Objectives: Lower urinary tract dysfunction can lead to chronic kidney disease, which, despite surgical intervention, will progress to end-stage renal disease, requiring dialysis. Urologic pathology may damage a transplanted kidney, limiting patient and graft survival. Although smaller studies have suggested that urinary tract dysfunction does not affect graft or patient survival, this is not universally accepted. Northern Ireland has historically had the highest incidence of neural tube defects in Europe, giving rich local experience in caring for patients with lower urinary tract dysfunction. Here, we analyzed outcomes of renal transplant recipients with lower urinary tract dysfunction versus control recipients.
Materials and Methods: We identified 3 groups of kidney transplant recipients treated between 2001 and 2010; those in group 1 had end-stage renal disease due to lower urinary tract dysfunction with prior intervention (urologic surgery, long-term catheter, or intermittent self-catheterization), group 2 had end-stage renal disease secondary to lower urinary tract dysfunction without intervention, and group 3 had end-stage renal disease due to polycystic kidney disease (chosen as a relatively healthy control cohort without comorbid burden of other causes of end-stage renal disease such as diabetes). The primary outcome measured, graft survival, was death censored, with graft loss defined as requirement for renal replacement therapy or retransplant. Secondary outcomes included patient survival and graft function.
Results: In 150 study patients (16 patients in group 1, 64 in group 2, and 70 in group 3), 5-year death-censored graft survival was 93.75%, 90.6%, and 92.9%, respectively, with no significant differences in graft failure among groups (Cox proportional hazards model). Five-year patient survival was 100%, 100%, and 94.3%, respectively.
Conclusions: Individuals with a history of lower urinary tract dysfunction had graft and patient survival rates similar to the control group. When appropriately treated, lower urinary tract dysfunction is not a barrier to successful renal transplant.
Key words : Graft, Kidney Transplant, Reflux, Survival
Lower urinary tract dysfunction (LUTD) causes approximately 20% of end-stage renal disease in pediatric patients.1 There are numerous causes of LUTD that may be broadly categorized into structural developmental abnormalities (eg, posterior urethral valves, vesicoureteric reflux, and prune belly syndrome) and neurologic disorders causing bladder dysfunction (eg, spina bifida). In Northern Ireland, we have had the highest incidence in Europe of these patients, which may be because termination of pregnancy is largely illegal.2
Lower urinary tract surgery may be offered with a bespoke case-by-case approach, with the universal goal of creating a urinary reservoir that has low pressure, good compliance, and adequate urinary storage. Surgical options include construction of a Mitrofanoff catherizable stoma, augmented clam ileocystoplasty, ileal conduit, or ureteric reimplantation. Lower urinary tract dysfunction causes significant morbidity and decreased quality of life, even with our best management modalities. Despite surgical intervention, many patients will eventually reach end-stage renal disease (ESRD).
Overall, patients with LUTD represent a small proportion of the adult kidney transplant population worldwide at 0.2% to 2.3%, although this is considerably higher in Northern Ireland.3 It has been hypothesized that LUTD, with or without intervention, would be injurious to a transplanted kidney and cause premature graft failure.4-7 A recent study8 concluded that prior bladder surgery posed an increased risk of graft failure and infections. However, other recent literature has shown no significant difference in renal transplant outcomes.1,3,9-15 These studies have several limitations. Many had low numbers of patients included in the analyses (6-21 patients)3,12-14,16-19 and did not include a control group but merely compared their results to average graft and patient survival statistics.1,13,16,18 Not all control groups were matched.9,11,12 Most control groups consisted of patients with a “non-urologic” cause of ESRD but did not specify the cause of ESRD further or account for the differing causes as a confounding factor.3,9,20 This is an important aspect to consider; for example, those with ESRD due to diabetes would have a poorer prognosis than those with autosomal dominant polycystic kidney disease. Many studies had relatively short periods of follow-up of between 2 and 6 years8,11,12,17,20,21 and spanned over different decades; thus, patients would have been taking different immunosuppressant drugs.15,19,21 Furthermore, some studies had large numbers of living-donor kidney transplants1,14,20 in the study group versus the control group, and there were no adjustments for this confounding factor. Due to these numerous limitations, the literature on this topic is unclear.
