Pediatr Transplantation 2014: 18: 150–154
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12207
Ureteral complications after renal transplant in children: Timing of presentation, and their open and endoscopic management Castagnetti M, Angelini L, Ghirardo G, Zucchetta P, Gamba PG, Zanon GF, Murer L, Rigamonti W. Ureteral complications after renal transplant in children: Timing of presentation, and their open and endoscopic management.
Marco Castagnetti1, Lorenzo Angelini1, Giulia Ghirardo2, Pietro Zucchetta3, PierGiorgio Gamba4, GiovanniFranco Zanon4, Luisa Murer2 and Waifro Rigamonti1
Abstract: We retrospectively reviewed the records of 24 consecutive patients undergoing treatment for ureteral complications after RTx in the period 2001–2012 to determine the timing of presentation of the complications, and their open or endoscopic management. Three patients (12%) had a necrosis of the transplanted ureter soon after RTx. All required open urinary diversion in a native ureter. Ten cases (42%) developed ureteral obstruction. Time of presentation was variable mainly in relation to the underlying cause. Endoscopic treatment was successful in two cases with urinary stones and open surgery in two with mid-ureteral obstruction. Six patients had VUJ stenosis, three underwent open reimplantation, whereas temporary double-J stent placement was successfully performed in the remainder. Eleven patients (46%) had VUR. It seldom presented in the first year after RTx. Endoscopic treatment was attempted in all and was successful in all the six cases without vs. only one of the five with lower urinary tract pathology (p = 0.01). Endoscopic treatment is an option in patients with VUR in the absence of lower urinary tract pathology. It is an option also for the treatment of stones and can be attempted in case of VUJ stenosis. Ureteral necrosis always requires open treatment.
1
Urology Unit, Section of Paediatric Urology, Department of Oncological and Surgical Sciences, University Hospital of Padova, Padua, Italy, 2 Paediatric Nephrology Unit, Department of Paediatrics, University Hospital of Padova, Padua, Italy, 3Nuclear Medicine, University Hospital of Padova, Padua, Italy, 4Paediatric Surgery Unit, University Hospital of Padova, Padua, Italy Key words: bladder function – kidney – renal transplantation – anuria – LUTS – nocturia – children – pediatrics Marco Castagnetti, MD, Section of Paediatric Urology, Urology Unit, University Hospital of Padova, Monoblocco Ospedaliero, Via Giustiniani, 2, 35128 – Padua – Italy Tel.: 0039 049 8212737 Fax: 0039 049 8212721 E-mail: [email protected] Accepted for publication 15 November 2013
Ureteral complications can occur in up to onefourth of cases after RTx in children; they may harm graft function and even lead to graft loss or patient death, if not promptly treated (1–3). Reportedly, major ureteral complications after RTx include VUR complicated by UTI that occur in 10–12% of cases, ureteral obstruction that occurs in 5–8% of cases, ureteral necrosis that occurs in 1–8% of cases, and anastomotic leakage that occurs in 0–2% of cases (1–3). Many studies have focused on the prevalence of such complications and the possible risk factors for them (2–4), whereas little is known about their timing of presentation and management.
Abbreviations: ESRD, end-stage renal disease; RTx, renal transplant; UPJ, ureteropelvic junction; UTI, urinary tract infections; VUJ, vesico-ureteral junction; VUR, vesicoureteral reflux
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Regarding the latter, in particular, reports about the role of endoscopic management are occasional (4–6). This is instead of interest, taking into consideration that the development of miniaturized instruments has made increasingly common and popular in the pediatric population the use of endourological and endoscopic procedures for the management of benign ureteral conditions such as VUR, primary non-refluxing megaureter, urinary stones, and ureteral traumas (7–11). In the present report, we aimed to determine the timing of appearance of ureteral complications after RTx, and the role of open or endoscopic treatments in their management. Materials and methods Between January 2002 and June 2012, we performed 196 pediatric RTx (131 males). Overall follow-up in these patients was 6.4 (1–11.5) yr. In accordance with the Hel-
Ureteral complications after renal transplant sinki Declaration of 1975, we retrospectively reviewed the case notes of 24 (12%) consecutive patients (20 males) undergoing additional treatment at our institution for ureteral complications after RTx in the same period. Cause of ESRD in the study cases included nephrologic conditions (n = 15), prune belly syndrome (n = 3), posterior urethral valves (n = 4), and neurogenic bladder (n = 2). All the patients had undergone deceased donor RTx at a median (range) age of 8.3 (1.8–17.9) yr. Median (range) follow-up after the last surgery was 5.2 (1–11.5) yr. Our standard approach during transplant was to perform an extravesical reimplantation of the ureter of the transplanted kidney to the bladder of the recipient. No stent was left in anuric patients, whereas an external trans-anastomotic drainage was left for eight days in all the cases with preserved diuresis for monitoring the urine output of the transplanted kidney. After transplant, our policy was to avoid any additional urological investigations other than renal ultrasound in asymptomatic patients with stable renal function and no upper tract dilatation. Technetium-99 m-mercaptoacetylglycine scintigraphy was always performed in the suspicion of obstruction, whereas a combination of voiding cystourethtography and acute or chronic technetium99 m-dimercaptosuccinic acid scintigraphy was used in patients developing UTI. If lower urinary tract dysfunction was suspected, also a full urodynamic evaluation was obtained. Bladder and bowel function were always optimized with behavioral and medical interventions before embarking on any surgical treatments. For the cases included in the present study, we recorded type of complication, mode of presentation, timing of presentation, kind of treatment, and final outcome (including graft loss rate and graft function defined as estimated glomerular filtration rate (12)). Timing of presentation was defined as the time elapsed between RTx and the first treatment of the complication. Complications were categorized as VUR in the transplanted ureter, obstruction of the transplanted ureter, necrosis of the transplanted ureter, and leakage of the ureterovesical anastomosis. According to the previous studies, patients were differentiated into those with upper and those with lower tract pathologies. The former included all the ESRD cases due to a renal disease, whereas the latter, all the ESRD cases due to urological conditions causing lower urinary tract dysfunction. To determine the influence of the complication of graft survival and function, graft loss rate and graft function in the study cases were compared to those in patients undergoing RTx during the study period.
