- Email: [email protected]
Trends in Renal Transplantation Rates in Patients with Congenital Urinary Tract Disorders
Neuropathic Bladder
Trends in Renal Transplantation Rates in Patients with Congenital Urinary Tract Disorders Herman S. Bagga,* Songhua Lin, Alun Williams, Jesse Schold, Nathan Chertack, David Goldfarb and Hadley Wood From the Departments of Urology (HSB, DG, HW) and Quantitative Health Sciences (SL, JS), Cleveland Clinic and Case Western Reserve University of Medicine (NC), Cleveland, Ohio, and Transplant Unit, Department of Paediatric Urology, Nottingham Children’s Hospital (AW), Nottingham, United Kingdom
Purpose: Improved bladder and renal management benefit patients with congenital uropathy and congenital pediatric kidney disease. This may translate to delayed initial renal transplantation in these patients, and improved graft and patient survival. Our primary study purpose was to determine whether patients with congenital uropathy and congenital pediatric kidney disease have demonstrated later time to first transplantation and/or graft survival. Materials and Methods: SRTR (Scientific Registry of Transplant Recipients) was analyzed for first renal transplant and survival data in patients with congenital uropathy and congenital pediatric kidney disease from 1996 to 2012. Congenital uropathy included chronic pyelonephritis/reflux, prune belly syndrome and congenital obstructive uropathy. Congenital pediatric kidney disease included polycystic kidney disease, hypoplasia, dysplasia, dysgenesis, agenesis and familial nephropathy. Results: A total of 7,088 patients with congenital uropathy and 24,315 with congenital pediatric kidney disease received a first renal transplant from 1996 to 2012. A significant shift was seen in both groups toward older age at initial renal transplantation in those 18 through 64 years old. In the congenital uropathy group this effect was most facilitated by decreased renal transplantion in patients between 18 and 35 years old (38% in 1996 vs 26% in 2012). The congenital pediatric kidney disease group showed a substantial decrease in patients who were 35 to 49 years old (from 39% to 29%). At 10-year followup the congenital uropathy group showed better graft and patient survival than the congenital pediatric kidney disease group. However, aged matched comparison revealed comparable survival rates in the 2 groups. Conclusions: Analysis of trends in the last 14 years demonstrated that patients with both lower and upper tract congenital anomalies experienced delayed time to the first renal transplant. Furthermore, patients had similar age matched graft and patient survival whether the primary source of renal demise was the congenital lower or upper tract. These findings may indicate that improved urological and nephrological care are promoting renal preservation in both groups.
Abbreviations and Acronyms CKD ¼ chronic kidney disease CPKD ¼ congenital pediatric kidney disease CU ¼ congenital uropathy DD ¼ deceased donor transplant ESRD ¼ end stage renal disease LD ¼ living donor transplant RT ¼ renal transplant Accepted for publication October 1, 2015. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. * Correspondence: Center for Genitourinary Reconstruction, Glickman Urologic Institute, Cleveland Clinic, 9500 Euclid Ave./Q10-1, Cleveland, Ohio 44195 (telephone: 216-4034282; e-mail: [email protected]).
Key Words: kidney transplantation, congenital, kidney diseases, graft survival, mortality
0022-5347/16/1954-1257/0 THE JOURNAL OF UROLOGY® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2015.10.004 Vol. 195, 1257-1262, April 2016 Printed in U.S.A.
www.jurology.com
j
1257
1258
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
KIDNEY transplantation remains the gold standard treatment for children with ESRD, providing a known survival advantage over hemodialysis.1 Congenital causes such as anomalies of the upper and lower urinary tract, and hereditary nephropathies are disproportionately responsible for the development of CKD in children. In the United States approximately 60% of pediatric CKD is attributable to such congenital disorders.2 Progression of CKD in these patients is variable and depends on several factors, including severity of underlying disease, early recognition of the problem, proper selection of management strategies and various socioeconomic factors.2 In the United States the modern era has been marked by improved understanding of congenital disease states leading to CKD as well as advancements in prenatal screening, and more aggressive bladder and nephrological management strategies with improved access to care. We postulated that such advancements in the treatment of patients with congenital urinary tract disorders may slow progression to ESRD and secondarily delay time to the first RT in these patients. Furthermore, such advances could also translate to improved RT graft and patient survival. To investigate this hypothesis the primary objectives of this study were to determine whether patients with CU and CPKD have demonstrated later time to the first transplant and/or graft survival.
