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Volume: 19 Issue: 4 April 2021

FULL TEXT

ARTICLE
Renal Transplant in Pediatric Patients With Congenital Abnormalities of the Lower Urinary Tract

Objectives: Congenital abnormalities of the lower urinary tract can result in end-stage renal disease and are responsible for a significant number of renal transplants. Management of these patients is not always consensual, and more evidence is required about the frequency of associated complications. Our aim was to report the experience of a Pediatric Renal Transplant Unit with renal transplant in pediatric patients with congenital abnormalities of the lower urinary tract.

Materials and Methods: Data on renal transplants performed in pediatric patients with congenital abnormalities of the lower urinary tract between January 1, 2009, and December 31, 2019, in this center were retrospectively reviewed.

Results: Fifty-three pediatric renal transplants were performed in the institution during the considered time period. Of these, 26 transplants were performed in 24 patients with congenital abnormalities of the lower urinary tract, and 14 were male. The median age at the time of renal transplant was 10.5 years (interquartile range, 5.25-15 years), and the most frequent diagnoses were neurogenic bladder (n = 7; 29%) and posterior urethral valve (n = 7; 29%). Three patients (13%) underwent preemptive renal transplant, 15 were on peritoneal dialysis (63%), and 6 were on hemodialysis (25%). A total of 81 pyelonephritides were diagnosed in the 24 patients, mostly attributed to Escherichia coli, followed by Klebsiella pneumonia. The median follow-up was 92.5 months (interquartile range, 52.3-114 months). For patients with congenital abnormalities of the lower urinary tract, graft survival was 92.3% at 1, 5, and 10 years, with no deaths reported.

Conclusions: Renal transplant is the treatment of choice for pediatric patients with end-stage renal disease. The procedure does not seem to be associated with worse patient outcomes. Additionally, despite the significant number of pyelonephritides cases, it does not seem to result in decreased graft or patient survival.


Key words : End-stage renal disease, Neurogenic bladder, Urinary tract infection

Introduction

Congenital abnormalities of the lower urinary tract (CALUT) comprise a vast spectrum of malforma­tions, including in the ureter, bladder, and urethra. Patients with CALUT frequently present with primary vesicoureteral reflux, neurogenic bladder, and posterior urethral valves, among other types of bladder obstruction, which can be associated with kidney malformation and other abnormalities outside the urinary tract.1

Congenital abnormalities of the lower urinary tract can lead to end-stage renal disease and accounts for a significant number of renal transplants (RTs). According to the last Annual Transplant Report of the North American Pediatric Renal Trials and Collaborative Studies (ATR-NAPRTCS), obstructive uropathy and reflux nephropathy are responsible for 15.3% and 5.1% of RTs in end-stage renal disease, respectively.2

Patients with CALUT may require surgical intervention before or during RT. After surgery, voiding mechanisms may remain undamaged, but in some cases intermittent self-urinary catheterization or even urinary diversion may be necessary.3 Since Kelly and colleagues reported the first successful kidney transplant on an ileal urinary diversion in 1966, advances have been made in primary bladder rehabilitation, surgical bladder repair, and transplant in these patients.4 Nevertheless, questions persist with regard to indications for surgical procedure and frequency of complications, especially urinary tract infections (UTIs).

Patients with renal tract malformations submitted to RT have specific problems, which have only been addressed in a limited number of long-term follow-up studies.3,5 The aim of this study was to report the experiences of a pediatric renal transplant unit with RT in pediatric CALUT patients.

Materials and Methods

A descriptive, retrospective study was conducted based on the medical records of pediatric patients submitted to RT between January 1, 2009, and December 31, 2019, at the Pediatric Renal Transplant Unit of Centro Hospitalar Universitário do Porto.

A total of 53 pediatric RTs were performed during the considered time period at this center. Patients with CALUT diagnosis submitted to RT were included, and non-CALUT patients (N = 26), that is, those with only upper urinary tract malformations (renal dysplasia, renal atrophy), glomerular and cystic diseases, and cystinosis, were excluded.

Demographic, clinical, and laboratory data were collected. Graft survival was defined as functioning kidney without the need for dialysis or graft removal during follow-up. Patient and graft survival were calculated with the Kaplan-Meier method, and the log-rank test was used to compare groups. Descriptive statistical analysis was performed with SPSS software (version 23).

