in Naples. Of these, approximately 200 required hospitalization for infections, and 52 were diagnosed with a UTI. Among the 52 cases, only 31 were antibiotic-naïve at the time of urine culture, making them eligible for our study. Table 1 presents the characteristics of the enrolled patients, while Table 2 provides details about the characteristics of the UTIs, including the corresponding microbiological etiological agents, treatments, and clinical outcomes.

Table 1 Characteristics of enrolled patients.

Characteristics		Value
Age in years, median (IQR)		56 (37-72)
Sex, n (%)
	Male	16 (52)
	Female	15 (48)
Comorbidities, n (%)
	Hypertension	27 (87)
	Obesity	15 (48)
	Type II diabetes mellitus	4 (13)
	Cardiovascular disease	2 (6)
	Hypothyroidism	2 (6)
	COPD	1 (3)
Type of transplant, n (%)
	Kidney transplant	30 (97)
	Kidney - pancreas transplant	1 (3)
Indication for the transplant, n (%)
	Chronic renal failure	13 (42)
	ADPKD	8 (27)
	Systemic lupus erythematosus	3 (10)
	IgA nephropathy	2 (6)
	VUR	2 (6)
	Hypertensive nephropathy	2 (6)
	Diabetic nephropathy	1 (3)
Induction immunosuppressive therapy, n (%)
	Basiliximab + methylprednisolone	31 (100)
Immunosuppressive therapy at diagnosis, n (%)
	Tacrolimus – mycophenolate - steroids	16 (52)
	Tacrolimus – everolimus - steroids	3 (10)
	Cyclosporine – mycophenolate - steroids	1 (3)
	Cyclosporine – everolimus - steroids	1 (3)
	Tacrolimus - steroids	6 (20)
	Cyclosporine - steroids	4 (12)
Time from transplant in months, mean (IQR)		49 (2-312)
	TOE	T1
WBC as cell/µL, median (IQR)	14220 (4380-21740)	9885 (3760-15920)
PLT as cell/µL, median (IQR)	379000 (68000-512000)	274000 (83000-492000)
Creatinine in mg/dL, median (IQR)	2.2 (1.5-4.7)	1.9 (1.4-3.5)
Bilirubin in mg/dL, median (IQR)	1.4 (0.9-2.9)	1.1 (0.7-2.3)
CRP in mg/L median (IQR)	55 (9-130)	29 (4-68)

ADPKD: Autosomal dominant polycystic kidney disease; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; IQR: Interquartile range; PLT: Platelets; TOE: Time of enrollment, T1 time of 4 days post-therapy; VUR: Vesicoureteral reflux.

Table 2 Characteristics of urinary tract infections.

Items		Value
UTIs, n (%)	cUTIs	22 (71)
	cUTIs and bacteremia	5 (16)
	Urosepsis	4 (13)
Microbiological agents isolated2, n (%)	Escherichia coli ESBL1	10 (32)	Meropenem	6 (19)
			Ertapenem	4 (13)
	Klebsiella pneumoniae ESBL1	6 (19)	Meropenem	4 (13)
			Ertapenem	2 (6)
	Pseudomonas aeruginosa MDR	4 (13)	Meropenem	4 (13)
	Klebsiella pneumoniae no - ESBL	2 (7)	Piperacillin/tazobactam	2 (7)
	Enterococcus faecium VRE	2 (7)	Daptomycin	2 (7)
	Enterococcus faecium Ampi-S	2 (7)	Piperacillin/tazobactam	1 (3)
			Amoxicillin/clavulanate	1 (3)
	Klebsiella pneumoniae CRE	1 (3)	Ceftazidime/avibactam	1 (3)
	Escherichia coli no - ESBL	1 (3)	Piperacillin/tazobactam	1 (3)
	Pseudomonas aeruginosa no - MDR	1 (3)	Ciprofloxacin	1 (3)
	Proteus mirabilis ESBL	1 (3)	Meropenem	1 (3)
	Citrobacter farmeri ESBL	1 (3)	Meropenem	1 (3)
Overall targeted antibiotic therapy, n (%)	Meropenem		15 (48)
	Ertapenem		7 (23)
	Piperacillin/tazobactam		4 (13)
	Daptomycin		2 (7)
	Ciprofloxacin		1 (3)
	Amoxicillin/clavulanate		1 (3)
	Ceftazidime/avibactam		1 (3)
Duration of targeted therapy in days, median (IQR)	14 (7-18)
Length of stay in days, median (IQR)	15 (8-20)
Outcome
Alive	31 (100)

