Urodynamic Risk Factors for Recurrent Febrile Graft Pyelonephritis in Kidney Transplant Recipients: A Retrospective Study

Authors: Jun Kamei, Ei‐ichiro Takaoka, Takehiro Ohyama, Sho Nishida, Daiji Watanabe, Aya Niimi, Yuta Yamada, Toru Sugihara, Satoshi Ando, Haruki Kume, Daiki Iwami, Tetsuya Fujimura

Abstract

Objectives

We aimed to assess lower urinary tract function and morphological changes in kidney transplant recipients with a history of graft pyelonephritis and investigate the association between specific types of lower urinary tract dysfunction and the risk of recurrent graft pyelonephritis.

Methods

We retrospectively reviewed the medical records of kidney transplant recipients hospitalized for febrile graft pyelonephritis more than 1 year after transplantation between April 2019 and October 2023. Patients underwent cystography and urodynamic studies after infection control and were followed up for at least 12 months. They were classified based on urodynamic findings, and recurrence‐free survival was analyzed.

Results

Twenty‐four patients were included. Vesicoureteral reflux of the grafted kidney was observed in 20 (83.3%) patients. Detrusor overactivity, detrusor underactivity, and low‐compliance bladders were diagnosed in 8 (33.3%), 12 (50.0%), and 7 (29.2%) patients, respectively. Based on urodynamic findings, treatment and bladder management were modified in 20 patients. During a median follow‐up of 33 months, seven patients developed recurrent graft pyelonephritis. Detrusor overactivity remained an independent risk factor for recurrent graft pyelonephritis (odds ratio, 21.4; p = 0.04). Patients with detrusor overactivity or underactivity but not low‐compliance bladder had significantly shorter recurrence‐free survival compared with those without these dysfunctions (p = 0.017, 0.038, and 0.38, respectively).

Conclusions

Persistent lower urinary tract dysfunction, particularly detrusor overactivity, is a significant risk factor for recurrent graft pyelonephritis. Comprehensive evaluation of vesicoureteral reflux and lower urinary tract function via urodynamic studies is important to improve posttransplant outcomes in patients with a history of graft pyelonephritis.

Introduction

Renal transplantation is increasingly performed worldwide as a treatment for end‐stage renal disease. Lower urinary tract symptoms (LUTS), including urinary frequency and dysuria, frequently occur in kidney transplant recipients, often as a consequence of anuria and bladder disuse during long‐term maintenance hemodialysis [1]. Although these symptoms typically improve within several months after transplantation, a subset of patients continues to experience persistent lower urinary tract dysfunction (LUTD) [2, 3].

Urinary tract infections (UTIs) are common complications following kidney transplantation, particularly during the first postoperative year [4, 5]. Among these, acute graft pyelonephritis is a clinically significant infection associated with an increased risk of graft dysfunction, graft loss, and patient mortality [5, 6]. Therefore, prevention of such infections is important for long‐term posttransplant care.

In patients with recurrent graft pyelonephritis, surgical correction may be indicated when the vesicoureteral reflux (VUR) of the grafted kidney is evident. However, limited evidence exists regarding the relationship between persistent LUTD and graft pyelonephritis after kidney transplantation, despite the well‐established association between severe LUTD (such as much postvoid residual urine, low compliance [LC] bladder, and detrusor overactivity [DO]) and febrile UTIs [7].

This study aimed to evaluate lower urinary tract function and morphological changes in kidney transplant recipients who developed graft pyelonephritis during the chronic posttransplant phase. We further investigated whether specific types of LUTD were associated with an increased risk of recurrent graft pyelonephritis, despite appropriate bladder management.

Methods

Study Design and Ethics

We conducted a retrospective study of kidney transplant recipients hospitalized for febrile graft pyelonephritis more than 1 year after transplantation between April 2019 and October 2023. All participants underwent cystography and urodynamic studies (UDS) after treatment for pyelonephritis to evaluate bladder deformity, VUR, and lower urinary tract function. The patients were followed up for a minimum of 12 months. The Medical Research Ethics Committee of our hospital approved this study (approval A22‐023). The requirement for written informed consent was waived due to the retrospective nature of the study.

Data Collection

Clinical information, including cystographic and urodynamic findings, bladder management, additional interventions, and graft pyelonephritis recurrence was extracted from medical records.

Cystography was performed using 50% contrast medium instilled via a 12‐Fr Nelaton catheter by spontaneous titration until the patient experienced a strong urge to void or urinary leakage. Bladder deformity and VUR of the transplanted kidneys were graded at the end of cystography according to established grading systems [8, 9]. Bladder deformities were classified as Grade 0—round or oval bladder with a smooth wall; Grade 1—round or oval bladder with mild wall irregularities; Grade 2—presence of a mild bladder diverticulum; and Grade 3—severe bladder diverticulum, also described as a ‘pine tree‐shaped bladder.’ [8].