The study was approved by our institution and was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from each patient’s legal guardians before RT.

Results

A total of 26 RT (49%) were performed in 24 CALUT patients, 14 of whom were male (58%). The median age at transplant was 10.5 years (interquartile range [IQR], 5.25-15 years).

The most frequent CALUT diagnoses were neurogenic bladder (n = 7; 29%) and posterior urethral valves (n = 7; 29%), followed by vesicoureteral reflux (n = 5; 21%) (Table 1). Twelve patients presented other malformations (50%), including myelomenin­gocele in the 7 patients with neurogenic bladder (29%; 4 with hydrocephalus) (Table 2).

Anatomical and functional evaluations of the urinary tract, including ultrasonography, cystography, or urodynamic test, were performed for all patients before transplant. Eighteen patients were submitted to surgical intervention (75%), some to more than 1 surgery, as follows: primary valve ablation (n = 7), unilateral nephrectomy of the native kidneys (to mitigate major reflux and recurrent UTI, n = 8), enterocystoplasty (patients with neurogenic bladder and Hinman syndrome, n = 4), surgical repair of vesicoureteral reflux (n = 3), and vesicostomy (n = 3). There were 10 patients on intermittent catheterization to allow voiding (patients with neurogenic bladder, Hinman syndrome, posterior urethral valves [n = 1], and major genitourinary malformation).

Three patients required preemptive RT (13%), and the remaining patients were on peritoneal dialysis (n = 15; 63%) and hemodialysis (n = 6; 25%). The median time on dialysis was 23 months (IQR, 5-38 months).

Twenty-two patients were submitted to RT only once (92%). Two patients required a second transplant (8%; living donor) after deceased donor graft failure in the first hours following first RT. These patients were submitted to a desensitization protocol before the second RT. Overall, 3 grafts were from living donors (12%; of which 2 were parents [8%] and 1 was a sibling [4%]), and the remaining grafts were from unrelated deceased donors (n = 23; 88%).

Renal transplant procedures were performed by experienced surgeons using a standardized technique. All patients had a double J catheter and a bladder catheter during surgery. Only 1 patient was submitted to unilateral nephrectomy during RT. The 2 patients with prune belly syndrome required graft nephrostomy. No urological surgical complications or wound infections were reported. The double J catheter was removed after 1 month.

The immunosuppressive protocol used in our center is based on immunological risk stratification.6 Patients in this study underwent an immunosup­pressive scheme consisting of a combination of antithymocyte globulin (n = 20; 83%) or basiliximab (n = 4; 17%) plus methylprednisolone, tacrolimus, and mycophenolic acid. Maintenance immunosup­pression consisted of prednisolone, tacrolimus, and mycophenolic acid for all patients.

All patients received antibiotic prophylaxis with cefoxitin during RT and when wound drainage was needed. Candidiasis prophylaxis with nystatin was administered during the first month and Pneumocystis jirovecii prophylaxis with cotrimoxazole was administered during the first 6 months post-RT. Urinary tract infection prophylaxis was generally not implemented.

All patients received valganciclovir during the first 6 months following RT, unless both donor and recipient tested negative for cytomegalovirus (CMV) IgG. If the recipient tested negative for CMV IgG and the donor tested positive, then the patients also received anti-CMV immunoglobulin. Donor/recipient CMV status was as follows: 11 D+/R+, 9 D-/R+, 1 D+/R-, and 3 D-/R-. There were 10 patients who developed post-RT CMV infection (42%), but none experienced invasive CMV disease.

Graft donors had a median age of 14 years (IQR, 6-27 years) and a median pre-RT creatinine of 0.8 mg/dL (IQR, 0.6-1.1 mg/dL).