MATERIALS AND METHODS Data Source SRTR is a national database of transplant statistics collected by OPTN (Organ Procurement and Transplantation Network), a collection of hospitals and organ procurement organizations across the United States. Since 1987, SRTR has maintained comprehensive information on all solid organ transplants in the country with current and past information on the full spectrum of transplant activity. Data include information on organ donors, candidates and recipients as well as organ specific and patient outcomes.3
Variables SRTR was queried to identify the first RT, and graft and patient survival data in patients with CU and CPKD between 1996 and 2012. The study was limited to the period after 1996 due to some incomplete data in SRTR prior to this year. CU included diagnostic codes 3007 (chronic pyelonephritis/reflux), 3036 (prune belly) and 3052 (congenital obstructive uropathy). CPKD included codes 3008 (polycystic kidney disease), 3025 (hypoplasia, dysplasia, dysgenesis, agenesis) and 3032 (familial nephropathy). In addition to time of transplantation, characteristics of donors and recipients were extracted from identified cases, including age, gender, race, body mass index and comorbidity data. Furthermore, recipient transplant and kidney function data were collected.
Statistical Analyses Descriptive statistics were used to examine the distribution of clinical characteristics of and between the CU and CPKD groups. Univariate analysis and its associated p values were used to evaluate differences in the unadjusted prevalence of the mentioned characteristics. SASÒ Proc freq and gplot procedures were applied to calculate the percent of frequencies, which are simple proportions of number per age group over the total transplant number per year. Scatterplots were constructed, and simple regression models and associated p values were used to evaluate differences in each age group. Also, to support the results regression models focused on age and diagnosis groups, and the first RT year. Test results revealed that in general all were statistically significantly associated with recipient age at first RT (p <0.0001). The younger age group (18 to 35 years) in the CU group and the middle age group (35 to 49 years) in the CPKD group substantial decreased with time and were strongly associated with patient age at the first RT. Graft and patient survival were evaluated using the Kaplan-Meier method. Analyses were performed with SAS 9.2 for UNIX. The Cleveland Clinic institutional review board gave this study exempt status.
RESULTS Study Population A total of 7,088 patients with CU and 24,315 with CPKD received a first RT between 1996 and 2012. Of patients with CU the preoperative diagnosis was chronic pyelonephritis/reflux in 3,768, prune belly syndrome in 380 and congenital obstructive uropathy in 2,940. Of patients with CPKD the preoperative diagnosis was polycystic kidney disease in
A
B
Figure 1. Age at first RT as percent of all RTs with time in patients with CU (A) and CPKD (B).
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
21,657, kidney hypoplasia, dysplasia, dysgenesis or agenesis in 2,259 and familial nephropathy in 399. When considering the entire population, there were decreasing DDs and increasing LDs with time. In 1996 at the start of the study period 64.7% of patients received a DD while 35.3% received a LD. By the end of the study period in 2012 there were 56.5% DDs compared to 43.5% LDs. This trend was significant during the study (p <0.0001). The same significant trend was seen when considering only adults (age 18 years or greater) with a DD in 69.3% and a LD in 30.7% in 1996 compared to 56.1% and 43.9%, respectively, in 2012 (p <0.0001). When considering pediatric cases only, the trend was reversed with a DD in 38% and a LD in 62% in 1996 compared to 59.6% and 40.4%, respectively, in 2012 (p <0.0001). Supplementary tables 1 and 2 (http://jurology. com/) list RT donor and recipient variables among all patients in the CU and CPKD groups. On age matched comparison the 2 groups had mostly similar cognitive ability, body mass index, hypertension and diabetes rates. Age at First RT Figure 1 shows age at first RT in the CU and CPKD groups during the study period. However, analysis
1259
of individual age groups revealed several significant trends (figs. 2 and 3). Figure 2 shows the proportion of patients with CU who received the first RT in the age groups between 18 and 65 years or greater. Figure 3 shows similar information on patients with CPKD. Renal Transplantation Candidacy. Analysis was also performed of patient candidacy for renal transplantation by age group with time. Results mirrored that of age at time of the first RT. There was no significant change in average age at the time of transplant candidacy in the CU and CPKD groups. Graft and Patient Survival. Figure 4 shows graft and
patient survival after the initial RT with time. When considering graft survival at 5 years, both groups demonstrated approximately 90% survival. However, at 10-year followup patients with CU had better graft survival than those with CPKD (80.7% vs 75.9%, p <0.001). When considering patient survival after renal transplantation, the CU and CPKD groups again showed similar survival at 5 years (93.2% vs 95%, p >0.05). Correspondingly at 10 years patients with CU demonstrated significantly better survival than those with CPKD
A
B
C
D
Figure 2. Percent of patients with CU who received first RT with time between ages 18 to 34 (A), 35 to 49 (B), 50 to 64 (C ) and 65 years or older (D).
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
1260
A
B
C
D
Figure 3. Percent of patients with CPKD who received first RT with time between ages 18 to 34 (A), 35 to 49 (B), 50 to 64 (C ) and 65 years or older (D).
(82.3% vs 77%, p <0.001). However, when comparing patients with CU and CPKD in age groups, graft and patient survival differences were not significant. This finding suggests an effect of age rather than of etiology.
