Objectives: We aimed to the determine urinary tract infection and graft survival rates in pediatric renal transplant recipients with lower urinary tract dysfunction with particular focus on neurogenic bladder, posterior urethral valve, and vesicoureteral reflux nephropathy.

Materials and Methods: Patients were grouped according to primary diseases as those with and without lower urinary tract dysfunction. Urinary tract infections during year 1 posttransplant were inves­tigated. Estimated glomerular filtration rate was calculated using Schwartz formula.

Results: Our study investigated 133 kidney transplant recipients. Lower urinary tract dysfunction was found in 58 patients (43.6%): 25 with posterior urethral valve, 24 with vesicoureteral reflux nephropathy, and 9 with neurogenic bladder. Rates of posttransplant urinary tract infection were higher in patients with lower urinary tract dysfunction than in those without during both the first 6 months posttransplant (24.6% vs 10.8%; P = .037) and between posttransplant months 6 and 12 (24.6% vs 8.2%; P = .01). Patients with neurogenic bladder had the highest rate of urinary tract infections, and their estimated glomerular filtrations rates were lower compared with patients with posterior urethral valve and vesicoureteral reflux nephropathy at month 6 and years 1, 2, and 5 post­transplant (P < .001). The 5-year graft survival rates of patients without lower urinary tract dysfunction and those with vesicoureteral reflux nephropathy were similar (51.3% vs 51.6%; P = .891).

Conclusions: Graft survival rates of patients with posterior urethral valve and vesicoureteral reflux nephropathy were similar to those shown in patients without lower urinary system dysfunction; however, patients with neurogenic bladder had worse graft survival and urinary tract infection rates.

Key words : Kidney transplant, Neurogenic bladder, Urinary tract infection

Introduction

Lower urinary tract dysfunction (LUTD) is one of the most important causes of chronic renal failure in childhood.¹ According to a 2006 North American Pediatric Renal Trials and Collaborative Studies report, 15.8% of all cases of end-stage renal failure consist of obstructive uropathies, of which 5.1% are related to vesicoureteral reflux (VUR) nephropathy.² In a recent report from Turkey, the cause of end-stage renal failure was VUR nephropathy in 18.5%, neuro­genic bladder in 15.1%, and obstructive uropathies in 10.7% of cases.¹ Although renal transplant is the most successful treatment modality for chronic renal failure, physicians have some concern for disorders affecting the lower urinary tract system. In some studies, graft function was worse in patients with LUTD after renal transplant, whereas others showed no differences.^3,4 In this study, we aimed to determine rates of urinary tract infection (UTI) and graft survival in pediatric renal transplant recipients with LUTD with particular focus on neurogenic bladder, posterior urethral valve (PUV), and VUR nephropathy.

Materials and Methods

Study design and patients
Data of pediatric patients who underwent renal transplant between March 2005 and January 2014 and who had at least 6 months of follow-up were retrospectively evaluated. Patients and their parents provided consent for study inclusion. In addition, approval was obtained from Akdeniz University Faculty of Medicine, Clinical Research Ethics Committee. The patients were grouped according to primary factors causing renal failure: (1) those with LUTD (PUV, VUR nephropathy, and neurogenic bladder) and (2) those with other causes (non-LUTD). Patients in the VUR nephropathy group included those with primary VUR and secondary VUR due to recurrent UTIs. Patients in the neurogenic bladder group included those with meningomyelocele, VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) syndrome, prune belly, Ochoa syndrome, and non-neurogenic neurogenic bladder.

Demographic data, information on prior dialysis treatment, and duration of dialysis treatment were recorded. Pretransplant evaluations of patients with LUTD included a detailed urologic examination, retrograde voiding cystourethrogram, uroflowmetry, and urodynamic examination, if necessary. Corrective procedures such as bladder augmentation before transplant were also recorded.

Study definitions
Renal transplant recipients were examined daily in the first week posttransplant, twice per week in the first month, weekly in months 2 and 3, and then biweekly and monthly after month 3 and month 6, respectively. At each examination, serum creatinine and cystatin C levels and blood levels of immuno­suppressive drugs were measured and urinalysis was performed. Estimated glomerular filtration rate (eGFR), which was determined using the Schwartz equation derived from serum creatinine and cystatin C (eGFR [mL/min] = 10.2 × [body cell mass/cystatin C]E 0.40 × [height × body surface area/creatinine] E 0.65), was calculated at posttransplant months 6, 12, and 24.⁵

The presence of leukocyte esterases, nitrites, and leukocytes in the urine was analyzed using the Iris iQ 200 urine analyzer (Beckman Coulter, High Wycombe, UK). Pyuria was accepted as the presence of > 5 leukocytes/high-power field in the urine; urinary cultures were obtained from patients with pyuria under suitable conditions. Blood agar and MacConkey agar were used as urine culture media; the presence of more than 100 000 colony-forming units/mL on midflow urine samples was accepted as positive.

