Letters to the Editor
* 2014 Lippincott Williams & Wilkins
CDC 0, and indeterminate SAB. In January 2013, C4d+, and in February 2013, C4d+. Coronary angiogram was performed on August 2012 which revealed normal coronary arteries. Because of the concerns for noncompliance, belatacept was initiated in March 2013 for maintenance therapy in addition to her current immunosuppressive regimen of tacrolimus, sirolimus, mycophenolate mofetil, and prednisone. Belatacept was dosed at 750 mg (10 mg/kg) intravenously on days 0, 7, 14, 28, and for the subsequent 2 months, then 500 mg monthly thereafter. The patient received a total of eight doses of belatacept. Tacrolimus and sirolimus levels still fluctuated while on belatacept and at some points were below the lower limit of detection. Biopsies after starting belatacept remained grade 0, negative for cellular rejection and histologic features of antibody mediated rejection (macrophages, endothelial swelling), but C4d staining was not performed. Coronary angiogram performed on July 2013 revealed normal coronary arteries. Echocardiography report from October 2013 revealed left ventricular ejection fraction of 61%. The patient expired because of cardiac arrest in October 2013. Autopsy was not performed. Figure 1 depicts the timeline of the rejection episodes from transplant to patient death.
of avoiding nephrotoxicity. The renal function benefit and safety profile seen in the early posttransplant period continued through the 5-year period in the low and more intense regimens of belatacept compared to cyclosporine (3). Additionally, rate of infections and malignancies were similar between regimens (3). Despite the lack of evidence for belatacept use in heart transplant recipients, this report provides some evidence for its potential use in this population. The patient in this case had a history of noncompliance along with fluctuating and oftentimes undetectable tacrolimus and sirolimus levels even during concomitant belatacept use. Belatacept was able to maintain immunosuppression in this patient as evidenced by the lack of rejection episodes since belatacept initiation. Unlike traditional maintenance medications, belatacept requires intravenous administration at an infusion center, allowing providers to have some confidence the noncompliant patient receives an immunosuppressive medication regularly. However, long-term use and outcomes in larger heart transplant populations have yet to be determined. Cher Y. Enderby1 Phillip Habib2 Parag C. Patel2 Daniel S. Yip2 Stephanie Orum2 Jeffrey D. Hosenpud2
DISCUSSION In the kidney transplant population, belatacept has been used as an alternative maintenance medication to the calcineurin inhibitors with the goal
1
Department of Pharmacy Mayo Clinic Jacksonville, FL
2
e75
Department of Transplantation Mayo Clinic Jacksonville, FL
The authors declare no funding or conflicts of interest. Address correspondence to: Cher Y. Enderby, Pharm.D., BCPS, BCNSP, Department of Pharmacy, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: [email protected] Received 9 May 2014. Accepted 10 July 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9807-e74 DOI: 10.1097/TP.0000000000000404
REFERENCES 1.
2.
3.
4.
5.
Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belataceptbased immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535. Medina Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes of BENEFITEXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant 2012; 12: 630. Rostaing L, Vincenti F, Grinyo J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant 2013; 13: 2875. LaMattina JC, Jason MP, Hanish SI, et al. Safety of belatacept bridging immunosuppression in hepatitis c-positive liver transplant recipients with renal dysfunction. Transplantation 2014; 97: 133. Posselt AM, Szot GL, Frassetto LA, et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 2010; 90: 1595.
Successful Rescue of Transplant Ureteral Obstruction by Boari Flap bstructive uropathy, which might affect 2% to 7.5% of renal transplant patients, remains one of the most important causes of morbidity after renal transplantation (1). Although conservative treatment with ureteric stenting could effectively treat most of the patients with ureteral stricture, definite surgical intervention would be required for those with complete ureteral obstruction. Reviewing 997 renal transplant recipients in a single transplant center, we
O
identified five male patients, aged from 14 to 47 years, suffering from ureteral obstruction. Boari flap operations were successfully performed in all five cases to reestablish their urinary outflow. Among them, three had transplants from live donors and two from deceased donors. Two patients were actually having their second transplants and encountered with episodes of acute rejection before the ureteral complications. Of the five cases, one with live-donor transplantation developed massive urine leakage 10 days
after transplantation and was identified with complete ureteral necrosis during the rescue operation. Otherwise, the remaining four patients had ureteral stricture and eventually total obstruction, although the initial nephrostomy drainage and ureter stenting were successfully conducted (Fig. 1A). The ureteral obstruction happened within 1 year (1Y11 months) in four patients. However, one with frequent femoral vein cannulation and infection before transplantation developed progressive pelvic
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e76
www.transplantjournal.com
Transplantation
& Volume 98, Number 7, October 15, 2014
FIGURE 1. A, Antegrade urography at post-transplant 5 months revealing total obstruction of the lower graft ureter just 2 weeks after removal of the first successful stenting double-J catheter. B, The Boari flap: the bladder was opened and then reformed as a muscular flap with submucosal tunneling for urinary reconstruction. A double-J catheter was placed in the lumen for stenting.