DISCUSSION This study shows that patients with congenital uropathies and nephropathies trended toward later age at the first transplant during the 14-year period that we examined in the SRTR database. Furthermore, after age matching patients with CU and CPKD we found equivalent 10-year graft and patient survival in the 2 groups. These findings may be explained by 1 or more changes during the study period, including 1) improved donor and recipient selection,1 2) improved prenatal screening and care,4 3) improved posttransplantation medical care and surveillance,1 and 4) improved and early intervention and care for afflicted patients prior to transplantation. There are multiple strategies to care for patients with CU and CPKD before renal replacement therapy. The improved use of such measures could be
preserving compromised renal units prior to the development of ESRD and postponing the need for transplantation. Among patients with CPKD treatment strategies include appropriate hypertension management, hormone supplementation, protein replacement, nutritional supplementation and when appropriate, medical therapies such as steroid or immunosuppressive agents.4e7 Care for patients with CU, such as those with posterior urethral valves, prune belly syndrome, myelomeningocele, obstructive megaureters and significant vesicoureteral reflux, include appropriate use of anticholinergics, intermittent catheterization, antibiotics and appropriate surgical intervention. Particularly among adolescent and young adult recipients behavioral strategies for compliance before and after transplantation may also have great impact.8e11 Older age at renal transplantation can be a favorable outcome by delaying major surgery in patients. Furthermore, preserving native function can help avoid some of the metabolic, biochemical and fluid balance problems faced by transplant recipients. In addition, significant psychosocial issues are associated with transplantation and related hospitalizations, which would preferably be
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
A
B
Figure 4. Graft (A) and patient (B) survival after renal transplantation by group with time.
delayed. This is particularly true in the adolescent population.12 Also, older adolescents who undergo kidney transplantation are known to be at higher risk for graft loss than other age groups. This is potentially due to noncompliance during a high risk age window seen during the transition from this age to adulthood.13e15 Delaying transplantation in these patients has the advantage of allowing patient psychological maturation and could translate into improvements in self-care and graft survival. Interestingly we did not note any data to suggest significant shifts in transplantation age among those younger than 18 years. This may suggest that some of the most severely affected patients in both groups will progress to renal transplantation regardless of prenatal and postnatal medical therapies. It also may represent strict adherence to the concept of early or even preemptive transplantation in children with progressive kidney failure, which is a strategy known to confer a survival advantage.16 We found that the proportion of patients who received a deceased donor graft significantly decreased during the study period in favor of LDs. This was true in the entire population as well as in
1261
adults only considered as a subgroup. However, when considering only pediatric patients, the trend was reversed with significantly increasing DDs with time compared to LDs. This finding of increasing DDs compared to LDs among pediatric recipients was noted in prior analyses.17,18 It has been speculated that such findings may be the result of changes in deceased donor graft allocation policies since 2005. That is when policies were restructured to favor the allocation of deceased donor grafts to pediatric over adult candidates and to reduce associated waiting periods for these recipients. Furthermore, groups have also suggested that certain pediatric cohorts may actually achieve longer cumulative graft survival by preferentially choosing deceased donor grafts at a younger age and saving a LD for later in life.17e19 We also investigated patient and graft survival rates after the first RT. In an effort to investigate the efficacy of current bladder management strategies to maintain such safe bladders in patients with CU we compared survival data on patients with CU and CKPD after renal transplantation. The latter could then serve as a control group when investigating this issue. At 10-year followup we found small but statistically significant graft and patient survival advantage in patients with CU compared to patients with CKPD after the first RT, although there was no difference in survival between the 2 groups on age matched comparison. Ten-year graft survival rates exceeded those reported in the general population in the SRTR database in patients after receiving DDs and LDs. Current survival rates are reported to be in the 45% to 63% and 63% to 79% range for overall graft and patient survival, respectively.20 This is particularly interesting in the context of patients with CU who often have a decompensated lower urinary tract, which can leave transplanted renal units vulnerable to damage due to poor compliance, reflux and high pressure storage when not managed appropriately.16,21 We postulate that this may be due to patients in this study having been subjected to a lifetime of medical care and intervention, perhaps leading to improved medical surveillance, lifestyle choices and treatment compliance after transplantation compared with patients undergoing transplantation for other causes of ESRD. Further investigation of what these populations are doing or not doing to lead to a graft survival advantage may point to opportunities for all transplant recipients. While appropriate investigation of the bladder/ urinary reservoir and patient compliance is advocated in all patients with CU undergoing transplant evaluation, there exists a paucity of literature and/ or clinical guidelines on this topic. The development and promulgation of evaluation and treatment
1262
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
algorithms for patients with CU undergoing pretransplant optimization may further improve outcomes. Our study has several limitations. We were restricted to data available in the SRTR data set. We had limited information on the etiology of renal failure. We recognize that this database may not accurately characterize the primary etiology of renal demise, particularly if the cause is multifactorial. In addition, congenital uropathy is a broadly defined category that could represent several more specific etiologies, such as posterior urethral valves, congenital neuropathic bladders or other etiologies. When considering allograft survival, the data are impacted by several variables such as chronic rejection, compliance with medications, and other recipient and donor characteristics that were not obtainable, which could have affected outcomes. Also, although SRTR is a reliable data set, there is no way to confirm the consistency of data capture with time, including the fact that changes were made to data collection criteria through time, which may alter the completeness of data collection and the categorization of each patient. However, it is important to note that this data set is maintained by
UNOS (United Organ Sharing Program) and, thus, is the most reliable set that we have with which to work. Furthermore, we were unable to consider changes in kidney transplant allocation and distribution policies during the study interval, which most definitely have changed with time as UNOS organ sharing policies and medical advancements in living renal donation have changed.
