EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Chronic kidney disease caused by lower urinary tract abnormalities is a significant complication in pediatric care. Although there are conflicting reports about clinical outcomes in the past, favorable outcomes have been reported in recent years. Despite this, many centers still refrain from performing renal transplant in these patients. Here, we compared clinical outcomes of renal transplant recipients with and without lower urinary tract abnormalities.

Materials and Methods: Our study included 71 renal transplant recipients who were divided into 3 groups: 17 patients with abnormal lower urinary tracts having vesicoureteral reflux (group 1), 7 patients with abnormal lower urinary tracts having bladder dysfunction (group 2), and 47 patients with anatomically and functionally normal lower urinary tracts (group 3). We retrospectively compared demographic features, clinical course, graft survival, pre- and posttransplant incidence of urinary tract infections, and final graft function among the groups.

Results: There were no statistically significant differences among groups regarding median age at time of transplant, graft survival, median creatinine level, and median glomerular filtration rate (P > .05). Significant differences were shown in incidence of urinary tract infections between patients in groups 1 and 2 (abnormal lower urinary tracts) and group 3 (normal lower urinary tracts) before transplant (P < .05). Although frequency of urinary tract infections in groups 1 and 2 were moderately higher than shown in group 3 after transplant, this difference was not statistically significant.

Conclusions: Although the children with abnormal lower urinary tracts had slightly higher incidence of urinary tract infections, there were no differences between patients with abnormal and normal lower urinary tracts regarding allograft survival and function. In addition, proper follow-up of patients before and after transplant, based on our experience, should include educating patients and their parents about potential complications after transplant for the best outcome of renal transplant.

Key words : Abnormal lower urinary tract, Patient outcome, Renal transplantation, Urinary tract infection

Lower urinary tract (LUT) abnormalities, including bladder exstrophy, neuropathic bladder, posterior urethral valves, prune belly syndrome, and vesicoureteral reflux, are common causes of adolescent chronic kidney disease.^1-4 Renal transplant in these children is a crucial therapeutic strategy. A high number of complications have been reported in patients with abnormal LUT after renal transplant.^5-7 These complications contribute to reduced graft function and survival.^8-10 Therefore, these patients have been considered as “high risk” for renal transplant in previous years.^11,12 Currently, as a result of advances in surgical procedures and immunosuppressive treatment, better results have been reported in the literature.^13,14 For the best outcome of renal transplant in children with abnormal LUT, careful urologic evaluation must be done before transplant to have a suitable low-pressure reservoir with adequate capacity and compliance so that allograft injury can be avoided.^15-19 Based on this, we compared the clinical outcomes of renal transplant recipients with and without LUT complications during long-term follow-up after renal transplant.

Materials and Methods

Our study included 71 renal transplant recipients, with 35 boys (49.3%) and 36 girls (50.7%). The patients were divided into groups according to cause of chronic kidney disease: group 1 included 17 patients (23.9%; 4 boys and 13 girls) with abnormal LUT and vesicoureteral reflux, group 2 included 7 patients (9.9%; 4 boys and 3 girls) with abnormal LUT and bladder dysfunction, and group 3 included 47 patients (66.2%; 26 boys and 21 girls) with normal LUT. In group 1, cause of abnormal LUT was vesicoureteral reflux (17 patients). In group 2, causes of abnormal LUT were posterior urethral valves (3 patients) and neurogenic bladder (4 patients).

We retrospectively compared the demographic features, clinical course, graft survival, final graft function, and incidence of urinary tract infection (UTI) before and after transplant among the groups. Urinary tract infection was diagnosed when more than 10 white blood cells per high-power field view were visible, indicating a positive urine culture in a symptomatic patient. Urine cultures were evaluated according to the guidelines in the literature.20 Glomerular filtration rate was calculated with the Schwartz formula. Clinical follow-up before and after transplant was performed by the same physicians for all patients. One patient had bladder augmentation before transplant. Clean intermittent catheterization was prescribed for 7 patients so that a low-pressure reservoir with adequate capacity was available. All patients were treated with prednisone, mycophenolate mofetil, and calcineurin inhibitor-based immunosuppressive therapy. Renal transplant recipients with acute rejection episode were excluded from the study.