¹Also isolated from blood cultures (3 Escherichia coli extended-spectrum beta-lactamases, 2 Klebsiella pneumoniae extended-spectrum beta-lactamases).

²Isolated from urine culture. Ampi-S: Ampicillin-sensitive; CRE: Carbapenem-resistant Enterobacterales; cUTIs: Complicated urinary tract infections; ESBL: Extended-spectrum beta-lactamases; IQR: Interquartile range; MDR: Multidrug-resistant germ; UTIs: Urinary tract infections; VRE: Vancomycin-resistant Enterococci.

Notably, of the 31 patients enrolled, 26 (84%) had a history of urinary tract colonization in the post-transplant period, and 22 (71%) had experienced at least one previous episode of UTI in the post-transplant period. Among these patients, 15 (68%) had their last episode more than 6 months earlier, while 7 (32%) experienced the last episode of UTI within the last 6 months. The prevalence of UTIs was approximately 15%, with approximately 64% of cases caused by MDR pathogens.

Table 2 outlines the characteristics of the UTIs, the pathogens isolated, and the corresponding targeted antibiotic therapies. Among the enrolled patients, 16% had bacteremia, whereas 13% developed sepsis; however, none developed septic shock (Table 2). The median time interval between the onset of UTI-related symptoms and hospitalization was approximately 2 days (IQR: 1-4), while the median time interval between the onset of UTI-related symptoms and the initiation of empiric antibiotic therapy was 3 days (IQR: 1-4). The median (IQR) duration of targeted antibiotic therapy was 14 (7-18) days, while the median (IQR) duration of hospitalization was 15 (8-20) days. No patients died during the study period.

In univariate analysis for the risk of severe infection progression, we found that triple immunosuppressive therapy (OR: 1.8, 95%CI: 1.2-1.9, P value: 0.048), infection caused by MDR pathogens (OR: 1.5, 95%CI: 1.1-1.8, P = 0.044), and initiation of empiric antibiotic therapy more than 2 days after hospitalization (OR: 1.5, 95%CI: 1.1-1.7, P = 0.047) were significant risk factors (Table 3).

Table 3 Univariate analysis for severe evolution of infection.

Parameters	OR	95%CI	P value
Age > 60 years	1.1	0.6-1.4	0.126
Male sex	1.3	0.7-1.6	0.235
Comorbidity
Obesity BMI > 3 kg/m2	1.6	0.9-1.9	0.082
Cardiovascular disease	1.3	0.7-1.5	0.164
Diabetes mellitus	1.5	0.7-1.7	0.143
Triple vs dual immunosuppressive therapy	1.8	1.2-1.9	0.048
History of bacterial colonization	1.3	0.8-1.5	0.174
UTIs in the last 6 months	1.1	0.6-1.3	0.133
MDR microorganism infection	1.5	1.1-1.8	0.044
Appropriate empiric therapy	0.9	0.7-1.1	0.084
Timing between onset of symptoms and hospitalization > 3 days	1.3	0.9-1.8	0.093
Timing of empiric therapy initiation from hospitalization > 2 days	1.5	1.1-1.7	0.047

BMI: Body mass index; MDR: Multidrug-resistant germ; UTI: Urinary tract infection.