fibrosis and stricture of transplant ureter at 41 months after transplantation. The Boari flap operation was performed with meticulous dissection to expose the urinary bladder, graft kidney, and ureter. Intraoperative ultrasonography was used to locate of the ureteral stump and bladder by saline infusion into the percutaneous nephrostomy tube and Foley catheter, respectively. Color Doppler ultrasound was also used for localization of the iliac and renal vessels. The bladder was opened and then reformed as a muscular flap with submucosal tunneling (Fig. 1B). The bladder flap was reflected and anastomosed to the proximal ureteral stump in an end-to-end fashion. The flap was then tubularized and closed by two-layered continuous sutures with a stenting double-J catheter. Before Boari flap operations, all five patients experienced renal dysfunction; the serum creatinine level ranged from 2.9 to 17.5 (9.04T6.77) mg/dL. Their serum creatinine levels became stabilized at 1.3 to 2.3 (1.86T3.78) mg/dL 1 month after the operation. The difference in serum creatinine levels before and after operation reached statistical significance (P=0.0227). The hospital stay after operation ranged from 10 to 30 (17.4T9.0) days. No recurrence of ureteral stricture happened during a mean follow-up period of 31.4T11.7 months. So far, three of the five grafts have failed for nonurologic reasons: chronic rejection in two and poor compliance to medications in one.
Ureteral stenosis is a common complication after renal transplantation, and most of the cases could be well managed by antegrade or retrograde double-J catheterization. However, in the presence of necrosis or a long-segment stricture of the transplant ureter, to reestablish the continuity of the urinary tract becomes a formidable challenge (2). Direct reanastomosis of a small ureteral defect could be successful, only if tension-free sutures could be placed. However, during the reoperation surgery, all the structures around the ureter are usually fixed; a tension-free reanastomosis would warrant extensive dissection and increase the risk of injury to the renal and iliac vessels. In 1894, Boari developed a bladder flap procedure to bridge over the ureteral defect caused by trauma or surgical excision of distal ureteral lesions (3). Its advantages over other reconstructive techniques were obvious and profound because the defected urinary tract could be restored without operating on the ipsilateral renal vasculature or contralateral ureter (4). Although Boari flap has been reported a century ago, surgeons seemed reluctant to do it because of the difficulty in dissection of the transplant kidney. Injury of the renal or iliac vessels could be incurred during the operation of Boari flap. We would suggest intraoperative Doppler ultrasonography for the localization of the vital structures in the operation field. In addition,
ultrasonography could also be used to identify the ureteral stump and bladder. In our experience, no incidental injury to the iliac and renal vessels happened, and Boari flap was successfully conducted with minimal blood loss to reconstruct the urinary tract with sustained patency in every case. We believe that a pedicled flap of the bladder wall, which includes rich blood supply, offers an excellent chance for restoration of the distal ureteral defect after renal transplantation. In conclusion, for patients with transplant ureteral obstruction, Boari flap provided a good chance of recovery with good long-term results. Intraoperative Doppler ultrasonography could help forward the Boari flap operation by localization of the vascular and urinary structures. Po-Da Chen Chih-Yuan Lee Ching-Yao Yang Meng-Kun Tsai Department of Surgery National Taiwan University Hospital and National Taiwan University College of Medicine Taipei, Taiwan The authors declare no funding or conflicts of interest. Address correspondence to: Meng-Kun, Tsai, M.D., Ph.D., Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. E-mail: [email protected] P.D.C. and M.-K.T. participated in research design. P.-D.C. and M.-K.T. participated in data analysis and writing of the article. P.-D.C., C.-Y.L., C.-Y.Y., and M.-K.T. participated in performance of the research. Received 5 July 2014. Accepted 10 July 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9807-e75 DOI: 10.1097/TP.0000000000000407
REFERENCES 1.
2.
3. 4.
