Asymptomatic Bacteriuria in Kidney Transplant Recipients: Always Not to Treat?

Abstract

Asymptomatic bacteriuria (ASB) is a very frequent condition in kidney transplant recipients (KTRs). Guidelines advise against screening and treatment of ASB beyond the first month after renal transplantation. Here, we report the case of a 40-year-old female KTR with untreated ASB complicated with allograft pyelonephritis with urosepsis and acute kidney injury. The reported case highlights that ASB remains a grey area in the management of KTRs (after the first month), and there is a need for new ad hoc studies to identify which patients should be screened and eventually treated. Until new findings are available, it is suggested not to treat KTRs with ASB; however, if ASB is detected, stricter monitoring and non-antibiotic prophylaxis are necessary to favor prevention or prompt therapy of severe urinary tract infections.

1. Introduction

Immunosuppression-related infections still remain a major cause of morbidity and mortality in kidney transplant recipients (KTRs), with urinary tract infections (UTIs) being one of the most common among KTRs with a prevalence up to 70% [1,2,3]. Furthermore, KTRs may experience allograft pyelonephritis, often requiring hospitalization, which is associated with adverse graft outcomes such as rejection, impaired long-term graft function, allograft loss, and death [4,5].

The pathogenesis of allograft pyelonephritis in KTRs is influenced by two key factors: the shorter length of the transplanted ureter compared to native ureters and the absence of a sphincter acting as a barrier between the transplant and the native bladder. From a microbiological perspective, the primary causative agents of acute pyelonephritis are Gram-negative bacteria, accounting for 56% to 90% of cases. Among these, Escherichia coli is the predominant pathogen, followed by other uropathogens such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter cloacae. In contrast, Gram-positive bacteria, such as Staphylococcus saprophyticus and Streptococcus species, are rare causes of acute pyelonephritis [6,7,8,9].

Several strategies such as antibiotic prophylaxis could be used to reduce the risk of early UTIs and pyelonephritis in KTRs. However, the widespread use of antibiotic prophylaxis has led to a rising rate of resistance to ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMX) in recent years. This is a relevant concern, as TMP-SMX is not only used for UTI prevention but also plays a crucial role in preventing Pneumocystis Jirovecii pneumonia. A meta-analysis of six randomized studies involving 545 KTRs receiving prophylactic TMP-SMX therapy demonstrated a reduction in the risk of sepsis (relative risk [RR] 0.13, 95% CI 0.02–0.70) and bacteriuria (RR 0.41, 95% CI 0.31–0.56) [10,11]. However, increasing resistance to this antibiotic may soon alter these outcomes, necessitating the development of new preventive strategies.

Beyond antibiotic prophylaxis, a Cochrane metanalysis found that early stent removal (within two weeks) significantly reduced the risk of UTIs compared with late removal (RR 0.49, 95% CI 0.30–0.81), particularly when a bladder indwelling stent was used [12]. Conversely, another systematic review including 197 patients found no significant difference in UTI risk between early (<5 days postoperatively) and late (≥5 days postoperatively) removal of the bladder catheter in the post-transplant period [13].

It is also important to note that a negative urine culture in KTRs, when accompanied by abnormal urinalysis findings—such as pyuria, microscopic hematuria, pH > 7, and the presence of struvite crystals—does not entirely rule out UTIs. In such cases, Corynebacterium urealyticum should be considered, as it is a slow-growing organism with potent urease activity that requires selective media for isolation and that is resistant to common oral antibiotics [14,15]. Furthermore, it has also been reported that a negative urine culture, when accompanied by urinary symptoms (dysuria, urinary urgency, increased urinary frequency), may still indicate an ongoing UTI in female patients, predominantly caused by Escherichia coli. One study reported that 96% of symptomatic female patients with a negative urine culture tested positive for Escherichia coli using a high-sensitivity quantitative Escherichia coli PCR test [16].

In KTRs, empirical treatment for complicated UTIs and pyelonephritis typically includes an intravenous antibiotic with coverage against Pseudomonas, Enterococcus, and Gram-positive bacteria. It is crucial to obtain urine and blood cultures before initiating antibiotic therapy for allowing subsequent therapeutic adjustments based on antibiogram results. Most commonly used empirical antibiotics include piperacillin-tazobactam, meropenem, or combination therapy with vancomycin and cefepime, always ensuring dose adjustments based on kidney function. Currently, there is no clear consensus on the optimal duration of treatment. Many centers administer antibiotic therapy for 14 to 21 days, transitioning from intravenous to oral administration upon complete resolution of symptoms. If the antibiogram indicates sensitivity to fluoroquinolones—highly bioavailable agents—it is reasonable to switch from intravenous to oral therapy [17]. In a retrospective study, no difference was observed in the clinical outcome between KTRs treated with a short-course (6–10 days) versus prolonged (11–21 days) antibiotic therapy for complicated UTIs [18]. When using fluoroquinolones, it is important to consider their potential interaction with calcineurin inhibitors (tacrolimus and cyclosporine), as they can alter blood levels of these immunosuppressants. To prevent toxicity, a slight dose reduction of calcineurin inhibitors may be advisable. From a clinical point of view, differentiating complicated UTIs and allograft pyelonephritis from acute rejection can be challenging. However, fever and pain at the transplant site are generally more common in UTIs.