Some studies22 recommend bladder augmentation before transplant with the aim of creating a less hostile environment, as this allows anastomotic healing of the transplant ureter to recipient bladder without transplant immunosuppression. There is a counter-balancing argument that transplant first is a reasonable management strategy, ensuring that there is improved renal function at time of augmentation surgery. Transplant first also allows adequate urine output to ensure maintained patency of the new drainage system and thus, in some cases, will create a storage reservoir that will eventually accommodate increasing urine output without augmentation cystoplasty. A renal transplant procedure first would reduce the risk of anastomosing the ureter onto an augmented bladder, which commonly has a high bacterial and mucous load in the setting of oliguria while on dialysis. One study18 compared bladder augmentation first versus transplant first, finding no difference in incidence of urinary tract infection after transplant or subsequent graft function. There is a higher incidence of posttransplant urinary tract infections in patients with prior LUTD9,11-13,15,16; however, studies have suggested that urinary tract infections do not affect long-term graft function.10,21 The most common cause of graft loss in those with LUTD is so-called “chronic rejection.”15
We hypothesized that kidney transplant in patients with LUTD is a safe procedure and would have graft and patient outcomes comparable to those shown in renal transplant recipients without LUTD. Pathology in individuals with autosomal dominant polycystic kidney disease (ADPKD) is most commonly confined to the renal system. Cause of graft failure and death is rarely related to the ADPKD pathology. Therefore, these patients most closely mimic the LUTD population and were chosen to be the most suitable control group. In comparison, patients with, for example, diabetic neuropathy would skew the results as their pathology still has a profound effect on graft function and cause of death after transplant, which would cause outcomes that would contrast with those in LUTD patients. Therefore, ADPKD is a single-system renal disease suited for our study rather than, for example, diabetic neuropathy, where patients frequently have substantial comorbid disease burden.
Materials and Methods
Northern Ireland has a single renal transplant center serving a population of 1.8 million people. Clinical variables and outcomes of all renal transplant recipients included in the Northern Ireland Kidney Transplant Database were prospectively recorded. The patient source has received Research Ethics Committee approval for use as a research database (Northern Ireland Regional Ethics Committee 12/NI/0178). This study conformed to the ethical guidelines of the 1975 Helsinki Declaration. All patients gave written informed consent to be included in the database. In addition, Northern Ireland is unusual in having all citizens register on a national electronic health record, allowing access to blood test and radiology results, as well as medical notes. Use of this database thus permitted a large nationwide retrospective study with more reliable results than previously published studies with smaller cohorts. The high incidence of ESRD secondary to LUTD in Northern Ireland2 creates a unique opportunity to study renal transplant outcomes in this group of patients.
All renal transplants in Northern Ireland have been performed at a single center in the Regional Nephrology Unit at Belfast City Hospital since 1968. Patient follow-up is at Belfast City Hospital or one of the 4 regional nephrology units. The Northern Ireland Kidney Transplant Database, which prospectively records clinical variables and outcomes on all transplants, was interrogated for patients transplanted in the 10-year period between January 2001 and December 2010. Follow-up was until August 2016.
Those who had ESRD due to LUTD and who had interventions (urologic surgical procedure, place-ment of a long-term catheter, or clean intermittent catheterization) were classified as group 1. Those in the LUTD group but without intervention were classified as group 2. Group 3 (controls) consisted of patients with ADPKD only. The medical records of those with LUTD were interrogated to identify those who had surgery to address this dysfunction and to identify whether augmentation surgery or transplant was performed first or whether patients had long-term bladder catheter or had clean intermittent catheterization.
For this study, donor data recorded included age, sex, and transplant type (living or deceased).
Recipient details collected included age, sex, cause of ESRD, mode and length of time on renal replacement therapy, transplant date (and whether it was a preemptive transplant), total ischemic time, A-B-DR mismatching, and number of transplant procedures.