Posttransplant UTI was defined as pyuria and positive urinary cultures. However, recipients with neurogenic bladder and clear intermittent cathe­terization were also found to have fever, elevated C-reactive protein levels, or acute graft dysfunction for UTI diagnosis. Recurrent posttransplant UTI was defined as ≥ 2 UTIs in 6 months or ≥ 3 UTIs in 12 months.6 Other causes, including cold ischemia time, de novo donor-specific antibody positivity, acute rejection episodes, and opportunistic viral infections affecting graft survival other than posttransplant UTI, were not evaluated.

Ultrasonographic examination of the urinary system was performed once every 6 months in patients with LUTD and annually in non-LUTD patients. Voiding cystourethrogram was performed to investigate the presence of reflux in transplanted kidneys of patients who had hydronephrosis/hydro­ureteronephrosis or who had UTI during follow-up.

Immunosuppressive protocol
As induction treatment, methylprednisolone was commenced on the day of transplant at 500 mg/m², which was decreased to 80 mg/m2 on day 2 posttransplant and then gradually decreased until the maintenance dose of 5 mg/m²/day in month 3. In addition, induction treatment with antithymocyte globulin or basiliximab was administered in deceased-donor transplant recipients or in recipients with high immunologic risk. A calcineurin inhibitor (cyclosporine or tacrolimus), an antiproliferative agent (mycophenolate mofetil, mycophenolic acid, or azathioprine), and prednisone were used as maintenance immunosuppressive treatment. Targeted plasma tacrolimus levels were 10 to 12 ng/mL for the first 3 months, 8 to 10 ng/mL for the second 3 months, and 4 to 8 ng/mL after 6 months, whereas targeted cyclosporine trough blood plasma levels were 300 to 350 ng/mL, 250 to 300 ng/mL, and 150 to 250 ng/mL, respectively. All patients received cotrimoxazole prophylaxis for 9 months posttransplant. For reci­pients with UTI, cotrimoxazole prophylaxis was changed to prophylaxis with other antibiotics. Prophylaxis was maintained for as long as the VUR persisted. Immunosuppressive treatment doses were decreased during pyelonephritis treatment consi­dering the immunologic risks to patients.

Statistical analyses
Descriptive statistics are presented as frequency, percentage, mean, standard deviation, median, and minimum and maximum values. The Fisher exact test or Pearson chi-square test was used to analyze relationships between categorical variables. In the normality test, Shapiro-Wilks test was used for sample sizes smaller than 50, whereas the Kolmogorov-Smirnov test was used for sample sizes larger than 50. The Mann-Whitney U test was used when normal distribution was predicted, and the t test was used in contrary cases. For nonparametric comparisons of the 3 disease groups, the Kruskal-Wallis test was used, with Mann-Whitney U test used as a post hoc test in significant cases. Bonferroni correction was made for P values. Analysis of variance was used for comparisons of 3 groups when normal distribution was shown, and Tukey test was used for paired comparisons. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21, IBM Corporation, Armonk, NY, USA). P < .05 was accepted as statistically significant.

Results

Our study included 133 kidney transplant recipients, of which 83 were males (62.4%) and mean age was 9.75 ± 8.83 years. Mean age at time of transplant was 7.25 ± 6.71 years, and the mean follow-up was 3.69 ± 2.78 years. Of total patients, 58 (43.6%) had LUTD (PUV in 25, VUR nephropathy in 24, and neurogenic bladder in 9 patients) as the primary renal pathology (Table 1).

Mean age at time of transplant was higher in the LUTD group than in the non-LUTD group (12.29 ± 4.01 y vs 10.68 ± 4.81 y; P = .04) (Table 2). Patients with PUV had undergone transplant at a younger age versus patients with VUR nephropathy and neurogenic bladder (P = .003), with these pa­tients having similar ages at time of transplant. We observed no differences between LUTD and non-LUTD groups with regard to posttransplant follow-up (P = .83); however, patients with PUV had a longer follow-up than patients with VUR nephropathy and neurogenic bladder (P = .03). Patients with neurogenic bladder had the highest rate of transplants from a deceased donor and the longest dialysis period among all groups (Table 2).