Data were expressed as ratios, or as median and range. Nonparametric tests were used throughout including the Fisher’s exact test for comparison of categorical variables and the Mann–Whitney U-test for continuous ones. A p < 0.05 was considered significant.
Results
Ureteral complications requiring treatment included VUR in the transplanted kidney in 11 cases (46%), ureteral obstruction in 10 (42%), and ureteral necrosis in three (12%). No case required treatment because of anastomotic leakage in this series. The causes of ESRD according to the complications are listed in Table 1. Table 1 also lists the mode and timing of presentation of the different complications. Concerning ureteral obstruction, the underlying cause was a VUJ stenosis in six, urinary stone in two, and a stenosis along the ureter proximal to the VUJ in the remaining two cases. Stone formation was due to concretion around a retained stitch of the uretero-vesical anastomosis in one patient, whereas to an encrustation at the UPJ secondary to Corynebacterium infection in the other. Mid-ureteral obstruction was secondary to cytomegalovirus ureteritis in one case, whereas it had a purely ischemic origin without any sign of chronic rejection or infection in the other. Obstructions due to VUJ stenoses tended to present earlier than those due to mid-ureteral stenoses and stone formation, 65 (20–260) vs. 253 (127–366) days after RTx, p = 0.04. Of the patients with VUR, six (three females) had upper tract, whereas five (all males) lower tract pathology. The latter presented significantly earlier than the former, median (range) 1.2 (0.3–6.9) yr vs. 7.2 (1.9–15.8) yr, p = 0.01. In patients with symptomatic VUR, endoscopic injection of a bulking agent was attempted as primary treatment in all. RTx ureteral orifice location required a dye test with i.v. injection of a vital dye in seven cases, but the orifice could be visualized and accessed
Table 1. Ureteral complications after RTx
Complication
No. of cases
Ureteral necrosis Ureteral obstruction
3 10
VUR complicated by UTI
11
Cause of ESRD (n)
Presentation (n)
Upper tract pathology (3) Upper tract pathology (6) Lower tract pathology (4): Neurogenic bladder (2) Posterior urethral valves (2) Upper tract pathology (6) Lower tract pathology (5): Prune belly syndrome (3) Posterior urethral valves (2)
Persistent urinary leakage from drain (3) Worsening upper tract dilatation, stable renal function (2) Worsening upper tract dilatation and increasing serum creatinine (4) Worsening renal function without upper tract dilatation (4) Febrile UTI with stable renal function (2) Febrile UTI and increasing serum creatinine (5) Atypical signs but increasing serum creatinine (4)
Timing after RTx Median (range) 14 (8–22) days 6.3 (0.1–33) months
44 (13–104) months
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using a standard pediatric cystoscope in all. Injection sites were selected according to the anatomy of each case. Injection of a median of 1.3 (0.6–2) mL of dextranomer/hyaluronic acid copolymer (Deflux, Oceana Therapeutics Ltd, Dublin, Ireland) was required to achieve visual coaptation of the orifice. No complication or rise in serum creatinine was associated with the endoscopic procedure. After a median followup of 62 (26–104) months from endoscopic treatment, seven (63%) cases were clinically well without evidence of recurrent UTI. These included all of the six cases (three females) with upper tract pathology vs. only one of the five (all males) with lower tract pathology, p = 0.01. Of the four patients in whom endoscopic treatment failed (persistent VUR with recurrent UTI), three are currently on long-term antibiotic prophylaxis and one underwent open ureteral reimplantation eventually. Both cases with urinary stones were successfully treated endoscopically. The patient with a VUJ stone underwent cystoscopic removal of the stone and double-J stent insertion for one month. The patients with the UPJ stone underwent percutaneous removal of the stone followed by temporary local instillation of antibiotics via a nephrostomy tube. In the patients with VUJ stenosis, immediate open ureteral reimplantation was performed successfully in one case with a history of delayed and progressive obstruction. In two further cases, the VUJ could not be negotiated endoscopically; therefore, temporary diversion was obtained via a nephrostomy tube and open reimplantation was performed eventually. The remaining three patients (two with lower tract pathology) underwent double-J stent placement for four months. None required further treatment for the VUJ stenosis. Both patients with mid-ureteral obstruction underwent initial diversion via a nephrostomy tube. Final reconstruction included reimplantation of a ureteral segment proximal to the stenosis and urinary diversion in a native ureter, one each. After a median follow-up of 61 (12–138) months from treatment for the ureteral complication, all of these patients were free from further ureteral complications. All patients with ureteral necrosis underwent initial urinary diversion via a nephrostomy tube (n = 2) or a ureteral single-J stent (n = 1). Final treatment involved diversion in a native ureter by pyelo-ureteral anastomosis (n = 1) or ureteral substitution with a native ureter after nephrectomy of the native kidney (n = 2). After a median follow-up of 91 (44– 98) months from urinary tract reconstruction, 152