The median RT length of hospital stay was 14.8 days (IQR, 10.3-17 days). During hospitalization, 5 patients developed UTI (21%), and 3 developed acute tubular necrosis (13%). Urine cultures were performed after transplant, initially once a week and then monthly or every 3 months, depending on age. Urinary tract infection was diagnosed in the presence of a positive urine culture associated with symptoms and/or analytical abnormalities. During post-RT follow-up, 19 patients developed at least 1 UTI (79%). In the first month, 16 patients (67%; all neurogenic bladder patients, 4 posterior urethral valves patients, 1 vesicoureteral reflux patient, and the patients with prune belly syndrome, Hinman syndrome, and major genitourinary malformation) experienced 1 or more UTIs (3 patients had more than 1 episode), in a total of 20 episodes (11 acute cystitis and 9 pyelonephritides). A total of 76 UTIs (49 acute cystitis and 27 pyelonephritides) were reported from the second to the sixth month post-RT, after which 244 episodes (199 acute cystitis and 45 pyelonephritides) were reported until the end of the follow-up period. A total of 81 pyelonephritides episodes were diagnosed in the 24 CALUT patients, accounting for 0.49 episodes per patient-year. Several identified agents were multidrug-resistant organisms and required parenteral antibiotic therapy. The most common agent was Escherichia coli (n = 156), followed by Klebsiella pneumonia (n = 62), Enterococcus faecalis (n = 31), and Candida spp (n = 22). Two patients with neurogenic bladder developed septic shock due to pyelonephritides complications (8%), and 1 case required intensive care support (4%). For this reason, these patients were submitted to nephrostomy. One patient developed renal lithiasis (4%) and was submitted to surgical calculus extraction.

Presently, some patients (neurogenic bladder [n = 7], prune belly syndrome [n = 2], posterior urethral valves [n = 2], Hinman syndrome [n = 1], and major genitourinary malformation [n = 1]) have voiding disorder. Three require vesicostomy (13%), 2 ureterostomy (8%), and 8 bladder catheterization (33%; 2 of whom have a permanent bladder catheter and 6 require clean intermittent catheterization).

Most patients are currently on clinical and laboratory follow-up, but 1 is no longer followed at our center. At the present time, median follow-up is 92.5 months (IQR, 52.3-114 months) and median creatinine is 1.06 mg/dL (IQR, 0.90-1.36 mg/dL). Renal Doppler ultrasonography assessment was performed periodically and during acute illness. No radionuclide studies were routinely implemented for the patients.

In this cohort, 2 grafts were lost in the first 72 hours because of acute thrombosis of the great vessels (8%). Graft survival for patients with CALUT was 92.3% at 1, 5, and 10 years (Figure 1). During the same time period, non-CALUT graft survival was 100% at 1 year and 95% at 5 and 10 years, and overall graft survival of all pediatric patients submitted to RT at this center was 96.2% at 1 year and 93.8% at 5 and 10 years. No significant difference was found between CALUT and non-CALUT graft survival (log-rank test; chi-square = 0.382, P > .05). No deaths were reported during the considered period.

Discussion

Patients with CALUT may develop obstructive and reflux nephropathy, and consequently proteinuria, degeneration of remnant nephrons, glomerulos­clerosis, and tubular atrophy following end-stage renal disease.1 During the considered time period, 49% (n = 26) of the total pediatric RTs performed at this center were due to CALUT, which represents a significant number of patients. This can be explained by the fact that, despite an effective prenatal diagnosis in recent years, in the presence of a fetal anomaly, for cultural and religious reasons, our population does not always terminate pregnancy. Furthermore, this hospital is a medical and surgical reference center for these conditions.

Congenital abnormalities of the kidney and urinary tract (CAKUT) and CALUT have been associated with several gene mutations linked to syndromic and nonsyndromic phenotypes. The incidence of other concomitant malformations in these patients was 50%, with myelomeningocele as the most frequent, followed by cardiac abnormalities. Myelomeningocele is associated with neurogenic bladder and was one of the main causes of end-stage renal disease in this study and accounts for 13% of all RTs performed. Although myelomeningocele incidence is globally decreasing, attributable to folic acid supplementation during pregnancy and prenatal diagnosis, the high incidence reported in this study is probably a result of this center’s expertise, and it should be noted that a substantial survival increase has been achieved for these patients in recent years.7

Bladder dysfunction in myelomeningocele patients often leads to progressive deterioration of the upper urinary tract as a result of high pressure due to poor emptying, leading to vesicoureteral reflux, hydronephrosis, and subsequent kidney damage. These patients have an increased risk for recurrent UTIs, and the presence of ventriculo­peritoneal shunts creates challenges for peritoneal dialysis because of the increased risk of shunt infections.8,9