Four patients (44.4%) with neurogenic bladder had undergone bladder augmentation before trans­plant. Clean intermittent catheterization (CIC) was performed on 6 patients with PUV (24%) who had low bladder capacity and postvoid residue and 7 patients with neurogenic bladder (77%). Five patients with PUV (20%), 3 patients with VUR nephropathy (12.5%), and 1 patient with neurogenic bladder (11.2%) who had reflux in his native kidney underwent bilateral native nephrectomy during transplant. Unilateral nephrectomy was performed on 1 patient with PUV and VUR nephropathy, and bilateral ureteral ligation was performed on 1 patient with VUR nephropathy (Table 3).

Posttransplant UTI was reported in 15.7% of our recipients. Posttransplant UTI rates in the LUTD group were higher than rates in the non-LUTD group both at month 6 (24.6% vs 10.8%; P = .037) and between posttransplant months 6 and 12 (24.6% vs 8.2%; P = .01) (Table 4). Patients with neurogenic bladder had the highest UTI rate among other recipients at the first and second 6-month periods posttransplant (77.8% vs 66.7%). Among patients with neurogenic bladder, the incidence of UTIs was similar between patients who underwent augmen­tation and those who did not (75.0% vs 80.0%). Moreover, VUR nephropathy was more common among patients with UTIs than among those with PUV at the first 6-month posttransplant period (20.8% vs 8.3%; P = . 034). We found UTI rates to be similar among patients with PUV, VUR nephropathy, and non-LUTD during the second 6-month posttransplant period (16%, 16.7%, and 8.2%, respectively; P = .125).

There was no relationship between duration of dialysis and UTI rate (P = .48). Associations between CIC application and UTI rate could not be evaluated due to the limited number of patients.

During posttransplant year 1, 14.2% of patients had recurrent UTI. Seventeen patients (29.3%) in the LUTD group and 2 patients (2.6%) in the non-LUTD group had recurrent UTI (P < .001). Recurrent UTI was observed in 8 recipients with PUV (32.0%), 6 recipients with VUR nephropathy (25.0%), and 3 recipients with neurogenic bladder (33.3%) (P = .452). Recipients with recurrent UTIs were examined for presence of reflux in their transplanted kidneys. Posttransplant reflux was detected in 14 patients (25.9%) with LUTD, including 6 patients with PUV (24%), 5 patients with VUR nephropathy (20.8%), and 3 patients with neurogenic bladder (33.3%). Reflux was more often observed in LUTD than in non-LUTD patients (25.9% vs 10.6%; P = .036).

Estimated glomerular filtration rates were similar between LUTD and non-LUTD groups in the first 6 months and first year posttransplant; however, eGFR was significantly higher at posttransplant years 2 and 5 in the non-LUTD group (Table 5). In patients with neurogenic bladder, eGFR was found to be lower than shown in patients with PUV and VUR nephropathy at month 6 and years 1, 2, and 5 posttransplant (P < .001). The 5-year graft survival rate of patients with non-LUTD and VUR nephropathy was similar (51.3% vs 51.6%; P = .891). Graft function in patients with PUV and VUR nephropathy was similar in the first 6 months (70.8% vs 78.2%; P = .148) but poorer in the PUV group at years 1, 2, and 5 posttransplant (63.8%, 57.8%, and 44.7% vs 82.8%, 77.1%, and 51.6%; P = .047, .012, and .026, respectively).

During the 5-year period posttransplant, no significant differences were detected between eGFR values of patients with and without reflux in their transplanted kidneys (49.3% vs 53.6%; P = .125). Graft loss was observed in 1 patient with VUR nephropathy and in 2 patients with neurogenic bladder, whereas no patients with PUV had graft loss. The first patient with neurogenic bladder had graft loss due to BK nephropathy and acute humoral rejection. The second patient with graft loss had a deceased-donor kidney transplant and had frequent febrile UTIs early posttransplant despite CIC administration (8 times/day) and prophylaxis with 2 antibiotics. The patient with VUR nephropathy had graft loss because of acute humoral rejection.

Discussion

Our study found that patients with LUTD had graft function similar to those not at early stage after renal transplant but had deteriorated over time. Among our patient groups, patients with neurogenic bladder had the worst prognosis. In a study by Mendizábal and associates,7 1-year graft survival posttransplant in 15 patients with severe bladder dysfunction was 77%, which dropped to 62% at 5 years. Graft loss developed in 3 of 15 patients.7 In another study of 59 transplant recipients with PUV, 8-year graft survival was 59%, which was found to be similar to that of other patient groups.8 In patients with urinary tract dysfunction with prior intervention, urinary system dysfunction without intervention, and polycystic kidneys disease, graft survival was similar between these 3 groups.9 Yazici and associates found that the 5-year graft survival of 52 renal transplant recipients with reflux nephropathy was similar to that of patients who had undergone renal transplant due to other reasons.10 The above studies support our finding that graft function in patients with PUV and VUR nephropathy is similar to that of non-LUTD transplant recipients.