At transplant, patients in group 1 had a median age of 14.0 years (range, 4.5-21.0 y), patients in group 2 had a median age of 14.0 years (range, 5.0-20.0 y), and patients in group 3 had a median age of 13.5 years (range, 3.5-20 y) (P > .05). Median follow-up of patients in groups 1, 2, and 3 were 30 months (range, 5.0-84.0 mo), 24 months (range, 7.0-58.0 mo), and 22 months (range, 2-124 mo) (P > .05). Patients in group 1 had a median serum creatinine level of 0.93 mg/dL (range, 0.73-6.70 mg/dL), patients in group 2 had a median serum creatinine level of 1.20 mg/dL (range, 0.73-5.0 mg/dL), and patients in group 3 had a median serum creatinine level of 0.86 mg/dL (range, 0.43-5.8 mg/dL) (P > .05). In group 1, median glomerular filtration rate of patients was 67.2 mL/min/1.73 m2 (range, 9.2-89.6 mL/min/1.73 m2), with 62.6 mL/min/1.73 m2 (range, 15.0-77.0 mL/min/1.73 m2) for group 2 and 84.3 mL/min/1.73 m2 (range, 9.9-126.9 mL/min/1.73 m2) for group 3 (P > .05).

There were no significant differences in immunosuppressive treatment, graft survival, and donor type (living or deceased) among the groups (Table 1). Patient survival was 100% in all groups. In group 1, incidence of UTI was 13 of 17 patients (76.5%), with 4 of 7 patients (57.1%) in group 2 and 10 of 47 patients (21.3%) in group 3 before transplant. Although there were no differences in incidence of UTI before transplant between groups 1 and 2, there was a statistically significant difference between these 2 groups and group 3 (P < .05). Frequency of UTI in group 1 (9/17 patients; 52.0%) and group 2 (3/7 patients; 42.8%) was moderately higher than that of group 3 (13/47 patients; 27.6%) after transplant; however, the difference was not statistically significant (Table 1).

There were no statistically significant differences in allograft survival among the groups (P > .05), and there were no graft losses due to urologic problems. Allograft loss occurred in 3 patients (3/17; 17.6%) in group 1, with 1 patient (1/7; 14.2%) in group 2 and 6 patients (6/47; 12.8%) in group 3 having allograft loss. Regarding cause of graft loss in group 1, 2 grafts (2/3; 66.7%) were lost due to infection (1 disseminated Aspergillus infection and 1 Cytomegalovirus infection) and 1 graft was lost due to nonadherence of patient to the given treatment. In group 2, the graft loss of 1 patient was also due to nonadherence of patient to the given treatment. Reasons for graft loss in group 3 were recurrence of the original disease (4/6; 66.6%), BK virus infection (1/6; 16.7%), and nonadherence to treatment (1/6; 16.7%).

The most common reason for chronic kidney disease in pediatric patients is abnormal LUT, with studies reporting approximately 25% of pediatric renal transplant recipients having LUT abnormalities.^2,12,21,22 In addition, there is a risk of developing renal dysfunction of native kidneys resulting from chronically high intravesical pressures due to bladder dysfunction. The high intravesical pressure can also lead to progressive allograft dysfunction in patients with abnormal LUT similar to patient’s native kidneys.^23,24 Renal transplant in patients with abnormal LUT have thus been avoided because of poor outcomes.^{14,16,18,25-30} However, some researchers have reported favorable outcomes of renal transplant in patients with abnormal LUT if proper pre- and postoperative assessments and treatment of patients occur.^16,23,31-33 However, despite all of these good results, many centers still refrain from performing kidney transplants in these patients.^8,12

It has been reported that patients with abnormal LUT are younger and smaller than patients with normal LUT. This observation was due to many abnormal LUTs being congenital, facilitating recognition of these patients and referral of them to transplant centers at an earlier age of life than patients with normal LUT. This observation is in combination with patients with abnormal LUT being on organ wait lists for a long time.¹² The median age of patients with abnormal (groups 1 and 2) and normal (group 3) LUTs were equal in our study.