all these patients were free from further urological complications. Overall, during follow-up, one graft was lost (three and a half yr after last surgery) and median (range) clearance in the remaining at final follow-up was 94 (46–110) mL/min/1.73 mq. These findings were not statistically different (p > 0.05) from those in the overall population of the patients undergoing renal Tx where 21 grafts were lost (a median time of 0.9 yr after RTx, range 0.1–9.5 yr) and median (range) clearance at last follow-up in the remaining was 96 (42–129) mL/min/1.73 mq. Discussion
Ureteral complications can determine severe sequelae in transplanted kidneys. Therefore, prompt diagnosis and proactive treatment are mandatory to preserve graft function. Nevertheless, diagnosis of ureteral complications after RTx can sometime be puzzling (13). As others, we noted that UTI may be atypical due to the depressed immune response and significant obstruction can occur in the absence of upper tract dilatation. Additional confounding factors include that issues with immunosuppression can make a rise in serum creatinine difficult to interpret and the creatinine can rise also in the presence of extra-renal infections or infections in the native kidneys. The latter are non-functioning and therefore cannot be assessed on a renal nuclear scan. In terms of prevalence, 90% of ureteral complications requiring treatment in our patients were evenly divided between VUR and ureteral obstruction, ureteral necrosis counted for the remaining complications, whereas we did not observe any case of dehiscence of the vesico-ureteral anastomosis. Overall, these figures seem consistent with previous series (2, 3), but for VUR, which reported prevalence is extremely variable ranging from 7% to 100% (14). Variations can depend on the type of ureteral anastomosis performed at the time of RTx, refluxing vs. non-refluxing, and the criteria used for patient selection, as patients with lower urinary tract dysfunction or investigated after a UTI have a much higher prevalence of VUR. Still, one series reported a 60% VUR rate also in asymptomatic patients undergoing antireflux reimplantation (14). Complications were more common in males (20 of 24 cases), and this might be related to the higher prevalence of associate bladder dysfunction in this gender (2–4). In fact, 15 of our 24 cases had upper tract pathology as cause of their ESRD
Ureteral complications after renal transplant
and had no evidence of lower urinary tract dysfunction. In terms of timing of presentation, as expected, ureteral necrosis always occurred within the first three wk after RTx. At the opposite, VUR cases generally required treatment years after RTx. In keeping with Krishnan et al. (15), VUR tended to present significantly earlier in patients with concomitant lower urinary tract pathology than in those without. Timing of presentation of ureteral obstruction was in between the previous two. This is slightly in contrast to the series by Routh et al. (3) where all ureteral obstructions but one presented within 30 days of RTx. Moreover, we identified two main patterns of presentation according to the level and cause of the obstruction. VUJ stenoses usually require treatment quite early (within months of RTx), whereas obstructions occurring along the ureter and those due to stone formation tended to present later on. The fact that stones might require time to develop is intuitive, and our experience confirms that retained sutures are an important risk factor (16). The different timing between the other two conditions might instead reflect a different underlying mechanism. VUJ stenoses are generally due to ischemia of the terminal ureter, whereas mid-ureteral ones are due to infective ureteritis or chronic rejection (4, 17). Of note, also one of our two stones was infective in origin. Irtan et al. (2) previously reported a similar case of Corynebacterium encrustative pyelitis. In terms of treatment, urinary tract diversion was always attempted in our cases of ureteral necrosis, but it never allowed for spontaneous healing of the urinary tract. We still believe, however, that external diversion remains an essential step in the suspicion of ureteral necrosis to determine the level of the necrosis and to temporize final reconstruction while waiting for demarcation of the necrotic urinary tract segment to occur. In all the cases, definitive treatment involved urinary diversion into a native ureter, which emphasizes the need to avoid any ureterectomy even in patients requiring nephrectomy before RTx (2). In case of ureteral obstruction, results of endoscopic treatment were variable. Endoscopic or endourological procedures proved effective in cases with stones. Although both these procedures were uneventful in our patients and the superficial location of transplanted kidneys makes a percutaneous approach appealing, it should be underscored that such procedures require caution in RTx patients. Ureters of transplanted kidneys can be poorly compliant for retrograde instrumentation, and appreciation of the