Ali-Asgari M, Dadkhah F, Ghadian A, et al. Impact of ureteral length on urological complications and patient survival after kidney transplantation. Nephrourol Mon 2013; 5(4): 878. Faenza A, Nardo B, Catena MP, et al. Ureteral stenosis after kidney transplantation: interventional radiology or surgery? Transplant Proc 2001; 33: 2045. Boari A. Contribute sperementale alla plastica delle uretere. Atti Accad Med Ferrara 1894; 14: 444. Olsson CA, Norlen LJ. Combined Boari bladder flap-psoas bladder hitch procedure in ureteral replacement. Scand J Urol Nephrol 1986; 20(4): 279.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
* 2014 Lippincott Williams & Wilkins
CDC 0, and indeterminate SAB. In January 2013, C4d+, and in February 2013, C4d+. Coronary angiogram was performed on August 2012 which revealed normal coronary arteries. Because of the concerns for noncompliance, belatacept was initiated in March 2013 for maintenance therapy in addition to her current immunosuppressive regimen of tacrolimus, sirolimus, mycophenolate mofetil, and prednisone. Belatacept was dosed at 750 mg (10 mg/kg) intravenously on days 0, 7, 14, 28, and for the subsequent 2 months, then 500 mg monthly thereafter. The patient received a total of eight doses of belatacept. Tacrolimus and sirolimus levels still fluctuated while on belatacept and at some points were below the lower limit of detection. Biopsies after starting belatacept remained grade 0, negative for cellular rejection and histologic features of antibody mediated rejection (macrophages, endothelial swelling), but C4d staining was not performed. Coronary angiogram performed on July 2013 revealed normal coronary arteries. Echocardiography report from October 2013 revealed left ventricular ejection fraction of 61%. The patient expired because of cardiac arrest in October 2013. Autopsy was not performed. Figure 1 depicts the timeline of the rejection episodes from transplant to patient death.
of avoiding nephrotoxicity. The renal function benefit and safety profile seen in the early posttransplant period continued through the 5-year period in the low and more intense regimens of belatacept compared to cyclosporine (3). Additionally, rate of infections and malignancies were similar between regimens (3). Despite the lack of evidence for belatacept use in heart transplant recipients, this report provides some evidence for its potential use in this population. The patient in this case had a history of noncompliance along with fluctuating and oftentimes undetectable tacrolimus and sirolimus levels even during concomitant belatacept use. Belatacept was able to maintain immunosuppression in this patient as evidenced by the lack of rejection episodes since belatacept initiation. Unlike traditional maintenance medications, belatacept requires intravenous administration at an infusion center, allowing providers to have some confidence the noncompliant patient receives an immunosuppressive medication regularly. However, long-term use and outcomes in larger heart transplant populations have yet to be determined. Cher Y. Enderby1 Phillip Habib2 Parag C. Patel2 Daniel S. Yip2 Stephanie Orum2 Jeffrey D. Hosenpud2
DISCUSSION In the kidney transplant population, belatacept has been used as an alternative maintenance medication to the calcineurin inhibitors with the goal
1
Department of Pharmacy Mayo Clinic Jacksonville, FL
2
e75
Department of Transplantation Mayo Clinic Jacksonville, FL
The authors declare no funding or conflicts of interest. Address correspondence to: Cher Y. Enderby, Pharm.D., BCPS, BCNSP, Department of Pharmacy, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: [email protected] Received 9 May 2014. Accepted 10 July 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9807-e74 DOI: 10.1097/TP.0000000000000404
REFERENCES 1.
2.
3.
4.
5.
Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belataceptbased immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am J Transplant 2010; 10: 535. Medina Pestana JO, Grinyo JM, Vanrenterghem Y, et al. Three-year outcomes of BENEFITEXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys. Am J Transplant 2012; 12: 630. Rostaing L, Vincenti F, Grinyo J, et al. Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant 2013; 13: 2875. LaMattina JC, Jason MP, Hanish SI, et al. Safety of belatacept bridging immunosuppression in hepatitis c-positive liver transplant recipients with renal dysfunction. Transplantation 2014; 97: 133. Posselt AM, Szot GL, Frassetto LA, et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 2010; 90: 1595.
Successful Rescue of Transplant Ureteral Obstruction by Boari Flap bstructive uropathy, which might affect 2% to 7.5% of renal transplant patients, remains one of the most important causes of morbidity after renal transplantation (1). Although conservative treatment with ureteric stenting could effectively treat most of the patients with ureteral stricture, definite surgical intervention would be required for those with complete ureteral obstruction. Reviewing 997 renal transplant recipients in a single transplant center, we
O
identified five male patients, aged from 14 to 47 years, suffering from ureteral obstruction. Boari flap operations were successfully performed in all five cases to reestablish their urinary outflow. Among them, three had transplants from live donors and two from deceased donors. Two patients were actually having their second transplants and encountered with episodes of acute rejection before the ureteral complications. Of the five cases, one with live-donor transplantation developed massive urine leakage 10 days
after transplantation and was identified with complete ureteral necrosis during the rescue operation. Otherwise, the remaining four patients had ureteral stricture and eventually total obstruction, although the initial nephrostomy drainage and ureter stenting were successfully conducted (Fig. 1A). The ureteral obstruction happened within 1 year (1Y11 months) in four patients. However, one with frequent femoral vein cannulation and infection before transplantation developed progressive pelvic
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
e76
www.transplantjournal.com
Transplantation
& Volume 98, Number 7, October 15, 2014
FIGURE 1. A, Antegrade urography at post-transplant 5 months revealing total obstruction of the lower graft ureter just 2 weeks after removal of the first successful stenting double-J catheter. B, The Boari flap: the bladder was opened and then reformed as a muscular flap with submucosal tunneling for urinary reconstruction. A double-J catheter was placed in the lumen for stenting.