In univariate analysis for the risk of prolonged hospitalization, infection with MDR pathogens (OR: 1.7, 95%CI: 1.1-1.9, P = 0.047), and a delay of more than 2 days in the start of empiric therapy (OR: 1.6, 95%CI: 1.1-1.7, P = 0.042) were identified as risk factors. In multivariate analysis for the risk of severe infection progression, infection caused by MDR strains (OR: 1.7, 95%CI: 1.2-1.8, P = 0.043), triple immunosuppressive therapy (OR: 1.6, 95%CI: 1.1-1.7, P = 0.046), and initiation of empiric antibiotic therapy more than 2 days after hospitalization (OR: 1.3, 95%CI: 1.1-1.6, P = 0.047) were found to be independent risk factors for infection deterioration (Table 4).

Table 4 Multivariate regression analysis for severe evolution of infection.

Parameters	OR	95%CI	P value
Age > 60 years	1.3	0.7-1.5	0.158
Male sex	1.2	0.8-1.3	0.231
Comorbidity
Obesity BMI > 30 kg/m2	1.4	0.9-1.6	0.093
Cardiovascular disease	1.3	0.7-1.4	0.334
Diabetes mellitus	1.5	0.7-1.8	0.245
Triple vs dual immunosuppressive therapy	1.6	1.1-1.7	0.046
History of bacterial colonization	1.3	0.8-1.5	0.187
UTIs in the last 6 months	1.4	0.7-1.8	0.132
MDR microorganism infection	1.7	1.2-1.8	0.043
Appropriate empiric therapy	0.9	0.7-1.1	0.083
Timing between onset of symptoms and hospitalization > 3 days	1.5	0.9-1.7	0.092
Timing of empiric therapy initiation from hospitalization > 2 days	1.3	1.1-1.6	0.047

BMI: Body mass index; MDR: Multidrug-resistant germ; UTI: Urinary tract infection.

DISCUSSION

Our study highlights the significant challenge posed by UTIs in kidney transplant patients. In fact, most patients (71%) in our study had experienced at least one episode of UTI in their medical history, and almost all (84%) had a history of urinary tract colonization.

Our data are consistent with findings reported in the literature[19-21]. While we observed a similar prevalence of UTIs (15% vs 15%-25%), our study showed a higher prevalence of infections caused by MDR organisms compared to other studies (64% vs 15%-40%)[19-22]. The predominance of Enterobacterales in the microbial etiology was confirmed, along with a similar prevalence of Enterobacterales ESBL strains, and an increasing number of MDR organisms in our cohort[23].

The higher rate of MDR organisms in our cohort compared to other studies could be attributed to differences in study periods and geographical locations. Regional differences in the prevalence of MDR pathogens may reflect varying antimicrobial stewardship practices, as well as differing local epidemiologies. Our study indicates that triple immunosuppressive therapy, infection caused by MDR organisms, and a delay of more than 2 days between hospitalization and the initiation of empiric antibiotic therapy were significant risk factors for severe infection progression.

Regarding triple immunosuppressive therapy, our findings align with several other studies that have highlighted the association with an increased risk of severe infections[24,25]. For instance, Chuang et al[23] demonstrated that triple immunosuppressive therapy, particularly in combination with azathioprine or mycophenolate, increased the risk of severe UTIs. Similarly, Wu et al[26] showed that triple immunosuppressive therapy heightened the risk of urosepsis. These studies underscore the importance of regularly reassessing immunosuppressive therapy and considering dose adjustments to mitigate the risk of infections in transplant recipients.

Our study also confirms the detrimental impact of infections caused by MDR pathogens on the progression of infection, as reported in previous studies[27]. The increasing prevalence of MDR organisms is a major concern in the management of UTIs in kidney transplant recipients, highlighting the need for continuous monitoring and adaptation of antimicrobial strategies.