In the first years after transplantation, asymptomatic bacteriuria (ASB) is also a very frequent condition. ASB is defined as the presence of one or more bacteria species in the urine at specified counts (≥10⁵ CFU/mL or ≥10⁸ CFU/L), irrespective of the presence of pyuria, in the absence of signs or symptoms attributable to UTIs [19]. The guidelines from Infectious Diseases Society of America (IDSA) in 2005 did not provide specific recommendations for screening or treating ASB in kidney or other solid organ transplant recipients [19]. However, in 2019, these Clinical Practice Guidelines have been updated and clearly advised against screening and treatment for ASB beyond the first month after renal transplantation (strong recommendation with high-quality evidence) [20].

2. Detailed Case Description

Here, we report the case of a 40-year-old female affected by chronic kidney disease (CKD) secondary to IgA vasculitis diagnosed by renal biopsy when she was 10 years old. In April 2022, after five years of incremental peritoneal dialysis without a previous history of UTI, she received a deceased-donor kidney transplant (two mismatches, Panel Reactive Antibodies: 0%, Donor Specific Antibodies negative with a serum creatinine of 0.9 mg/dL at time of discharge). The patient was referred, in August 2023, to our outpatient nephrology clinic because of vomiting, diarrhea, and fever in the past two days. A routine urine culture performed as screening and collected two weeks earlier had revealed the presence of 105 CFU of Escherichia coli without leukocytes or red blood cells at the evaluation of urinary sediment; at that time, she did not receive antibiotics, as she was fully asymptomatic.

The patient showed blood pressure of 80/50 mmHg, mean arterial pressure (MAP) of 60 mmHg, heart rate of 104 bpm, and meso-gastric and right-iliac region pain with no fever or dysuria. Blood gas analysis showed metabolic acidosis (pH: 7.27; HCO³⁻: 18 mmol/L; lactates: 3 mmol/L; pO₂: 95 mmHg; pCO₂: 33 mmHg). The patient was admitted to hospital and treated with rapid intravenous fluid administration (isotonic crystalloid boluses). Blood test results showed leukocytosis (white blood cells: 35.000 mm³ (94% granulocytes)) and high levels of reactive C-protein (34 mg/dL) and procalcitonin (>100 ng/mL). Based on the worsening clinical picture, empirically, ceftazidime 1 g/day iv was immediately started. On the first day of hospitalization, clinical picture worsened with stage 3 acute kidney injury (AKI) associated with sepsis and diuresis contraction (

Table 1. Laboratory and clinical parameters before and during hospitalization.

	Day −14	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8
Creatinine (mg/dL)	1.1	4.9	6.4	4.6	3.0	2.3	1.7	1.4	1.2
Urea (mg/dL)	37	96	209	225	184	126	84	59	48
WBC (uL)	5510	35,000	20,120	10,460	7750	8450	7590	9444	8280
CRP (mg/dL)	0.11	34	24	12.8	7.3	6.9	5.2	4.7	3.2
Procalcitonin (ng/mL)	<0.5	130	71.6	NA	NA	3.7	1.5	0.8	NA
Blood Pressure (mmHg)	120/70	80/50	90/60	120/60	120/60	120/70	145/90	140/90	160/90
Heart Ratio (bpm)	76	90	82	63	77	77	97	70	95
Body Temperature (°C)	36.3	36.6	36.5	36.2	37.7	37.7	37.6	37.1	36.5

WBC, white blood cell; CRP, C-reactive protein; NA, not available. Day −14 means 14 days before admission.

).

Hydration therapy was increased by infusing high-volume fluids with an improvement in hemodynamic measurements. Immunosuppressive therapy (tacrolimus, mycophenolic acid and prednisone) was consequently tapered, with mycophenolic acid withdrawal.