All patients had been started on the same immuno-suppressant regimen (mycophenolate mofetil, tacrolimus, and prednisolone).
Creatinine levels in functioning grafts at 1 and 5 years were documented. Outcomes studied were graft loss and death. Time until graft loss was calculated from date of transplant to the date of return to renal replacement therapy or retransplant, rounding up or down to the nearest whole number in months. Those who died with a functioning graft were censored for graft loss. Subsequent renal replacement therapy mode was documented. Clinical records and discharge letters were viewed to identify recipients who were noncompliant with immunosuppressive medication.
All variables were descriptively analyzed. Graft and patient survival results were investigated using a Cox proportional hazards model. This included potential confounding variables, which differed between the study groups for recipient and donor age and type of dialysis. The Cox model was used to adjust for these differences rather than matching the patients. Differences between the study groups were examined using chi-square tests for categorical variables and analysis of variance for continuous variables. Values were considered statistically significant if P < .05. Data were analyzed with SPSS version 23 for Windows (SPSS, Inc., Chicago, IL, USA).
During the 10-year study period, 472 transplant procedures were performed in Northern Ireland. Of these, 80 patients had ESRD due to LUTD (group 1 and group 2 patients) and 70 had ADPKD (control group 3 patients). Of the patients with ESRD due to LUTD, 16 had bladder surgery and/or catheter interventions (group 1) and 64 had ESRD due to LUTD without intervention (group 2).
Lower urinary tract dysfunction
In group 1, 5 patients had ESRD due to congenital neurogenic bladder, 2 due to acquired neurogenic bladder, 5 due to congenital stricture of ureterovesical orifice, 1 due to chronic pyelonephritis, 2 due to posterior urethral valves, and 1 due to vesicoureteric reflux. Ten patients had surgical intervention to the urinary tract (80% of surgical procedures were before transplant), 2 had long-term catheters, and 7 used clean intermittent catheterization (4 used clean intermittent catheterization only, 3 had clean intermittent catheterization plus surgery). Four patients had a clam ileocystoplasty, one of which was created after transplant. One patient had diathermy to posterior urethral valve, one had an ileal conduit, one had a colonic conduit, and two received ureteric reimplantations. A urostomy was created after transplant in one individual. Table 1 demonstrates the procedures conducted for each cause of ESRD.
In group 2, 1 patient had ESRD due to congenital neurogenic bladder, 4 due to congenital stricture of ureterovesical orifice, 11 due to chronic pyelonephritis, 2 due to posterior urethral valves, and 46 due to vesicoureteric reflux.
The mean donor age, sex, and type of donation are shown in Table 2. For 1 patient in group 2, the type of donor was unknown. The age of one donor in group 1 was unknown. In group 2, the sex was unknown for 3 donors. Donors were categorized as deceased donors, all donated after brain death, or living donors.
As shown in Table 3, recipients in the control group (group 3) were significantly older (P < .001), and there was a significant difference in type of renal replacement therapy among groups 1, 2, and 3 (P = .046). For group 1, this was the first transplant for 15 recipients (93.7%), with 1 recipient (6.3%) having a second transplant. In group 2, this was the first transplant for 52 (81.3%), second transplant for 8 (12.5%), and third for 4 recipients (6.2%). In group 3, this was the first transplant for 65 (92.9%), second transplant for 4 (5.7%), and third for 1 recipient (1.4%). Noncompliance with immunosuppressive medications (see Table 3) on at least one occasion was documented from patient history or from low serum levels of immunosuppressive drugs.