Cases of obstructive uropathy characterized by posterior urethral valve were also responsible for a significant proportion of RTs in this study (13%, similar to that described in ATR-NAPRTCS).2

Most patients underwent corrective surgery before transplant, with all posterior urethral valve cases submitted to surgery, which is a mandatory procedure in these situations.10 Four patients were submitted to enterocystoplasty before RT. In patients with neurogenic bladder, bladder augmentation is indicated whenever bladder capacity and compliance are reduced or in the event of detrusor overactivity, when all conservative and minimally invasive treatments have failed.11

The optimal CALUT treatment is controversial. Graft survival does not seem to be negatively affected when kidney transplant is drained into a reconstructed bladder.7,11-13 Although it seems beneficial, not all patients in this cohort underwent enterocystoplasty or corrective surgery before RT. Intermittent or permanent bladder catheterization was retained to allow voiding and help prevent high-pressure reflux into the graft or residual urine after voiding.

Urinary tract infection is the most common infection after RT, and CALUT patients are at increased risk of these infections.12,14,15 Urinary tract infections represented a very relevant complication in this study. These are associated with serious morbidity and are potentially life-threatening, accounting for 2 cases of septic shock. Although some authors argue that UTIs, particularly pyelonephritis, can acutely compromise graft success and are an important risk factor for graft disfunction, others found no correlation between pyelonephritis and graft or patient survival, as in the present work.14,16-18

Our study reported a large UTI prevalence, with a pyelonephritis incidence of 0.49 episodes per patient-year, greater than the 0.044 to 0.31 episodes per patient-year reported in the general RT population.3,19 The significant number of UTIs reported here may be a consequence of colonization, anatomic abnormalities intrinsic to CALUT patients, presence of catheters, or perhaps immunosup­pression.17,19-21 As a result of multiple broad-spectrum antibiotic therapies and hospitalizations, some patients had multiresistant UTIs that required long periods of antibiotic therapy and prolonged hospitalization. Moreover, because adequate bladder capacity and urinary drainage are key factors to decrease UTI risk, nephrostomy or vesicostomy were sometimes required in these patients.5 Because UTI prophylaxis was generally not prescribed, the benefit of this measure could not be assessed in this study.

Cytomegalovirus infection is associated with higher rates of morbidity and mortality and lower rates of graft survival.22 Despite the unfavorable CMV donor/recipient status in this study (only D-/R- in 3 cases) and the frequent use of antithymocyte globulin (80%) in induction immuno­sup­pressive therapy, no invasive CMV disease was reported, which demonstrated the effectiveness of the antiviral chemoprophylaxis.

Clinical, laboratory, and ultrasonography monitoring are fundamental aspects during follow-up. For a thorough assessment, renal scintigraphy with the radioisotope technetium-99m (99mTc-diethylenetriaminepentaacetic acid or 99mTc-mercaptoacetyltriglycine) can be used to assess the structure, blood flow, and graft function.23,24

The overall graft survival in this study was 92.3%, which is encouraging compared with other studies that have reported a graft survival rate between 87.6% and 100% at 5 years and between 62.5% and 98% at 10 years.3,12,13,25 This graft survival rate is very similar to the non-CALUT global RT results in this center, with no significant difference between both. These data indicate that pediatric CALUT patients had graft outcomes similar to other pediatric RT recipients, as presented in some other recent studies.15,18,21,25 Overall patient survival was also favorable, with no reported deaths.

Conclusions

Renal transplant is the treatment of choice for pediatric patients with end-stage renal disease. Although RT in CALUT patients may be challenging, this study demonstrates that it does not seem to be associated with worse than expected outcomes. Despite the significant number of pyelonephritides reported, incidence was similar to other series and does not seem to be associated with a reduction in graft or patient survival. A longer follow-up is required for better outcome assessment in these patients.


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Volume : 19
Issue : 4
Pages : 310 - 315
DOI : 10.6002/ect.2020.0325


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From the Unit of Pediatric Nephrology of the Pediatric Department – Centro Materno-Infantil do Norte – Centro Hospitalar Universitário do Porto, Portugal
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Rafael Figueiredo, CMIN-Centro Materno-Infantil Norte. Rua da Maternidade, 4050-371 Porto, Portugal
Phone: +351 936 246 204
E-mail: rafaelcostafigueiredo@gmail.com