CONCLUSIONS Patients with CKD due to congenital urinary tract disorders are at high risk for requiring a RT. Analyses of trends during the last 14 years demonstrate that adults with congenital upper and lower urinary tract anomalies are undergoing renal transplantation at an older age. This may be due to improved recognition and management of these disorders, the promotion of native renal function preservation and the concomitant delay in the need for transplantation. Furthermore, patients in both groups demonstrated excellent and comparable 10-year graft and overall survival regardless of whether the primary source of renal demise was the congenital upper or lower tract.
REFERENCES 1. Dharnidharka VR, Fiorina P and Harmon WE: Kidney transplantation in children. N Engl J Med 2014; 371: 549. 2. Harambat J, van Stralen KJ, Kim JJ et al: Epidemiology of chronic kidney disease in children. Pediatr Nephrol 2011; 27: 363. 3. Leppke S, Leighton T, Zaun D et al: Scientific Registry of Transplant Recipients: collecting, analyzing, and reporting data on transplantation in the United States. Transplant Rev (Orlando) 2013; 27: 50. 4. Kuwertz-Broeking E, Brinkmann OA, Lengerke Von HJ et al: Unilateral multicystic dysplastic kidney: experience in children. BJU Int 2004; 93: 388. 5. Mansoor O, Chandar J, Rodriguez MM et al: Long-term risk of chronic kidney disease in unilateral multicystic dysplastic kidney. Pediatr Nephrol 2011; 26: 597. 6. Sweeney WE Jr and Avner ED: Diagnosis and management of childhood polycystic kidney disease. Pediatr Nephrol 2011; 26: 675. 7. Jalanko H: Congenital nephrotic syndrome. Pediatr Nephrol 2009; 24: 2121. 8. Lopez Pereira P, Martinez Urrutia MJ, Espinosa L et al: Long-term consequences of posterior urethral valves. J Pediatr Urol 2013; 9: 590.
9. Seidel NE, Arlen AM, Smith EA et al: Clinical manifestations and management of prune-belly syndrome in a large contemporary pediatric population. Urology 2015; 85: 211. 10. Farrugia M-K, Hitchcock R, Radford A et al: British Association of Paediatric Urologists consensus statement on the management of the primary obstructive megaureter. J Pediatr Urol 2014; 10: 26. 11. Tullus K: Vesicoureteric reflux in children. Lancet 2015; 385: 371. 12. Anthony SJ, Hebert D, Todd L et al: Child and parental perspectives of multidimensional quality of life outcomes after kidney transplantation. Pediatr Transplant 2009; 14: 249. 13. Andreoni KA, Forbes R, Andreoni RM et al: Agerelated kidney transplant outcomes: health disparities amplified in adolescence. JAMA Intern Med 2013; 173: 1524. 14. Van Arendonk KJ, King EA, Orandi BJ et al: Loss of pediatric kidney grafts during the “high-risk age window”: insights from pediatric liver and simultaneous liver-kidney recipients. Am J Transplant 2015; 15: 445. 15. Bobanga ID, Vogt BA, Woodside KJ et al: Outcome differences between young children
and adolescents undergoing kidney transplantation. J Pediatr Surg 2015; 50: 996. 16. Ishitani M, Isaacs R, Norwood V et al: Predictors of graft survival in pediatric living-related kidney transplant recipients. Transplantation 2000; 70: 288. 17. Van Arendonk KJ, Boyarsky BJ, Orandi BJ et al: National trends over 25 years in pediatric kidney transplant outcomes. Pediatrics 2014; 133: 594. 18. Magee JC, Krishnan SM, Benfield MR et al: Pediatric transplantation in the United States, 1997-2006. Am J Transplant 2008; 8: 935. 19. Van Arendonk KJ, Chow EK, James NT et al: Choosing the order of deceased donor and living donor kidney transplantation in pediatric recipients: a Markov decision process model. Transplantation 2015; 99: 360. 20. Scientific Registry of Transplant Recipients, Health Resources and Services Administration: 2012 Annual Data Report. Available at http:// srtr.transplant.hrsa.gov/annual_reports/2012/ Default.aspx. Accessed October 1, 2015. 21. Aki FT, Aydin AM, Dogan HS et al: Does lower urinary tract status affect renal transplantation outcomes in children? Transplant Proc 2015; 47: 1114.