In group 1, 13 of 16 grafts were still functioning in August 2016, 6 years after termination of recruitment in our study spanning from 2001 to 2010. Two grafts failed due to chronic rejection, and one failed perhaps due to donor disease (donor had hypertension and ischemic heart disease). These patients have since had a subsequent retransplant. In group 2, of 13 graft losses, 1 was lost due to hyperacute rejection, 1 due to donor problems (en bloc pediatric donor with small kidneys), 3 due to vascular events, and 8 due to chronic rejection. Twelve of these patients (92.3%) have gone on to have another transplant. In group 3, of 5 graft losses, 1 was lost due to acute rejection, 3 due to chronic rejection, and 1 due to donor pathology (donor fibrosis on biopsy). Three of these patients have gone on to have another transplant. Each patient was included in the analysis once only (eg, if they received a transplant in 2001 and were retransplanted in 2008, only the information from the 2001 transplant was analyzed). One-year graft survival was 100%, 92.2%, and 98.6%, respectively, for groups 1, 2, and 3. Five-year graft survival was 93.75%, 90.6%, and 92.9%, respectively. A Kaplan-Meier curve representing estimates from the Cox proportional hazards model for graft failure is shown in Figure 1. For group 1 versus control, hazard ratio was 1.221 (95% confidence interval, 0.216-6.908; P = .822). For group 2 versus control, hazard ratio was 1.848 (95% confidence interval, 0.531-6.437; P = .335). This adjusted for renal replacement therapy type, recipient age, and donor age as potential confounders as there were significant differences among the groups for these variables. Ischemia time and matching were comparable across all 3 groups, with no significant difference and therefore not adjusted for in the analysis. Mean follow-up (SD) was 119 (44) months, 112 (37) months, and 103 (36) months, respectively (P = .2). The Cox proportional hazards assumptions were checked visually by inspection of Kaplan-Meier curves, and the assumption was met.
At end of follow-up, all patients were still alive in group 1. In group 2, 3 patients died with a functioning graft (1 death due to a cerebrovascular accident and 2 deaths due to sudden cardiac death). In group 3, 5 patients died with a functioning graft and 2 with a failed graft (1 had vascular access failure, 3 had malignant disease, 1 had peritonitis from perforation, 1 had calciphylaxis, and 1 had sudden cardiac death). One-year patient survival was 100%, 100%, and 100%, respectively, in groups 1, 2, and 3. Five-year patient survival was 100%, 100%, and 94.3%, respectively. The Kaplan-Meier curve (representing estimates from the Cox proportional hazards model for recipient survival) is shown in Figure 2. In group 1, hazard ratio was < 0.001 (P = .985). For group 2, hazard ratio was 0.744 (95% confidence interval, 0.139-3.98; P = .729). This was adjusted for renal replacement therapy type, recipient age, and donor age. The Cox proportional hazards assumption was checked visually by inspection of Kaplan-Meier curves, and the assumption was met.
Lower urinary tract dysfunction is a frequent cause of ESRD in the pediatric population and may necessitate bladder augmentation surgery and/or clean intermittent catheterization to optimize storage and emptying of the bladder. Despite this, many with LUTD will progress to ESRD and require a renal transplant. Our study confirmed that individuals with LUTD can receive transplants and have outcomes comparable with those with ADPKD, as demonstrated by the good long-term graft and patient survival rates in this cohort of patients.
Unsurprisingly, we observed a significant dif-ference for recipient age among the 3 study groups (P < .001). Those with ADPKD (group 3) typically have a later presentation and slower progression of chronic kidney disease to ESRD. Patients with ADPKD will therefore usually require a renal transplant at an older age (compared with individuals with ESRD associated with LUTD) and will therefore be more likely matched with an older donor due to the point-scoring system for the deceased-donor organ allocation scheme.23
There were significant differences among the 3 groups regarding type of renal replacement therapy (P = .046), and this was related to the fact that groups 1 and 2 had more preemptive renal transplants (18.7% and 17.2%, respectively) than group 3, in which only 8.6% had a preemptive transplant. This may be because patients with ADPKD have ineligible family member donors because of autosomal dominant genetics. Also, more pediatric transplant candidates were in groups 1 and 2, who are prioritized in deceased-donor organ allocation schemes and are more likely to receive living-donor transplants.
We observed no significant differences in 1-year and 5-year creatinine levels (P = .143 and P = .573) among the 3 groups, suggesting that graft function in groups 1 and 2 was not negatively affected by preexisting LUTD. It may also suggest that the pathology in group 1 causing ESRD had been adequately corrected by surgical intervention or catheterization before transplant.