fibrosis and stricture of transplant ureter at 41 months after transplantation. The Boari flap operation was performed with meticulous dissection to expose the urinary bladder, graft kidney, and ureter. Intraoperative ultrasonography was used to locate of the ureteral stump and bladder by saline infusion into the percutaneous nephrostomy tube and Foley catheter, respectively. Color Doppler ultrasound was also used for localization of the iliac and renal vessels. The bladder was opened and then reformed as a muscular flap with submucosal tunneling (Fig. 1B). The bladder flap was reflected and anastomosed to the proximal ureteral stump in an end-to-end fashion. The flap was then tubularized and closed by two-layered continuous sutures with a stenting double-J catheter. Before Boari flap operations, all five patients experienced renal dysfunction; the serum creatinine level ranged from 2.9 to 17.5 (9.04T6.77) mg/dL. Their serum creatinine levels became stabilized at 1.3 to 2.3 (1.86T3.78) mg/dL 1 month after the operation. The difference in serum creatinine levels before and after operation reached statistical significance (P=0.0227). The hospital stay after operation ranged from 10 to 30 (17.4T9.0) days. No recurrence of ureteral stricture happened during a mean follow-up period of 31.4T11.7 months. So far, three of the five grafts have failed for nonurologic reasons: chronic rejection in two and poor compliance to medications in one.
Ureteral stenosis is a common complication after renal transplantation, and most of the cases could be well managed by antegrade or retrograde double-J catheterization. However, in the presence of necrosis or a long-segment stricture of the transplant ureter, to reestablish the continuity of the urinary tract becomes a formidable challenge (2). Direct reanastomosis of a small ureteral defect could be successful, only if tension-free sutures could be placed. However, during the reoperation surgery, all the structures around the ureter are usually fixed; a tension-free reanastomosis would warrant extensive dissection and increase the risk of injury to the renal and iliac vessels. In 1894, Boari developed a bladder flap procedure to bridge over the ureteral defect caused by trauma or surgical excision of distal ureteral lesions (3). Its advantages over other reconstructive techniques were obvious and profound because the defected urinary tract could be restored without operating on the ipsilateral renal vasculature or contralateral ureter (4). Although Boari flap has been reported a century ago, surgeons seemed reluctant to do it because of the difficulty in dissection of the transplant kidney. Injury of the renal or iliac vessels could be incurred during the operation of Boari flap. We would suggest intraoperative Doppler ultrasonography for the localization of the vital structures in the operation field. In addition,
ultrasonography could also be used to identify the ureteral stump and bladder. In our experience, no incidental injury to the iliac and renal vessels happened, and Boari flap was successfully conducted with minimal blood loss to reconstruct the urinary tract with sustained patency in every case. We believe that a pedicled flap of the bladder wall, which includes rich blood supply, offers an excellent chance for restoration of the distal ureteral defect after renal transplantation. In conclusion, for patients with transplant ureteral obstruction, Boari flap provided a good chance of recovery with good long-term results. Intraoperative Doppler ultrasonography could help forward the Boari flap operation by localization of the vascular and urinary structures. Po-Da Chen Chih-Yuan Lee Ching-Yao Yang Meng-Kun Tsai Department of Surgery National Taiwan University Hospital and National Taiwan University College of Medicine Taipei, Taiwan The authors declare no funding or conflicts of interest. Address correspondence to: Meng-Kun, Tsai, M.D., Ph.D., Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. E-mail: [email protected] P.D.C. and M.-K.T. participated in research design. P.-D.C. and M.-K.T. participated in data analysis and writing of the article. P.-D.C., C.-Y.L., C.-Y.Y., and M.-K.T. participated in performance of the research. Received 5 July 2014. Accepted 10 July 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9807-e75 DOI: 10.1097/TP.0000000000000407
REFERENCES 1.
2.
3. 4.
Ali-Asgari M, Dadkhah F, Ghadian A, et al. Impact of ureteral length on urological complications and patient survival after kidney transplantation. Nephrourol Mon 2013; 5(4): 878. Faenza A, Nardo B, Catena MP, et al. Ureteral stenosis after kidney transplantation: interventional radiology or surgery? Transplant Proc 2001; 33: 2045. Boari A. Contribute sperementale alla plastica delle uretere. Atti Accad Med Ferrara 1894; 14: 444. Olsson CA, Norlen LJ. Combined Boari bladder flap-psoas bladder hitch procedure in ureteral replacement. Scand J Urol Nephrol 1986; 20(4): 279.
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