Trends in Renal Transplantation Rates in Patients with Congenital Urinary Tract Disorders Herman S. Bagga,* Songhua Lin, Alun Williams, Jesse Schold, Nathan Chertack, David Goldfarb and Hadley Wood From the Departments of Urology (HSB, DG, HW) and Quantitative Health Sciences (SL, JS), Cleveland Clinic and Case Western Reserve University of Medicine (NC), Cleveland, Ohio, and Transplant Unit, Department of Paediatric Urology, Nottingham Children’s Hospital (AW), Nottingham, United Kingdom
Purpose: Improved bladder and renal management benefit patients with congenital uropathy and congenital pediatric kidney disease. This may translate to delayed initial renal transplantation in these patients, and improved graft and patient survival. Our primary study purpose was to determine whether patients with congenital uropathy and congenital pediatric kidney disease have demonstrated later time to first transplantation and/or graft survival. Materials and Methods: SRTR (Scientific Registry of Transplant Recipients) was analyzed for first renal transplant and survival data in patients with congenital uropathy and congenital pediatric kidney disease from 1996 to 2012. Congenital uropathy included chronic pyelonephritis/reflux, prune belly syndrome and congenital obstructive uropathy. Congenital pediatric kidney disease included polycystic kidney disease, hypoplasia, dysplasia, dysgenesis, agenesis and familial nephropathy. Results: A total of 7,088 patients with congenital uropathy and 24,315 with congenital pediatric kidney disease received a first renal transplant from 1996 to 2012. A significant shift was seen in both groups toward older age at initial renal transplantation in those 18 through 64 years old. In the congenital uropathy group this effect was most facilitated by decreased renal transplantion in patients between 18 and 35 years old (38% in 1996 vs 26% in 2012). The congenital pediatric kidney disease group showed a substantial decrease in patients who were 35 to 49 years old (from 39% to 29%). At 10-year followup the congenital uropathy group showed better graft and patient survival than the congenital pediatric kidney disease group. However, aged matched comparison revealed comparable survival rates in the 2 groups. Conclusions: Analysis of trends in the last 14 years demonstrated that patients with both lower and upper tract congenital anomalies experienced delayed time to the first renal transplant. Furthermore, patients had similar age matched graft and patient survival whether the primary source of renal demise was the congenital lower or upper tract. These findings may indicate that improved urological and nephrological care are promoting renal preservation in both groups.
Abbreviations and Acronyms CKD ¼ chronic kidney disease CPKD ¼ congenital pediatric kidney disease CU ¼ congenital uropathy DD ¼ deceased donor transplant ESRD ¼ end stage renal disease LD ¼ living donor transplant RT ¼ renal transplant Accepted for publication October 1, 2015. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. * Correspondence: Center for Genitourinary Reconstruction, Glickman Urologic Institute, Cleveland Clinic, 9500 Euclid Ave./Q10-1, Cleveland, Ohio 44195 (telephone: 216-4034282; e-mail: [email protected]).
Key Words: kidney transplantation, congenital, kidney diseases, graft survival, mortality
0022-5347/16/1954-1257/0 THE JOURNAL OF UROLOGY® Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2015.10.004 Vol. 195, 1257-1262, April 2016 Printed in U.S.A.
www.jurology.com
j
1257
1258
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
KIDNEY transplantation remains the gold standard treatment for children with ESRD, providing a known survival advantage over hemodialysis.1 Congenital causes such as anomalies of the upper and lower urinary tract, and hereditary nephropathies are disproportionately responsible for the development of CKD in children. In the United States approximately 60% of pediatric CKD is attributable to such congenital disorders.2 Progression of CKD in these patients is variable and depends on several factors, including severity of underlying disease, early recognition of the problem, proper selection of management strategies and various socioeconomic factors.2 In the United States the modern era has been marked by improved understanding of congenital disease states leading to CKD as well as advancements in prenatal screening, and more aggressive bladder and nephrological management strategies with improved access to care. We postulated that such advancements in the treatment of patients with congenital urinary tract disorders may slow progression to ESRD and secondarily delay time to the first RT in these patients. Furthermore, such advances could also translate to improved RT graft and patient survival. To investigate this hypothesis the primary objectives of this study were to determine whether patients with CU and CPKD have demonstrated later time to the first transplant and/or graft survival.
MATERIALS AND METHODS Data Source SRTR is a national database of transplant statistics collected by OPTN (Organ Procurement and Transplantation Network), a collection of hospitals and organ procurement organizations across the United States. Since 1987, SRTR has maintained comprehensive information on all solid organ transplants in the country with current and past information on the full spectrum of transplant activity. Data include information on organ donors, candidates and recipients as well as organ specific and patient outcomes.3
Variables SRTR was queried to identify the first RT, and graft and patient survival data in patients with CU and CPKD between 1996 and 2012. The study was limited to the period after 1996 due to some incomplete data in SRTR prior to this year. CU included diagnostic codes 3007 (chronic pyelonephritis/reflux), 3036 (prune belly) and 3052 (congenital obstructive uropathy). CPKD included codes 3008 (polycystic kidney disease), 3025 (hypoplasia, dysplasia, dysgenesis, agenesis) and 3032 (familial nephropathy). In addition to time of transplantation, characteristics of donors and recipients were extracted from identified cases, including age, gender, race, body mass index and comorbidity data. Furthermore, recipient transplant and kidney function data were collected.