graft vasculature is essential before creating a percutaneous approach. Endoscopic stenting proved effective also in the three patients with VUJ stenosis in whom it was attempted. Smith et al. (4) previously reported cases of ureteral stenosis treated by ureteral stenting and dilatation. Their approach was more aggressive than ours, 35% of their cases underwent three or more stentings, and 25%, three or more ureteral dilatations. It is noteworthy, however, that one of their cases experienced graft loss after nine stentings and cases undergoing ureteral reimplantation exhibited a trend toward increased graft survival. In keeping with this experience, we believe that multiple attempts at stenting should be avoided, and ureteral reimplantation should be considered if a trail of stenting for 3–4 months fails. In keeping with Smith et al. (4), instead, our data support the principle that successful endoscopic treatment of ureteral obstruction can be achieved irrespective of the presence of lower urinary tract pathology. Endoscopic treatment of VUR in transplanted patients presents some technical challenges. The ureteral orifice is often in an abnormal position, and its identification may require a dye test and/ or an assistant applying suprapubic pressure to bring the bladder dome into view. The abnormal anatomy and the presence of scarring may also limit the ability to insert the needle in the correct position. Insertion of a urethral catheter within the ureter may help changing the orientation of the orifice during injection. We were initially concerned that the transplanted ureters, being more atonic and rigid than normal ones, could be more prone to develop obstruction after injection of a bulking agent. In keeping with others, however, we did not observe any complication related to the procedure (5, 6). The success rate of endoscopic treatment is lower than for primary VUR, around 60%. The presence of lower urinary tract dysfunction (more common in males) is an important risk factor for failure (5, 6). It is important to consider, however, that the adhesions from previous surgeries may make open treatment for VUR in RTx technically challenging as well, and also open reimplantation is not as successful as for the treatment of primary VUR. Krishnan et al. (15) reported that 30% of their RTx patients undergoing open ureteral reimplantation had persistent VUR after surgery and 35% had at least one postoperative complication, such as ureteral obstruction or recurrent pyelonephritis. Again lower urinary tract dysfunction proved to be an important risk factor for failure (15). Finally, it should be appreciated that the relation between VUR and UTI remains 153
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poorly understood, and some patients do not show recurrent infections despite the persistence of VUR after open or endoscopic surgery, whereas others develop recurrent infections despite VUR cure (14). This seems to us a further reason to pursue a minimally invasive management of VUR. Limitations to the present study include its retrospective nature and relatively small sample size. This is due to the fact that we included only patients requiring treatment for a ureteral complication after RTx, which represented about 12% of RTx we performed during the study period. Still, many procedures lack controls undergoing alternative treatments. Moreover, we did not rule out the presence of VUR or renal scars in patients without symptoms or alteration of renal function. This policy, however, is consistent with that at other pediatric transplant centers (2). To have a well-defined time point, we assessed the time elapsed between RTx and initial management of the complication, rather than the time between RTx and the presentation of the complication. Nevertheless, in RTx patients, treatment usually follows shortly the diagnosis of the complication. Conclusions
VUR and ureteral obstruction are the two most common complications after RTx. In our experience, ureteral necrosis was the earliest complication generally developing in the first weeks after RTx and ureteral obstruction followed usually developing within six months of surgery. Finally, VUR was seldom detected in the first year after RTx. Endoscopic treatment for VUR is an option in the absence of lower urinary tract dysfunction. In patients with ureteral obstruction, endoscopic treatment is definitely an option in patients with urinary stones, and a trial of stenting is also worth attempting in those with VUJ stenosis, if the junction can be negotiated. Ureteral necrosis always requires open surgery for urine diversion into a native ureter. Authors’ contributions Marco Castagnetti contributed to concept/design, data analysis/interpretation, and drafting of the article; Lorenzo Angelini and Giulia Ghirardo performed data collection and data analysis/interpretation and approved the article; Pietro Zucchetta, PierGiorgio Gamba, GiovanniFranco Zanon, Luisa Murer, and Waifro Rigamonti contributed to concept/design, critical revision of the article, and approval of the article.