The patient underwent an abdomen CT, which showed no alteration in the graft and excluded the presence of a gastro-intestinal or gynecological disorder. However, the contrast-enhanced ultrasonography (CEUS) showed a regular impregnation of the renal parenchyma with associated nuanced parietal enhancement of the excretory tracts suggestive of acute pyelonephritis (Figure 1).

Cultural tests revealed the presence of Escherichia coli in the urine and blood, confirming the diagnosis of urosepsis. The strain of Escherichia coli was the same as the one previously found in the urine 14 days earlier with identical antibiotic sensitivity profile. Based on the antibiogram and lack of need for glomerular filtration rate (GFR) adjustment, ceftriaxone 2 g/day iv treatment was started withholding ceftazidime (

Table 2. Blood culture and first urine culture (ASB) microbial profile and antibiotic sensitivity.

Selected organism:		Escherichia coli
Origin:		Blood culture		Collected on 18/AUG/2023
ANTIBIOGRAM
Antimicrobial	MIC	Interpretation	Antimicrobial	MIC	Interpretation
ESBL	NEG	-
Amoxicillin/clavulanic acid	>16	R	Meropenem	≤0.25	S
Piperacillin/tazobactam	≤4	S	Imipenem	≤0.25	S
Cefotaxime	≤0.25	S	Amikacin	4	S
Ceftriaxone	≤0.12	S	Gentamicin	≤1	S
Ceftazidime	≤0.12	S	Tobramycin	≤1	S
Ceftazidime/avibactam	≤0.12	S	Ciprofloxacin	≤0.06	S
Ceftolozane/tazobactam	≤0.25	S	Colistin	≤0.05	S
Cefepime	≤0.12	S	Trimethoprim/Sulfamethoxazole	≤20	S
Selected organism:		Escherichia coli
Origin:		Urine culture		Collected on 01/AUG/2023
ANTIBIOGRAM
Antimicrobial	MIC	Interpretation	Antimicrobial	MIC	Interpretation
ESBL	NEG	-	Meropenem	≤0.25	S
Amoxicillin/clavulanic acid	>16	R	Ertapenem	≤0.12	S
Piperacillin/tazobactam	≤4	S	Imipenem	≤0.25	S
Cefotaxime	≤0.25	S	Amikacin	4	S
Ceftriaxone	≤0.12	S	Gentamicin	≤1	S
Ceftazidime	≤0.12	S	Ciprofloxacin	≤0.06	S
Cefepime	≤0.12	S	Nitrofurantoin	≤16	S
Fosfomycin	≤16	S	Trimethoprim/Sulfamethoxazole	≤20	S

S, Sensitive; R, Resistant; MIC, Minimal Inhibitory Concentration; ESBL, Extended Spectrum Beta-Lactamase. Urine culture screened for bacteria and fungi.

).

After 14 days of antibiotic therapy, the infection was resolved, and the patient’s kidney function fully recovered (Table 1). After hospital discharge, the patient started a prophylaxis treatment for UTIs with cranberry juice, due to successful experience reported in general population. She was screened bi-monthly for UTI. In the subsequent 18 months of follow-up, no additional UTI episodes or relapse of asymptomatic bacteriuria were detected.

Ethical review and approval for this study were not required by the Ethics Committee of University of Campania “Luigi Vanvitelli” because it is a single case report ant the patient has been deidentified.

3. Discussion

We have presented a case report of an untreated ASB complicated with urosepsis and AKI that provides the opportunity of focusing on the screening and treatment of ASB in KTRs who are recognized to be prone to severe UTI. According to the 2019 IDSA guidelines [20], the patient was not treated for ASB because she did not exhibit any urinary symptoms or risk factors for UTIs, such as diabetes mellitus, neurogenic bladder, anatomical abnormalities and urinary tract catheters, and no previous UTIs were recorded before and after kidney transplantation. Apparently, there was no reason to suspect a rapid progression of ASB to severe sepsis and initial screening urine culture could be considered probably useless.

In the setting of KTRs, the prevalence of ASB ranges from 23–24% in the first month after surgery to 10–17% during the first year, decreasing down to 2–9% after one year from transplantation [20,21,22]. The 2019 IDSA guidelines recommend not treating ASB to prevent inappropriate use of antibiotics and the consequent development of antibiotic resistance [20]. Notably, these recent guidelines include for the first time specific advice for KTRs [19]. In particular, the expert panel recommends that ASB should not be treated in KTRs after one month from kidney transplantation because (1) treating ASB is unlikely to prevent pyelonephritis or rejection (reported as high-quality evidence); and (2) the treatment does not improve graft function (reported as moderate-quality evidence). Moreover, IDSA guidelines emphasize that screening is useless, given the high prevalence of ASB in KTRs, and potentially harmful because it could lead physicians to inappropriate use of antimicrobials, thereby contributing to antibiotic resistance. Given the high prevalence of multidrug-resistant microorganisms in KTRs, many of the pathogens responsible for ASB may not be effectively treated with oral antibiotics [20], and unnecessary antibiotic exposure could increase the risk of adverse effects as well as promote the development of multidrug-resistant strains, leading to symptomatic and difficult-to-treat UTIs [21].