Statistical Analyses Descriptive statistics were used to examine the distribution of clinical characteristics of and between the CU and CPKD groups. Univariate analysis and its associated p values were used to evaluate differences in the unadjusted prevalence of the mentioned characteristics. SASÒ Proc freq and gplot procedures were applied to calculate the percent of frequencies, which are simple proportions of number per age group over the total transplant number per year. Scatterplots were constructed, and simple regression models and associated p values were used to evaluate differences in each age group. Also, to support the results regression models focused on age and diagnosis groups, and the first RT year. Test results revealed that in general all were statistically significantly associated with recipient age at first RT (p <0.0001). The younger age group (18 to 35 years) in the CU group and the middle age group (35 to 49 years) in the CPKD group substantial decreased with time and were strongly associated with patient age at the first RT. Graft and patient survival were evaluated using the Kaplan-Meier method. Analyses were performed with SAS 9.2 for UNIX. The Cleveland Clinic institutional review board gave this study exempt status.
RESULTS Study Population A total of 7,088 patients with CU and 24,315 with CPKD received a first RT between 1996 and 2012. Of patients with CU the preoperative diagnosis was chronic pyelonephritis/reflux in 3,768, prune belly syndrome in 380 and congenital obstructive uropathy in 2,940. Of patients with CPKD the preoperative diagnosis was polycystic kidney disease in
A
B
Figure 1. Age at first RT as percent of all RTs with time in patients with CU (A) and CPKD (B).
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
21,657, kidney hypoplasia, dysplasia, dysgenesis or agenesis in 2,259 and familial nephropathy in 399. When considering the entire population, there were decreasing DDs and increasing LDs with time. In 1996 at the start of the study period 64.7% of patients received a DD while 35.3% received a LD. By the end of the study period in 2012 there were 56.5% DDs compared to 43.5% LDs. This trend was significant during the study (p <0.0001). The same significant trend was seen when considering only adults (age 18 years or greater) with a DD in 69.3% and a LD in 30.7% in 1996 compared to 56.1% and 43.9%, respectively, in 2012 (p <0.0001). When considering pediatric cases only, the trend was reversed with a DD in 38% and a LD in 62% in 1996 compared to 59.6% and 40.4%, respectively, in 2012 (p <0.0001). Supplementary tables 1 and 2 (http://jurology. com/) list RT donor and recipient variables among all patients in the CU and CPKD groups. On age matched comparison the 2 groups had mostly similar cognitive ability, body mass index, hypertension and diabetes rates. Age at First RT Figure 1 shows age at first RT in the CU and CPKD groups during the study period. However, analysis
1259
of individual age groups revealed several significant trends (figs. 2 and 3). Figure 2 shows the proportion of patients with CU who received the first RT in the age groups between 18 and 65 years or greater. Figure 3 shows similar information on patients with CPKD. Renal Transplantation Candidacy. Analysis was also performed of patient candidacy for renal transplantation by age group with time. Results mirrored that of age at time of the first RT. There was no significant change in average age at the time of transplant candidacy in the CU and CPKD groups. Graft and Patient Survival. Figure 4 shows graft and
patient survival after the initial RT with time. When considering graft survival at 5 years, both groups demonstrated approximately 90% survival. However, at 10-year followup patients with CU had better graft survival than those with CPKD (80.7% vs 75.9%, p <0.001). When considering patient survival after renal transplantation, the CU and CPKD groups again showed similar survival at 5 years (93.2% vs 95%, p >0.05). Correspondingly at 10 years patients with CU demonstrated significantly better survival than those with CPKD
A
B
C
D
Figure 2. Percent of patients with CU who received first RT with time between ages 18 to 34 (A), 35 to 49 (B), 50 to 64 (C ) and 65 years or older (D).
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
1260
A
B
C
D
Figure 3. Percent of patients with CPKD who received first RT with time between ages 18 to 34 (A), 35 to 49 (B), 50 to 64 (C ) and 65 years or older (D).
(82.3% vs 77%, p <0.001). However, when comparing patients with CU and CPKD in age groups, graft and patient survival differences were not significant. This finding suggests an effect of age rather than of etiology.