Filling cytometry and pressure‐flow studies (PFS) were performed using a Solar system (Laborie Medical Technologies, Ontario, Canada) following the standards of the International Continence Society, unless otherwise specified [10, 11]. Intravesical pressure was recorded using a 10‐Fr double‐lumen transurethral catheter, and abdominal pressure was measured using a transrectal balloon catheter. Maximum cystometric capacity was defined as the instilled volume at which a strong desire to void, urine leakage, or sustained detrusor pressure (Pdet) > 40 cmH2O occurred [12]. LC was defined as bladder compliance < 20 mL/cmH2O. Bladder outlet obstruction (BOO) was diagnosed by (PdetQmax—2Qmax) > 40 in male patients and by (PdetQmax—2.2Qmax) > 18 in female patients [13, 14]. Detrusor underactivity (DU) was diagnosed when the bladder contractility index (PdetQmax +5Qmax) was < 100 in male patients and PdetQmax was < 20 cmH2O, Qmax was < 15 mL/s, and voiding efficiency was < 90% in female patients [13, 15].

Statistical Analysis

The clinical characteristics, cystographic findings, and recurrence rates of graft pyelonephritis were compared between patients with and without DO, DU, and LC. Pyelonephritis‐free survival was assessed using the Kaplan–Meier method and compared using the log‐rank test. Parametric and non‐parametric tests were used to analyze continuous variables, whereas the χ ^2^ test or Fisher exact test was used to analyze categorical variables where appropriate. All variables p < 0.1 in the univariate analysis were included in the multivariate logistic regression analysis. Differences were considered statistically significant at p < 0.05. JMP (version 17, SAS Institute Inc., Cary, NC, USA) was used to perform statistical analysis.

Results

During the study period, 450 post‐kidney transplant patients were under outpatient follow‐up, and 28 (6.2%) were hospitalized for graft pyelonephritis. Two of the hospitalized patients could not undergo UDS due to advanced age and limited activities of daily living, and two declined UDS. Therefore, 24 patients (10 male and 14 female) met the inclusion criteria. The patient characteristics are summarized in Table 1. The Lich‐Gregoir extravesical ureterovesical reimplantation technique was used in all 24 cases. Six patients underwent preemptive kidney transplantation, whereas the remaining 18 had a history of hemodialysis, including 17 with periods of anuria. The median number of graft pyelonephritis episodes was three, and the median time from transplantation to UDS was 70.5 months. The comorbidities included diabetes mellitus (n = 8), central nervous system disorders (n = 5), and spinal cord disorders (n = 3). Two male patients used α‐1 adrenoceptor antagonists. Clean intermittent catheterization was performed in four patients, and one patient used an indwelling catheter. No patient underwent surgical correction for VUR before UDS.

Cystography revealed grade 1 and 2 bladder deformities in 12 (50.0%) and 2 (8.3%) patients, respectively; no grade 3 deformities were observed. VUR in the grafted kidney was observed in 20 patients (83.3%) and graded as grade 1 in 2 (8.3%), grade 2 in 6 (25.0%), grade 3 in 7 (29.2%), and grade 4 in 5 (20.8%) patients.

The UDS results are summarized in Table 2. On cystometry, 12 patients demonstrated normal storage function, DO was diagnosed in 8 patients, and LC in 7 patients. The PFS indicated DU in 12 patients, with no patients demonstrating BOO.

To prevent recurrent pyelonephritis, bladder management and/or treatment was modified in 20 patients based on urodynamic and cystographic findings. The modified treatments included medication adjustments (n = 9), surgical procedures (n = 8), behavioral therapy (n = 5), and changes in bladder management (n = 4). During a median follow‐up period of 33 months (range: 16–49 months), 7 patients experienced recurrent graft pyelonephritis. Table 3 compares the clinical and urodynamic characteristics of patients with and without DO, LC, and DU. Patients with LC or DU had significantly longer dialysis duration and were more likely to experience anuria, compared with patients without these conditions. DO was significantly associated with pyelonephritis recurrence, despite treatment modification. Clinical characteristics of patients with and without bladder deformities were compared but showed no significant differences (Supplementary Table S1).

The analyses of the risk factors for recurrent graft pyelonephritis, including patient background and UDS findings, are shown in Table 4. Not only univariate but also multivariate regression analysis revealed that DO was an independent risk factor for pyelonephritis recurrence (odds ratio, 21.4; 95% confidence 1.2–397.5; p = 0.04). The Kaplan–Meier curves for pyelonephritis‐free survival based on the presence or absence of DO, LC, and DU are shown in Figure 1. Patients with DO or DU had significantly shorter recurrence‐free survival, compared with those without these conditions (log‐rank test, p = 0.017 and 0.038, respectively). In contrast, no significant difference in recurrence‐free survival was observed between patients with and without LC (log‐rank test, p = 0.38). Pyelonephritis‐free survival was also analyzed based on the presence of bladder deformity and VUR grade ≤ 2 vs. ≥ 3, but no significant differences were observed (log‐rank test, p = 0.75 and 0.61, respectively, Figure S1). In contrast, when stratified, the VUR status into three groups, pyelonephritis‐free survival was significantly worse in patients with VUR grade ≥ 3 and DO (log‐rank test, p = 0.041, Figure 1D). In addition, patients were divided into four groups based on treatment modifications following UDS, namely bladder management changes, surgical correction of VUR, medication adjustments, and others (no change or behavioral therapy only). Pyelonephritis‐free survival did not differ significantly among these groups (log‐rank test, p = 0.36; Figure 2).