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References 1. ZAONTZ MR, HATCH DA, FIRLIT CF. Urological complications in pediatric renal transplantation: Management and prevention. J Urol 1988: 140: 1123–1128. 2. IRTAN S, MAISIN A, BAUDOUIN V, et al. Renal transplantation in children: Critical analysis of age related surgical complications. Pediatr Transplant 2010: 14: 512–519. 3. ROUTH JC, YU RN, KOZINN SI, NGUYEN HT, BORER JG. Urological complications and vesicoureteral reflux following pediatric kidney transplantation. J Urol 2013: 189: 1071–1076. 4. SMITH KM, WINDSPERGER A, ALANEE S, HUMAR A, KASHTAN C, SHUKLA AR. Risk factors and treatment success for ureteral obstruction after pediatric renal transplantation. J Urol 2010: 183: 317–322. 5. WILLIAMS MA, GIEL DW, COLLEEN HASTINGS M. Endoscopic deflux injection for pediatric transplant reflux: A feasible alternative to open ureteral reimplant. J Pediatr Urol 2008: 4: 341–344. 6. VEMULAKONDA VM, KOYLE MA, LENDVAY TS, et al. Endoscopic treatment of symptomatic refluxing renal transplant ureteroneocystostomies in children. Pediatr Transplant 2010: 14: 212–215. 7. PURI P, KUTASY B, COLHOUN E, HUNZIKER M. Single center experience with endoscopic subureteral dextranomer/hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux. J Urol 2012: 188: 1485–1489. 8. CASTAGNETTI M, CIMADOR M, SERGIO M, DE GRAZIA E. Double-J stent insertion across vesicoureteral junction–is it a valuable initial approach in neonates and infants with severe primary nonrefluxing megaureter? Urology 2006: 68: 870– 875. 9. CHRISTMAN MS, KASTURI S, LAMBERT SM, KOVELL RC, CASALE P. Endoscopic management and the role of double stenting for primary obstructive megaureters. J Urol 2012: 187: 1018–1022. 10. SMALDONE MC, CORCORAN AT, DOCIMO SG, OST MC. Endourological management of pediatric stone disease: Present status. J Urol 2009: 181: 17–28. 11. RUSSELL RS, GOMELSKY A, MCMAHON DR, ANDREWS D, NASRALLAH PF. Management of grade IV renal injury in children. J Urol 2001: 166: 1049–1050. 12. SCHWARTZ GJ, WORK DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 2009: 4: 1832–1843. 13. COULTHARD MG, KEIR MJ. Reflux nephropathy in kidney transplants, demonstrated by dimercaptosuccinic acid scanning. Transplantation 2006: 82: 205–210. 14. RANCHIN B, CHAPUIS F, DAWHARA M, et al. Vesicoureteral reflux after kidney transplantation in children. Nephrol Dial Transplant 2000: 15: 1852–1858. 15. KRISHNAN A, SWANA H, MATHIAS R, BASKIN LS. Redo ureteroneocystostomy using an extravesical approach in pediatric renal transplant patients with reflux: A retrospective analysis and description of technique. J Urol 2006: 176: 1582–1587. 16. KHOSITSETH S, GILLINGHAM KJ, COOK ME, CHAVERS BM. Urolithiasis after kidney transplantation in pediatric recipients: A single center report. Transplantation 2004: 78: 1319–1323. 17. FUSARO F, MURER L, BUSOLO F, RIGAMONTI W, ZANON GF, ZACCHELLO G. CMV and BKV ureteritis: Which prognosis for the renal graft? J Nephrol 2003: 16: 591–594.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12207
Ureteral complications after renal transplant in children: Timing of presentation, and their open and endoscopic management Castagnetti M, Angelini L, Ghirardo G, Zucchetta P, Gamba PG, Zanon GF, Murer L, Rigamonti W. Ureteral complications after renal transplant in children: Timing of presentation, and their open and endoscopic management.
Marco Castagnetti1, Lorenzo Angelini1, Giulia Ghirardo2, Pietro Zucchetta3, PierGiorgio Gamba4, GiovanniFranco Zanon4, Luisa Murer2 and Waifro Rigamonti1
Abstract: We retrospectively reviewed the records of 24 consecutive patients undergoing treatment for ureteral complications after RTx in the period 2001–2012 to determine the timing of presentation of the complications, and their open or endoscopic management. Three patients (12%) had a necrosis of the transplanted ureter soon after RTx. All required open urinary diversion in a native ureter. Ten cases (42%) developed ureteral obstruction. Time of presentation was variable mainly in relation to the underlying cause. Endoscopic treatment was successful in two cases with urinary stones and open surgery in two with mid-ureteral obstruction. Six patients had VUJ stenosis, three underwent open reimplantation, whereas temporary double-J stent placement was successfully performed in the remainder. Eleven patients (46%) had VUR. It seldom presented in the first year after RTx. Endoscopic treatment was attempted in all and was successful in all the six cases without vs. only one of the five with lower urinary tract pathology (p = 0.01). Endoscopic treatment is an option in patients with VUR in the absence of lower urinary tract pathology. It is an option also for the treatment of stones and can be attempted in case of VUJ stenosis. Ureteral necrosis always requires open treatment.
1
Urology Unit, Section of Paediatric Urology, Department of Oncological and Surgical Sciences, University Hospital of Padova, Padua, Italy, 2 Paediatric Nephrology Unit, Department of Paediatrics, University Hospital of Padova, Padua, Italy, 3Nuclear Medicine, University Hospital of Padova, Padua, Italy, 4Paediatric Surgery Unit, University Hospital of Padova, Padua, Italy Key words: bladder function – kidney – renal transplantation – anuria – LUTS – nocturia – children – pediatrics Marco Castagnetti, MD, Section of Paediatric Urology, Urology Unit, University Hospital of Padova, Monoblocco Ospedaliero, Via Giustiniani, 2, 35128 – Padua – Italy Tel.: 0039 049 8212737 Fax: 0039 049 8212721 E-mail: [email protected] Accepted for publication 15 November 2013
Ureteral complications can occur in up to onefourth of cases after RTx in children; they may harm graft function and even lead to graft loss or patient death, if not promptly treated (1–3). Reportedly, major ureteral complications after RTx include VUR complicated by UTI that occur in 10–12% of cases, ureteral obstruction that occurs in 5–8% of cases, ureteral necrosis that occurs in 1–8% of cases, and anastomotic leakage that occurs in 0–2% of cases (1–3). Many studies have focused on the prevalence of such complications and the possible risk factors for them (2–4), whereas little is known about their timing of presentation and management.