We found that mean graft survival in those with LUTD who needed intervention (group 1) was not significantly different from survival rates in groups 2 and 3. Our findings support the hypothesis that kidney transplant in patients with LUTD is a safe procedure with good outcomes. Those who needed bladder augmentation surgery or catheterization fared no worse that those who did not. This may be because these treatments effectively reduced the harmful effects that their condition would have had on the allograft. Therefore, our study and other large studies1,12,15,20,24 do not support previously held views4-6 that grafts in these surgical patients would fare worse due to the severity of the recipient’s urologic condition. Although these studies may have found significant differences for graft function and patient survival, the results were based on small patient numbers. Srinivasan and associates8 found that those with bladder surgery had inferior graft survival on multivariate analysis but those with bladder dysfunction without surgery did not demonstrate worse outcomes. The median follow-up for recipients who had bladder surgery in the study by Srinivasan and associates8 was 4 years, whereas our median follow-up for group 1 was 11.5 years. The difference between their findings and ours may be due to the differing lengths of follow-up, recipient age, and type of bladder surgery.
Our study showed 5-year graft survival to be 93.75% and 90.5% in groups 1 and 2. These results are better than many other studies (90% in Yazici and associates,21 84% and 74% in Nahas and associates,20 88.9% in Taghizadeh and associates,18 75.2% and 84.3% in Srinivasan and associates,8 68.7% in Torricelli and associates,19 65% in Reinberg and associates,24 and 64% in DeFoor and associates17). However, it should be acknowledged that some of these studies included patients from as early as 1989, and so poorer graft survival may be partly due to older immunosuppression regimens. The most common cause of graft loss was chronic rejection, which correlated with other studies.15,21 The Cox proportional hazards model results for recipient survival for groups 1 and 2 and the 5-year patient survival rate of 100% in groups 1 and 2 compare well with other studies (97% in Khositseth and associates,15 91.2% in Torricelli and associates,19 and 75.2% and 90% in Srinivasan and associates8).
We only studied patients who were transplanted between 2001 and 2010, which somewhat limited the numbers and power of our analysis. The chosen time period, however, facilitated a more complete dataset, as our medical records have been digitalized since 2000, and also reduced confounding factors given the homogeneity of transplant practice and immuno-suppressive regimens. There was a significant difference in recipient age in the control group, but this confounder was accounted for in statistical analysis. The high graft and patient survival rates across all 3 groups meant a limited number of events in the population during follow-up.
In summary, we found no statistically significant difference in graft function and graft and patient survival between the study groups and control group. Those with lower urinary tract dysfunction who receive appropriate and timely treatment can receive renal transplants with successful outcomes comparable to renal transplant patients with ADPKD.
Volume : 17
Issue : 1
Pages : 11 - 17
DOI : 10.6002/ect.2017.0137
From the the 1Regional Nephrology Unit, Belfast City Hospital, Belfast, Northern
Ireland, UK; the 2Centre for Public Health, Queen’s University Belfast, Royal
Victoria Hospital, Belfast, Northern Ireland, UK; and the 3Department of
Urology, Harvard Medical School, Massachusetts General Hospital, Boston,
Acknowledgements: We acknowledge the contribution of statistical advice given by Dr. Chris Cardwell, Centre for Public Health, Queen’s University Belfast, Royal Victoria Hospital, BT12 6BA. We also acknowledge the Northern Ireland Medical and Dental Association and Queens University Belfast who funded the staff position of author, Rebekah Wilson, who led this research. There are no conflicts of interest among any of the authors.
Corresponding author: Rebekah Wilson, Regional Nephrology Unit, Belfast City Hospital, Lisburn Road, Belfast, Northern Ireland BT9 7AB, UK
Phone: +44 7849494145
Table 1. Causes of End-Stage Renal Disease in Groups 1, 2, and 3 and Type of Intervention
Table 2. Donor Demographics and Characteristics
Table 3. Recipient Demographics, Characteristics, and Outcomes
Figure 1. Kaplan-Meier Curves for Graft Survival
Figure 2. Kaplan-Meier Curves for Patient Survival