Discussion

In this study, we evaluated the morphological changes and lower urinary tract function in kidney transplant recipients with a history of graft pyelonephritis and assessed whether specific types of LUTD, namely DO, DU, and LC, were associated with the risk of recurrent graft pyelonephritis. These patients frequently exhibited both VUR and various forms of LUTD. DO was significantly associated with an increased risk of recurrent graft pyelonephritis, despite adjustments in bladder management or drug treatment based on UDS findings. Both DO and DU were associated with recurrence within shorter time periods, whereas LC was not.

UTIs occur most frequently within the first year after transplantation and tend to decrease thereafter [4, 6]. This trend is likely due to the stabilization of renal function and urine production, which facilitates bacterial washout from the bladder and immune responses, reduced frequency of urinary tract manipulations, and recovery of bladder function [2, 3, 16]. Established risk factors for posttransplant UTIs include older age, female sex, diabetes mellitus, and graft VUR [17]. Although previous studies have suggested that prolonged hemodialysis or anuria may result in persistent LUTD, few have examined the direct impact of LUTD on recurrent graft pyelonephritis [18]. A recent study reported DO prevalence decreased from 81.3% to 43.8% after renal transplantation in patients with defunctionalized bladders [19]. In contrast, data on LC and DU after renal transplantation are scarce, although some studies suggest that bladder compliance in most patients with LC improves post‐transplantation [3, 19]. In our cohort, 33.3%, 58.3%, and 29.2% of the patients exhibited DO, DU, and LC, respectively, and only 29.2% demonstrated no evidence of these dysfunctions. These findings suggest that persistent LUTD is common among kidney transplant recipients who develop graft pyelonephritis and likely contributes to recurrent infection.

VUR, a well‐known risk factor for graft pyelonephritis, was observed in 83.3% of patients [17, 20]. Although VUR can occur primarily because of ureterovesical anastomosis during transplantation, it may also arise secondarily from severe LUTD. Primary VUR is typically managed surgically using anti‐reflux procedures; however, secondary VUR caused by LUTD requires correction of the underlying LUTD or bladder management to maintain low intravesical pressure and prevent recurrent febrile UTI [21, 22]. Because differentiating between primary and secondary VUR in kidney transplant recipients is challenging, we used the presence of DO as a surrogate marker to explore this distinction. We compared pyelonephritis‐free survival among three patients with VUR grade ≥ 3 and DO, those with VUR grade ≥ 3 without DO, and those with VUR grade ≤ 2. Notably, survival was significantly worse in patients with VUR grade ≥ 3 accompanied by DO. These findings highlight the importance of assessing the underlying pathology of LUTD in transplant recipients with VUR, as it may have critical implications for preventing graft pyelonephritis and preserving allograft function.

DO remained an independent risk factor for recurrent graft pyelonephritis even after treatment adjustments, although these findings should be interpreted with caution. The small sample size and wide confidence intervals limit the statistical reliability and generalizability of the results. These results are consistent with previous studies linking DO to upper urinary tract deterioration and febrile UTIs in patients with a neurogenic bladder [7]. Although DU was associated with shorter pyelonephritis‐free survival, it was not a significant risk factor. This may be because of the small sample size in our study. Similarly, LC did not emerge as a significant risk factor, possibly because the degree of compliance deterioration was relatively mild in this cohort; no patients had bladder compliance < 10 mL/cmHO, a threshold often considered clinically meaningful for poor compliance [23]. Furthermore, treatment modifications based on UDS findings were not significantly associated with pyelonephritis‐free survival in our cohort. These results may reflect both the individualized nature of the interventions to prevent UTI recurrence and the limited statistical power due to the small sample size.

This study has some limitations. This was a single‐center, retrospective study with a small sample size. Statistical analysis with high reliability could not be performed in this study because of the small sample size. In addition, UDS was not routinely performed in patients with graft pyelonephritis prior to the study period, and its timing was not standardized, resulting in heterogeneity in patient backgrounds. This study focused on the recurrence of graft pyelonephritis in a selected group of patients with a history of graft pyelonephritis. Therefore, the prevalence and detailed characteristics of VUR and LUTD among kidney transplant recipients with no history of graft pyelonephritis followed up at our institute remain unknown. Larger prospective studies with standardized protocols are needed to clarify the role of LUTD in the risk of graft pyelonephritis after kidney transplantation.

In conclusion, DO appears to be a significant risk factor for recurrent graft pyelonephritis in kidney transplant recipients, even after appropriate bladder management. Both DO and DU were associated with early recurrence. Comprehensive assessment of VUR and LUTD using UDS should be considered in patients with a history of graft pyelonephritis to prevent recurrent infections and improve graft survival outcomes.

Ethics Statement

The protocol for this research project was approved by a suitably constituted Ethics Committee of the institution, and it conforms to the provisions of the Declaration of Helsinki (Committee of Jichi Medical University, approval no. A22‐023).

Consent

The requirement for written informed consent was waived owing to the retrospective nature of the study.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information