Abbreviations: ESRD, end-stage renal disease; RTx, renal transplant; UPJ, ureteropelvic junction; UTI, urinary tract infections; VUJ, vesico-ureteral junction; VUR, vesicoureteral reflux
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Regarding the latter, in particular, reports about the role of endoscopic management are occasional (4–6). This is instead of interest, taking into consideration that the development of miniaturized instruments has made increasingly common and popular in the pediatric population the use of endourological and endoscopic procedures for the management of benign ureteral conditions such as VUR, primary non-refluxing megaureter, urinary stones, and ureteral traumas (7–11). In the present report, we aimed to determine the timing of appearance of ureteral complications after RTx, and the role of open or endoscopic treatments in their management. Materials and methods Between January 2002 and June 2012, we performed 196 pediatric RTx (131 males). Overall follow-up in these patients was 6.4 (1–11.5) yr. In accordance with the Hel-
Ureteral complications after renal transplant sinki Declaration of 1975, we retrospectively reviewed the case notes of 24 (12%) consecutive patients (20 males) undergoing additional treatment at our institution for ureteral complications after RTx in the same period. Cause of ESRD in the study cases included nephrologic conditions (n = 15), prune belly syndrome (n = 3), posterior urethral valves (n = 4), and neurogenic bladder (n = 2). All the patients had undergone deceased donor RTx at a median (range) age of 8.3 (1.8–17.9) yr. Median (range) follow-up after the last surgery was 5.2 (1–11.5) yr. Our standard approach during transplant was to perform an extravesical reimplantation of the ureter of the transplanted kidney to the bladder of the recipient. No stent was left in anuric patients, whereas an external trans-anastomotic drainage was left for eight days in all the cases with preserved diuresis for monitoring the urine output of the transplanted kidney. After transplant, our policy was to avoid any additional urological investigations other than renal ultrasound in asymptomatic patients with stable renal function and no upper tract dilatation. Technetium-99 m-mercaptoacetylglycine scintigraphy was always performed in the suspicion of obstruction, whereas a combination of voiding cystourethtography and acute or chronic technetium99 m-dimercaptosuccinic acid scintigraphy was used in patients developing UTI. If lower urinary tract dysfunction was suspected, also a full urodynamic evaluation was obtained. Bladder and bowel function were always optimized with behavioral and medical interventions before embarking on any surgical treatments. For the cases included in the present study, we recorded type of complication, mode of presentation, timing of presentation, kind of treatment, and final outcome (including graft loss rate and graft function defined as estimated glomerular filtration rate (12)). Timing of presentation was defined as the time elapsed between RTx and the first treatment of the complication. Complications were categorized as VUR in the transplanted ureter, obstruction of the transplanted ureter, necrosis of the transplanted ureter, and leakage of the ureterovesical anastomosis. According to the previous studies, patients were differentiated into those with upper and those with lower tract pathologies. The former included all the ESRD cases due to a renal disease, whereas the latter, all the ESRD cases due to urological conditions causing lower urinary tract dysfunction. To determine the influence of the complication of graft survival and function, graft loss rate and graft function in the study cases were compared to those in patients undergoing RTx during the study period.
Data were expressed as ratios, or as median and range. Nonparametric tests were used throughout including the Fisher’s exact test for comparison of categorical variables and the Mann–Whitney U-test for continuous ones. A p < 0.05 was considered significant.
Results
Ureteral complications requiring treatment included VUR in the transplanted kidney in 11 cases (46%), ureteral obstruction in 10 (42%), and ureteral necrosis in three (12%). No case required treatment because of anastomotic leakage in this series. The causes of ESRD according to the complications are listed in Table 1. Table 1 also lists the mode and timing of presentation of the different complications. Concerning ureteral obstruction, the underlying cause was a VUJ stenosis in six, urinary stone in two, and a stenosis along the ureter proximal to the VUJ in the remaining two cases. Stone formation was due to concretion around a retained stitch of the uretero-vesical anastomosis in one patient, whereas to an encrustation at the UPJ secondary to Corynebacterium infection in the other. Mid-ureteral obstruction was secondary to cytomegalovirus ureteritis in one case, whereas it had a purely ischemic origin without any sign of chronic rejection or infection in the other. Obstructions due to VUJ stenoses tended to present earlier than those due to mid-ureteral stenoses and stone formation, 65 (20–260) vs. 253 (127–366) days after RTx, p = 0.04. Of the patients with VUR, six (three females) had upper tract, whereas five (all males) lower tract pathology. The latter presented significantly earlier than the former, median (range) 1.2 (0.3–6.9) yr vs. 7.2 (1.9–15.8) yr, p = 0.01. In patients with symptomatic VUR, endoscopic injection of a bulking agent was attempted as primary treatment in all. RTx ureteral orifice location required a dye test with i.v. injection of a vital dye in seven cases, but the orifice could be visualized and accessed
Table 1. Ureteral complications after RTx
Complication
No. of cases
Ureteral necrosis Ureteral obstruction
3 10
VUR complicated by UTI
11
Cause of ESRD (n)
Presentation (n)
Upper tract pathology (3) Upper tract pathology (6) Lower tract pathology (4): Neurogenic bladder (2) Posterior urethral valves (2) Upper tract pathology (6) Lower tract pathology (5): Prune belly syndrome (3) Posterior urethral valves (2)
Persistent urinary leakage from drain (3) Worsening upper tract dilatation, stable renal function (2) Worsening upper tract dilatation and increasing serum creatinine (4) Worsening renal function without upper tract dilatation (4) Febrile UTI with stable renal function (2) Febrile UTI and increasing serum creatinine (5) Atypical signs but increasing serum creatinine (4)