There have been a few studies about the effects of LUTD on graft survival. In 21 adult renal transplant patients with spinal cord injury, patients had fewer UTIs compared with that shown pretransplant (85.7% vs 42.9%), although graft loss developed in 2 transplant recipients within the first 18 months.11 However, we could not determine whether these patients had catheterization. In the medical literature, it is known that the most important factor in the development of UTIs is increasing bladder pressure. Nahas and associates4 reported that graft function at year 5 was similar among patients with urologic abnormalities with sufficient bladder capacity, patients with insufficient bladder capacity who have bladder drainage, and recipients with no urologic problems (74%, 84%, and 75%). Although the importance of having detailed urologic evaluations pretransplant is emphasized in this study, regular and permanent catheterization for reducing the intravesical pressure was determined as an important factor for graft outcome.⁴

In our transplant recipients, the overall UTI rate was 15.7%. The UTI rates of recipients in the LUTD group were higher than in the non-LUTD group, with the highest UTI rate observed in patients with neurogenic bladders. Similarly, the recurrent UTI rates were also higher in the LUTD group. However, recurrent UTI rates were similar among patients with PUV, VUR nephropathy, and neurogenic bladder. According to Melek and associates, posttransplant UTI frequency in patients with VUR nephropathy and in patients with abnormal lower urinary tracts were higher than in patients with normal urinary tracts, although this difference was not statistically significant.¹² Fallahzadeh and associates reported that childhood UTI rate posttransplant was 17.3% and that the primary disease was not a determinant of posttransplant UTI.¹³ In a study of 40 children, posttransplant UTI rate and recurrent UTI rate were 36% and 28%, respectively.14 In a study from Bilginer and associates, 3 of 11 recipients with LUTD (neurogenic bladder in 5 patients and PUV in 6 patients) developed recurrent UTIs after transplant.¹⁵ In a multicenter study that analyzed UTIs, the incidence of UTI was 21.4% before transplant and 38.1% after transplant (P = .002). This study also found that posttransplant UTIs occurred earlier in female patients than in male patients.¹⁶ In our study, the rate of posttransplant UTI was lower than shown in other studies, with primary renal disease found to be the determining factor in UTI development posttransplant.

Patients who developed UTIs were examined for reflux in their transplanted kidneys, which revealed no significant relationship between reflux and graft function. Similarly, a study from Lee and colleagues demonstrated that reflux in graft kidney was a risk factor for UTIs but it did not affect graft function.¹⁷

We found no difference between the LUTD and non-LUTD groups in terms of the duration of dialysis; however, among patients with LUTD, the duration of dialysis pretransplant was higher in those with neurogenic bladder than in patients with PUV and VUR nephropathy. Concerns about living-donor transplant in patients with neurogenic bladder led to prolonged dialysis. For the same reason, the number of deceased-donor transplant procedures was higher among patients with neurogenic bladder versus the other groups. Long wait times for transplant while on dialysis decreases bladder capacity by prolonging the oligo/anuric phase. In a study that investigated the relationship between duration of dialysis and bladder capacity in adult recipients without LUTD, the bladder capacity of patients with a dialysis period longer than 60 months was less than 130 mL; the risk of reflux in the transplanted kidneys was higher in recipients with a dialysis duration of longer than 60 months.¹⁸ However, our study revealed no relationship between duration of dialysis and frequency of UTIs posttransplant.

The relatively faster decreases in doses of immunosuppressive agents due to emerging infec­tions in patients with neurogenic bladder and recurrent UTIs could increase the risk of rejection. Furthermore, it is not known whether residual urine enables the persistence of BK virus infections. Further studies are needed to find conclusive answers. In one among many studies to answer the question of whether LUTD is a factor in determining graft survival, rate of UTIs was increased in 25 of 60 pediatric renal transplant recipients with LUTD; however, primary disease was not found to be a determinant of graft function.¹⁹

Limitations of our study include its retrospective design and the small number of patients in the neurogenic bladder group. Therefore, the evaluation of some variables affecting survival rates in the neurogenic bladder group was not possible. The intermittent catheterization compliance in patients with neurogenic bladder was not determined. The incidence of UTIs after the first year posttransplant was not known due to insufficient medical records. Other causes affecting graft function, including cold ischemia time, acute humoral rejection, and BK virus nephropathy, were not considered in our study.

In conclusion, graft survival rates of patients with PUV and VUR nephropathy were similar to patients without LUTD, whereas patients with neurogenic bladder had worse graft survival and UTI rates. We recommend that pretransplant urologic examinations of patients with LUTD should be performed in detail and that these patients should be followed closely after transplant for the development of UTIs.

References:

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