Despite this, a European survey reported that among 244 transplant physicians from 138 institutions across 25 countries, 72% systematically screen KTRs for ASB during post-transplant surveillance and 54% prescribe antibiotics if ASB is detected [23]. However, an interesting observation is that IDSA recommendations are mainly based on a few observational studies and only one randomized clinical trial (RCT), which presents several important limitations (inadequate sample size, incomplete outcome data, low events rate). However, surprisingly, the recommendations for KTRs are considered as high- or moderate-level evidence. Indeed, this contrasts with the findings of a Cochrane review on the same topic, which classified the quality of evidence for all outcomes as low [24]. In addition, a recent meta-analysis, including 959 participants in four observational studies and five RCTs, indicated that antibiotic treatment for ASB in KTRs does not provide any significant advantage in reducing UTI recurrence, improving graft outcomes or enhancing long-term prognosis (hospitalization, graft loss, and mortality) [25]. However, the lack of sufficient evidence to provide clear clinical recommendations may be influenced by large variability of important risk factors for UTI in KTRs not adequately addressed in the single-center studies [26]. A recent retrospective study enrolling 508 KTRs identified diabetes, presence of ureteral stent, leukocyturia and hematuria as the main risk factors for developing overt infections when ASB is detected [27].

The lack of solid evidence underscores the urgent need for new diagnostic tools to detect ASB at high risk of severe UTI onset. In this regard, a recent study has reported that monocyte-derived dendritic cells (DCs) can be detected in the urine of KTRs with ASB and high bacterial counts, thus suggesting that DCs may be recruited during the course of a UTI and their frequency in urine may reflect the degree of infection [28]. Large-scale prospective studies are needed to explore whether these cells may be useful to discriminate between pathogenic ASB evolving in complicated UTI and “simple” ASB that can be resolved by the immune system. An additional attractive research area is the identification of the microbial factors associated with severe UTIs. A recent prospective study on KTRs found that PAP (pyelonephritis-associated pilus) elements are more expressed in patients with UTIs than ASB caused by Escherichia coli; the pap operon is a genes cluster that encodes the proteins required for production of P fimbriae, one of the main uro-virulence factors. These play a crucial role in the potential prevention of UTIs, which could have significant therapeutic implications. In mouse models, animals vaccinated against the FimH adhesin produced antibodies that blocked Escherichia coli from binding to human bladder cells in laboratory conditions [29]. In a separate study involving monkeys, vaccination with the Escherichia coli FimH adhesin-chaperone complex, combined with the MF59 adjuvant, induced a strong IgG antibody response against FimH. After being challenged with pathogenic Escherichia coli, three out of four vaccinated monkeys remained protected from bacteriuria and pyuria, while all four controls became infected. Currently, two vaccine formulations are available, both requiring frequent administration: a daily oral capsule containing membrane proteins from 18 Escherichia coli strains and a vaginal suppository containing ten heat-killed uropathogenic Escherichia coli strains. Both are available in Switzerland, but no vaccines against uropathogenic Escherichia coli have been approved in the United States. Research into these vaccines is ongoing, with efforts including the development of a tetravalent Escherichia coli bioconjugate vaccine that induces functional antibody responses against all targeted serotypes, and experimental studies in mice showing the potential of an adjuvanted UPEC antigen vaccine that could be delivered intranasally [30]. However, determination of whether KTRs might benefit from therapies directed toward P-fimbriated Escherichia coli needs to be tested in clinical trials evaluating, in particular, safety of a similar vaccine in a transplantation setting with a potential impact on immunity system and rejection risk [31].

4. Conclusions

The reported case highlights that ASB remains a grey area in the management of KTRs (after the first month) and there is a need for new ad hoc studies to identify which patients should be screened and eventually treated. Until new findings are available, it is suggested not to treat KTRs with ASB; however, if ASB is detected, stricter monitoring and non-antibiotic prophylaxis are necessary to favor prevention or a prompt therapy of UTI. In the absence of specific risk factors, we support a cautious approach to all KTRs with ASB including drinking no less than 1.5-2 L per day, voiding after intercourse, cranberry products, immunoprophylaxis, topical estrogen in postmenopausal woman, and possibly methenamin-hippurate [32].