Timing after RTx Median (range) 14 (8–22) days 6.3 (0.1–33) months
44 (13–104) months
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using a standard pediatric cystoscope in all. Injection sites were selected according to the anatomy of each case. Injection of a median of 1.3 (0.6–2) mL of dextranomer/hyaluronic acid copolymer (Deflux, Oceana Therapeutics Ltd, Dublin, Ireland) was required to achieve visual coaptation of the orifice. No complication or rise in serum creatinine was associated with the endoscopic procedure. After a median followup of 62 (26–104) months from endoscopic treatment, seven (63%) cases were clinically well without evidence of recurrent UTI. These included all of the six cases (three females) with upper tract pathology vs. only one of the five (all males) with lower tract pathology, p = 0.01. Of the four patients in whom endoscopic treatment failed (persistent VUR with recurrent UTI), three are currently on long-term antibiotic prophylaxis and one underwent open ureteral reimplantation eventually. Both cases with urinary stones were successfully treated endoscopically. The patient with a VUJ stone underwent cystoscopic removal of the stone and double-J stent insertion for one month. The patients with the UPJ stone underwent percutaneous removal of the stone followed by temporary local instillation of antibiotics via a nephrostomy tube. In the patients with VUJ stenosis, immediate open ureteral reimplantation was performed successfully in one case with a history of delayed and progressive obstruction. In two further cases, the VUJ could not be negotiated endoscopically; therefore, temporary diversion was obtained via a nephrostomy tube and open reimplantation was performed eventually. The remaining three patients (two with lower tract pathology) underwent double-J stent placement for four months. None required further treatment for the VUJ stenosis. Both patients with mid-ureteral obstruction underwent initial diversion via a nephrostomy tube. Final reconstruction included reimplantation of a ureteral segment proximal to the stenosis and urinary diversion in a native ureter, one each. After a median follow-up of 61 (12–138) months from treatment for the ureteral complication, all of these patients were free from further ureteral complications. All patients with ureteral necrosis underwent initial urinary diversion via a nephrostomy tube (n = 2) or a ureteral single-J stent (n = 1). Final treatment involved diversion in a native ureter by pyelo-ureteral anastomosis (n = 1) or ureteral substitution with a native ureter after nephrectomy of the native kidney (n = 2). After a median follow-up of 91 (44– 98) months from urinary tract reconstruction, 152
all these patients were free from further urological complications. Overall, during follow-up, one graft was lost (three and a half yr after last surgery) and median (range) clearance in the remaining at final follow-up was 94 (46–110) mL/min/1.73 mq. These findings were not statistically different (p > 0.05) from those in the overall population of the patients undergoing renal Tx where 21 grafts were lost (a median time of 0.9 yr after RTx, range 0.1–9.5 yr) and median (range) clearance at last follow-up in the remaining was 96 (42–129) mL/min/1.73 mq. Discussion
Ureteral complications can determine severe sequelae in transplanted kidneys. Therefore, prompt diagnosis and proactive treatment are mandatory to preserve graft function. Nevertheless, diagnosis of ureteral complications after RTx can sometime be puzzling (13). As others, we noted that UTI may be atypical due to the depressed immune response and significant obstruction can occur in the absence of upper tract dilatation. Additional confounding factors include that issues with immunosuppression can make a rise in serum creatinine difficult to interpret and the creatinine can rise also in the presence of extra-renal infections or infections in the native kidneys. The latter are non-functioning and therefore cannot be assessed on a renal nuclear scan. In terms of prevalence, 90% of ureteral complications requiring treatment in our patients were evenly divided between VUR and ureteral obstruction, ureteral necrosis counted for the remaining complications, whereas we did not observe any case of dehiscence of the vesico-ureteral anastomosis. Overall, these figures seem consistent with previous series (2, 3), but for VUR, which reported prevalence is extremely variable ranging from 7% to 100% (14). Variations can depend on the type of ureteral anastomosis performed at the time of RTx, refluxing vs. non-refluxing, and the criteria used for patient selection, as patients with lower urinary tract dysfunction or investigated after a UTI have a much higher prevalence of VUR. Still, one series reported a 60% VUR rate also in asymptomatic patients undergoing antireflux reimplantation (14). Complications were more common in males (20 of 24 cases), and this might be related to the higher prevalence of associate bladder dysfunction in this gender (2–4). In fact, 15 of our 24 cases had upper tract pathology as cause of their ESRD
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and had no evidence of lower urinary tract dysfunction. In terms of timing of presentation, as expected, ureteral necrosis always occurred within the first three wk after RTx. At the opposite, VUR cases generally required treatment years after RTx. In keeping with Krishnan et al. (15), VUR tended to present significantly earlier in patients with concomitant lower urinary tract pathology than in those without. Timing of presentation of ureteral obstruction was in between the previous two. This is slightly in contrast to the series by Routh et al. (3) where all ureteral obstructions but one presented within 30 days of RTx. Moreover, we identified two main patterns of presentation according to the level and cause of the obstruction. VUJ stenoses usually require treatment quite early (within months of RTx), whereas obstructions occurring along the ureter and those due to stone formation tended to present later on. The fact that stones might require time to develop is intuitive, and our experience confirms that retained sutures are an important risk factor (16). The different timing between the other two conditions might instead reflect a different underlying mechanism. VUJ stenoses are generally due to ischemia of the terminal ureter, whereas mid-ureteral ones are due to infective