To protect allograft function and have a satisfactory kidney transplant outcome, the first important point is that all patients with abnormal LUT should be prepared appropriately before transplant and should be followed regularly after transplant.^4,12,34 To fulfill this point, the first step is to correct structural urologic abnormalities and optimize the emptying and storage functions of the bladder, thus allowing for a sterile, compliant, and low-pressure (intravesical pressure below 30 cm H₂O) reservoir.^{1,8,9,14-16,18,35} In addition, patients with UTI complaints and signs and symptoms related to bladder dysfunction should be evaluated with voiding cystourethrogram, urodynamic study, or video urodynamic study before transplant. If the lower urinary tract does not meet the parameters of adequate function, medical therapy and clean intermittent catheterization can be started.^23,36-39 In addition, bladder augmentation may be required for transplant in some of these patients.^14,15

Saad and associates compared the results of renal transplant recipients with abnormal (29 patients) and normal LUT (74 patients). They found no differences in creatinine levels and estimated glomerular filtration rates between the patient groups.⁴⁰ In their study, the graft survival rate was 93.1% in patients with abnormal LUT and 91.1% in patients with normal LUT.⁴⁰ In another study, pediatric patients with urologic anomalies (n = 14) and patients with primary renal disease (n = 20) were compared. In the study, the posttransplant clinical outcome of pediatric renal transplant recipients with urological anomalies was comparable to that of patients with primary renal disease.²⁶ In addition, no graft was lost as a result of urologic complications,⁴⁰ similar to our study. We also found no differences in terms of allograft loss between our patient groups.

In some studies, although the mean serum creatinine levels at year 1 and the last follow-up were elevated in patients with abnormal LUT compared with levels shown in patients with normal LUT, differences were not statistically significant.^37,40 In our study, we also demonstrated no differences between groups regarding median creatinine levels and median glomerular filtration rate.

In general, the frequency of UTI and other complications is higher in renal transplant recipients having abnormal LUT. However, the overall course for these patients is generally no worse than for renal transplant recipients without LUT abnormalities. It has been reported that recipients with abnormal LUT have 2.7-fold higher risk to develop a UTI than patients with normal LUT.^3,6,12 Nahas and colleagues demonstrated that the frequency of urologic complications was higher in the group undergoing major urologic procedures; however, all of these complications were treated without compromising graft or patient survival.³⁶ Adams and colleagues reported that the long-term administration of antibiotics (prophylactics) reduced infection rates in their renal transplant recepients.⁴¹ In our study, we also found that the incidence of UTI in renal transplant recipients with abnormal LUT (group 1 and group 2) was higher than that of renal transplant recipients with normal LUT (group 3) after transplant, although the difference was not statistically significant. According to our treatment protocol, we also administer prophylactic antibiotics to patients who have risk of UTI to reduce the incidence of UTI.

It was reported that individualized treatment is the key for the success of a pediatric renal transplant program.³⁶ In addition, because graft loss due to nonadherence to treatment was higher in our study group, we agree that patient compliance to the given treatment is also important for the best outcome after renal transplant. Therefore, we believe that education of patients and their families before transplant is of primary importance to improving patient compliance to treatment. Although detailed explanations regarding complications after renal transplant were given to the patients and their parents in our study, some thought that there would be no problems after transplant, affecting patient adherence to the given therapy. If prophylactic antibiotic therapy is not followed or catheterization is not performed, allograft failure may occur. Therefore, we must ensure that patients and their parents receive proper knowledge about complications after transplant. An experienced team who can establish a good relationship with patient and family will be more successful, thus increasing adherence of patients to treatment and increasing the success of transplant.

Although children with abnormal LUT had a slightly higher incidence of UTI, there were no differences between patients with abnormal and normal LUT regarding allograft survival and function. Our data indicate that renal transplant is safe and effective when the urologic disease is properly managed. In addition, based on our experience, an individualized approach for each patient, with education of patients and their families regarding possible complications after transplant, is important for a satisfactory pediatric renal transplant.

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