DISCUSSION This study shows that patients with congenital uropathies and nephropathies trended toward later age at the first transplant during the 14-year period that we examined in the SRTR database. Furthermore, after age matching patients with CU and CPKD we found equivalent 10-year graft and patient survival in the 2 groups. These findings may be explained by 1 or more changes during the study period, including 1) improved donor and recipient selection,1 2) improved prenatal screening and care,4 3) improved posttransplantation medical care and surveillance,1 and 4) improved and early intervention and care for afflicted patients prior to transplantation. There are multiple strategies to care for patients with CU and CPKD before renal replacement therapy. The improved use of such measures could be
preserving compromised renal units prior to the development of ESRD and postponing the need for transplantation. Among patients with CPKD treatment strategies include appropriate hypertension management, hormone supplementation, protein replacement, nutritional supplementation and when appropriate, medical therapies such as steroid or immunosuppressive agents.4e7 Care for patients with CU, such as those with posterior urethral valves, prune belly syndrome, myelomeningocele, obstructive megaureters and significant vesicoureteral reflux, include appropriate use of anticholinergics, intermittent catheterization, antibiotics and appropriate surgical intervention. Particularly among adolescent and young adult recipients behavioral strategies for compliance before and after transplantation may also have great impact.8e11 Older age at renal transplantation can be a favorable outcome by delaying major surgery in patients. Furthermore, preserving native function can help avoid some of the metabolic, biochemical and fluid balance problems faced by transplant recipients. In addition, significant psychosocial issues are associated with transplantation and related hospitalizations, which would preferably be
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
A
B
Figure 4. Graft (A) and patient (B) survival after renal transplantation by group with time.
delayed. This is particularly true in the adolescent population.12 Also, older adolescents who undergo kidney transplantation are known to be at higher risk for graft loss than other age groups. This is potentially due to noncompliance during a high risk age window seen during the transition from this age to adulthood.13e15 Delaying transplantation in these patients has the advantage of allowing patient psychological maturation and could translate into improvements in self-care and graft survival. Interestingly we did not note any data to suggest significant shifts in transplantation age among those younger than 18 years. This may suggest that some of the most severely affected patients in both groups will progress to renal transplantation regardless of prenatal and postnatal medical therapies. It also may represent strict adherence to the concept of early or even preemptive transplantation in children with progressive kidney failure, which is a strategy known to confer a survival advantage.16 We found that the proportion of patients who received a deceased donor graft significantly decreased during the study period in favor of LDs. This was true in the entire population as well as in
1261
adults only considered as a subgroup. However, when considering only pediatric patients, the trend was reversed with significantly increasing DDs with time compared to LDs. This finding of increasing DDs compared to LDs among pediatric recipients was noted in prior analyses.17,18 It has been speculated that such findings may be the result of changes in deceased donor graft allocation policies since 2005. That is when policies were restructured to favor the allocation of deceased donor grafts to pediatric over adult candidates and to reduce associated waiting periods for these recipients. Furthermore, groups have also suggested that certain pediatric cohorts may actually achieve longer cumulative graft survival by preferentially choosing deceased donor grafts at a younger age and saving a LD for later in life.17e19 We also investigated patient and graft survival rates after the first RT. In an effort to investigate the efficacy of current bladder management strategies to maintain such safe bladders in patients with CU we compared survival data on patients with CU and CKPD after renal transplantation. The latter could then serve as a control group when investigating this issue. At 10-year followup we found small but statistically significant graft and patient survival advantage in patients with CU compared to patients with CKPD after the first RT, although there was no difference in survival between the 2 groups on age matched comparison. Ten-year graft survival rates exceeded those reported in the general population in the SRTR database in patients after receiving DDs and LDs. Current survival rates are reported to be in the 45% to 63% and 63% to 79% range for overall graft and patient survival, respectively.20 This is particularly interesting in the context of patients with CU who often have a decompensated lower urinary tract, which can leave transplanted renal units vulnerable to damage due to poor compliance, reflux and high pressure storage when not managed appropriately.16,21 We postulate that this may be due to patients in this study having been subjected to a lifetime of medical care and intervention, perhaps leading to improved medical surveillance, lifestyle choices and treatment compliance after transplantation compared with patients undergoing transplantation for other causes of ESRD. Further investigation of what these populations are doing or not doing to lead to a graft survival advantage may point to opportunities for all transplant recipients. While appropriate investigation of the bladder/ urinary reservoir and patient compliance is advocated in all patients with CU undergoing transplant evaluation, there exists a paucity of literature and/ or clinical guidelines on this topic. The development and promulgation of evaluation and treatment
1262
RENAL TRANSPLANTATION AND CONGENITAL URINARY TRACT DISORDERS
algorithms for patients with CU undergoing pretransplant optimization may further improve outcomes. Our study has several limitations. We were restricted to data available in the SRTR data set. We had limited information on the etiology of renal failure. We recognize that this database may not accurately characterize the primary etiology of renal demise, particularly if the cause is multifactorial. In addition, congenital uropathy is a broadly defined category that could represent several more specific etiologies, such as posterior urethral valves, congenital neuropathic bladders or other etiologies. When considering allograft survival, the data are impacted by several variables such as chronic rejection, compliance with medications, and other recipient and donor characteristics that were not obtainable, which could have affected outcomes. Also, although SRTR is a reliable data set, there is no way to confirm the consistency of data capture with time, including the fact that changes were made to data collection criteria through time, which may alter the completeness of data collection and the categorization of each patient. However, it is important to note that this data set is maintained by
UNOS (United Organ Sharing Program) and, thus, is the most reliable set that we have with which to work. Furthermore, we were unable to consider changes in kidney transplant allocation and distribution policies during the study interval, which most definitely have changed with time as UNOS organ sharing policies and medical advancements in living renal donation have changed.