ureteritis or chronic rejection (4, 17). Of note, also one of our two stones was infective in origin. Irtan et al. (2) previously reported a similar case of Corynebacterium encrustative pyelitis. In terms of treatment, urinary tract diversion was always attempted in our cases of ureteral necrosis, but it never allowed for spontaneous healing of the urinary tract. We still believe, however, that external diversion remains an essential step in the suspicion of ureteral necrosis to determine the level of the necrosis and to temporize final reconstruction while waiting for demarcation of the necrotic urinary tract segment to occur. In all the cases, definitive treatment involved urinary diversion into a native ureter, which emphasizes the need to avoid any ureterectomy even in patients requiring nephrectomy before RTx (2). In case of ureteral obstruction, results of endoscopic treatment were variable. Endoscopic or endourological procedures proved effective in cases with stones. Although both these procedures were uneventful in our patients and the superficial location of transplanted kidneys makes a percutaneous approach appealing, it should be underscored that such procedures require caution in RTx patients. Ureters of transplanted kidneys can be poorly compliant for retrograde instrumentation, and appreciation of the
graft vasculature is essential before creating a percutaneous approach. Endoscopic stenting proved effective also in the three patients with VUJ stenosis in whom it was attempted. Smith et al. (4) previously reported cases of ureteral stenosis treated by ureteral stenting and dilatation. Their approach was more aggressive than ours, 35% of their cases underwent three or more stentings, and 25%, three or more ureteral dilatations. It is noteworthy, however, that one of their cases experienced graft loss after nine stentings and cases undergoing ureteral reimplantation exhibited a trend toward increased graft survival. In keeping with this experience, we believe that multiple attempts at stenting should be avoided, and ureteral reimplantation should be considered if a trail of stenting for 3–4 months fails. In keeping with Smith et al. (4), instead, our data support the principle that successful endoscopic treatment of ureteral obstruction can be achieved irrespective of the presence of lower urinary tract pathology. Endoscopic treatment of VUR in transplanted patients presents some technical challenges. The ureteral orifice is often in an abnormal position, and its identification may require a dye test and/ or an assistant applying suprapubic pressure to bring the bladder dome into view. The abnormal anatomy and the presence of scarring may also limit the ability to insert the needle in the correct position. Insertion of a urethral catheter within the ureter may help changing the orientation of the orifice during injection. We were initially concerned that the transplanted ureters, being more atonic and rigid than normal ones, could be more prone to develop obstruction after injection of a bulking agent. In keeping with others, however, we did not observe any complication related to the procedure (5, 6). The success rate of endoscopic treatment is lower than for primary VUR, around 60%. The presence of lower urinary tract dysfunction (more common in males) is an important risk factor for failure (5, 6). It is important to consider, however, that the adhesions from previous surgeries may make open treatment for VUR in RTx technically challenging as well, and also open reimplantation is not as successful as for the treatment of primary VUR. Krishnan et al. (15) reported that 30% of their RTx patients undergoing open ureteral reimplantation had persistent VUR after surgery and 35% had at least one postoperative complication, such as ureteral obstruction or recurrent pyelonephritis. Again lower urinary tract dysfunction proved to be an important risk factor for failure (15). Finally, it should be appreciated that the relation between VUR and UTI remains 153
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poorly understood, and some patients do not show recurrent infections despite the persistence of VUR after open or endoscopic surgery, whereas others develop recurrent infections despite VUR cure (14). This seems to us a further reason to pursue a minimally invasive management of VUR. Limitations to the present study include its retrospective nature and relatively small sample size. This is due to the fact that we included only patients requiring treatment for a ureteral complication after RTx, which represented about 12% of RTx we performed during the study period. Still, many procedures lack controls undergoing alternative treatments. Moreover, we did not rule out the presence of VUR or renal scars in patients without symptoms or alteration of renal function. This policy, however, is consistent with that at other pediatric transplant centers (2). To have a well-defined time point, we assessed the time elapsed between RTx and initial management of the complication, rather than the time between RTx and the presentation of the complication. Nevertheless, in RTx patients, treatment usually follows shortly the diagnosis of the complication. Conclusions
VUR and ureteral obstruction are the two most common complications after RTx. In our experience, ureteral necrosis was the earliest complication generally developing in the first weeks after RTx and ureteral obstruction followed usually developing within six months of surgery. Finally, VUR was seldom detected in the first year after RTx. Endoscopic treatment for VUR is an option in the absence of lower urinary tract dysfunction. In patients with ureteral obstruction, endoscopic treatment is definitely an option in patients with urinary stones, and a trial of stenting is also worth attempting in those with VUJ stenosis, if the junction can be negotiated. Ureteral necrosis always requires open surgery for urine diversion into a native ureter. Authors’ contributions Marco Castagnetti contributed to concept/design, data analysis/interpretation, and drafting of the article; Lorenzo Angelini and Giulia Ghirardo performed data collection and data analysis/interpretation and approved the article; Pietro Zucchetta, PierGiorgio Gamba, GiovanniFranco Zanon, Luisa Murer, and Waifro Rigamonti contributed to concept/design, critical revision of the article, and approval of the article.
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