Another noteworthy finding from our study is that a delay of more than 2 days in initiating empiric antibiotic therapy after hospitalization was a significant risk factor for severe infection progression. This finding emphasizes the importance of timely initiation of empiric therapy, particularly as microbiological investigations are underway. In our case, the decision to start empirical therapy with piperacillin/tazobactam pending microbiological results was a prudent one. This approach aligns with the “WHO AWaRe Antibiotic” classification and supports antimicrobial stewardship efforts[28]. By promptly initiating empiric therapy, it is possible to avoid the use of broad-spectrum agents, such as carbapenems and quinolones, until the microbial etiology is identified, allowing for more targeted and appropriate treatment.

It is important to note that asymptomatic bacteriuria, even when caused by MDR organisms, should generally not be treated unless there are specific clinical indications[3-25]. The condition of asymptomatic bacteriuria during the early months post-transplantation remains a topic of debate, warranting further investigation in future studies.

While obesity is recognized as a potential risk factor for severe infection progression in the general population[29], our study was unable to demonstrate a significant role for obesity. This could be due to the relatively small sample size, which limited our ability to detect associations between obesity and adverse outcomes. As recommended by the WHO, promoting physical activity—such as walking, aerobics, resistance, and balance exercises—may help reduce the risk of infection progression in kidney transplant recipients. The WHO guidelines suggest at least 150 minutes of moderate-intensity, or 75 minutes of vigorous-intensity aerobic physical activity, per week[28,29].

One of the key findings of our study was the importance of early hospitalization, ideally within 3 days of symptom onset, to prevent severe infection progression. Early intervention is critical in managing UTIs in transplant recipients and reducing the risk of complications such as sepsis or graft loss. For prolonged hospitalization, infection with MDR organisms and delays in initiating appropriate antibiotic therapy were identified as significant risk factors. Delays in therapy initiation can prolong hospitalization and increase the likelihood of poor clinical outcomes.

While our study provides valuable insights into the management of UTIs in kidney transplant patients, we acknowledge several limitations. First, the sample size of 31 patients limits the generalizability of our findings. Additionally, the retrospective, monocentric design of the study may introduce biases and limit the external validity of our results. A larger, multicenter, prospective study would be beneficial to confirm these findings and explore additional risk factors and treatment strategies.

In conclusion, our study underscores the challenges posed by UTIs in kidney transplant patients, particularly in the context of MDR infections. Prompt initiation of empiric antibiotic therapy, careful management of immunosuppressive therapy, and early hospitalization are key factors in preventing severe infection progression and improving clinical outcomes in this vulnerable patient population.

CONCLUSION

Our real-life experience underscores the ongoing challenge posed by UTIs in kidney transplant patients. The growing issue of antimicrobial resistance significantly impacts the management and outcomes of infections in solid organ transplant recipients. The rising prevalence of MDR pathogens makes it increasingly difficult to treat infections effectively, emphasizing the need for vigilant surveillance and adaptive antimicrobial strategies. Additionally, the role of immunosuppressive therapy in this context requires careful consideration. Given its central role in preventing graft rejection, immunosuppressive therapy must be balanced against the heightened risk of infections it introduces. Regular therapeutic re-evaluation and dose adjustments could help mitigate this infection risk, particularly in the face of MDR organisms. Of particular interest is the approach to initiating antibiotic therapy empirically. Our study suggests that prompt initiation of empiric antibiotic therapy upon the commencement of microbiological investigations may reduce the risk of severe infection progression. By starting broad-spectrum antibiotics early, before microbiological results are available, clinicians can help control infections more effectively and prevent the worsening of clinical conditions such as sepsis or graft loss. These findings highlight key areas for further exploration. Additional studies and clinical trials are needed to confirm these results, refine the optimal strategies for UTI management in kidney transplant recipients, and develop guidelines that integrate early empiric therapy, antimicrobial stewardship, and immunosuppressive management to improve patient outcomes.