CONCLUSIONS Patients with CKD due to congenital urinary tract disorders are at high risk for requiring a RT. Analyses of trends during the last 14 years demonstrate that adults with congenital upper and lower urinary tract anomalies are undergoing renal transplantation at an older age. This may be due to improved recognition and management of these disorders, the promotion of native renal function preservation and the concomitant delay in the need for transplantation. Furthermore, patients in both groups demonstrated excellent and comparable 10-year graft and overall survival regardless of whether the primary source of renal demise was the congenital upper or lower tract.
REFERENCES 1. Dharnidharka VR, Fiorina P and Harmon WE: Kidney transplantation in children. N Engl J Med 2014; 371: 549. 2. Harambat J, van Stralen KJ, Kim JJ et al: Epidemiology of chronic kidney disease in children. Pediatr Nephrol 2011; 27: 363. 3. Leppke S, Leighton T, Zaun D et al: Scientific Registry of Transplant Recipients: collecting, analyzing, and reporting data on transplantation in the United States. Transplant Rev (Orlando) 2013; 27: 50. 4. Kuwertz-Broeking E, Brinkmann OA, Lengerke Von HJ et al: Unilateral multicystic dysplastic kidney: experience in children. BJU Int 2004; 93: 388. 5. Mansoor O, Chandar J, Rodriguez MM et al: Long-term risk of chronic kidney disease in unilateral multicystic dysplastic kidney. Pediatr Nephrol 2011; 26: 597. 6. Sweeney WE Jr and Avner ED: Diagnosis and management of childhood polycystic kidney disease. Pediatr Nephrol 2011; 26: 675. 7. Jalanko H: Congenital nephrotic syndrome. Pediatr Nephrol 2009; 24: 2121. 8. Lopez Pereira P, Martinez Urrutia MJ, Espinosa L et al: Long-term consequences of posterior urethral valves. J Pediatr Urol 2013; 9: 590.
9. Seidel NE, Arlen AM, Smith EA et al: Clinical manifestations and management of prune-belly syndrome in a large contemporary pediatric population. Urology 2015; 85: 211. 10. Farrugia M-K, Hitchcock R, Radford A et al: British Association of Paediatric Urologists consensus statement on the management of the primary obstructive megaureter. J Pediatr Urol 2014; 10: 26. 11. Tullus K: Vesicoureteric reflux in children. Lancet 2015; 385: 371. 12. Anthony SJ, Hebert D, Todd L et al: Child and parental perspectives of multidimensional quality of life outcomes after kidney transplantation. Pediatr Transplant 2009; 14: 249. 13. Andreoni KA, Forbes R, Andreoni RM et al: Agerelated kidney transplant outcomes: health disparities amplified in adolescence. JAMA Intern Med 2013; 173: 1524. 14. Van Arendonk KJ, King EA, Orandi BJ et al: Loss of pediatric kidney grafts during the “high-risk age window”: insights from pediatric liver and simultaneous liver-kidney recipients. Am J Transplant 2015; 15: 445. 15. Bobanga ID, Vogt BA, Woodside KJ et al: Outcome differences between young children
and adolescents undergoing kidney transplantation. J Pediatr Surg 2015; 50: 996. 16. Ishitani M, Isaacs R, Norwood V et al: Predictors of graft survival in pediatric living-related kidney transplant recipients. Transplantation 2000; 70: 288. 17. Van Arendonk KJ, Boyarsky BJ, Orandi BJ et al: National trends over 25 years in pediatric kidney transplant outcomes. Pediatrics 2014; 133: 594. 18. Magee JC, Krishnan SM, Benfield MR et al: Pediatric transplantation in the United States, 1997-2006. Am J Transplant 2008; 8: 935. 19. Van Arendonk KJ, Chow EK, James NT et al: Choosing the order of deceased donor and living donor kidney transplantation in pediatric recipients: a Markov decision process model. Transplantation 2015; 99: 360. 20. Scientific Registry of Transplant Recipients, Health Resources and Services Administration: 2012 Annual Data Report. Available at http:// srtr.transplant.hrsa.gov/annual_reports/2012/ Default.aspx. Accessed October 1, 2015. 21. Aki FT, Aydin AM, Dogan HS et al: Does lower urinary tract status affect renal transplantation outcomes in children? Transplant Proc 2015; 47: 1114.