Preclinical Studies Prior to First-in-Human Bladder Transplant Leave Questions Unanswered

Is the treatment of bladder pathology on the verge of changing? Researchers from the University of Southern California are investigating the potential utility of bladder transplantation. Their recent study added to the scant literature on preclinical bladder autotransplantation in anticipation of a first-in-human trial.¹

According to Dr. Gill and colleagues, in the realm of urology, kidney transplantation is the only mainstay transplant procedure. Transplantation of the uterus has also been performed with positive results.²

The current standard-of-care approach following cystectomy includes using a segment of bowel to create an orthotopic neobladder or creating a urinary diversion via a conduit, which is associated with significant morbidity, with a complication incidence rate of 40% to 80% and readmission rates of up to 30% within 3 months of surgery.³ Patient-related factors—for example, inadequate intestinal length or short mesentery—may impact the feasibility of a bowel-based diversion.

The drawbacks of the current approach led the authors to optimistically conclude that “bladder transplantation, if technically and logistically feasible, may circumvent some of these issues in a highly selected, small subset of eligible patients, wherein immunosuppression and the potential need for intermittent catheterization would be deemed as medically and ethically acceptable trade-offs.” Thus, they pursued preclinical trials of vascularized composite bladder allograft (VCBA) prior to any phase 0 trials and hoped to improve upon the surgical technique and technical outcomes of VCBA. The authors utilized 3 sequential, vascularized model settings: a living porcine model, a pulsatile human cadaveric model, and a heart-beating, brain-dead human research donor model. Surgery was performed robotically across all 3 models.

The living porcine model was selected because the genitourinary and vascular anatomy of a pig is similar to that of a human. VCBA autotransplantation included en bloc retrieval of the VCBA. Researchers took care to preserve the perivesical mesenteric apron and vascular structures at the level of the internal iliac vessels, hypothermic perfusion, extracorporeal back-table vascular reconstruction, vascular anastomosis, revascularization, and vesicourethral anastomosis. Firefly immunofluorescence was used to assess vascular viability.

Three living porcine specimens were included. Operative time improved from 5.7 hours to 2.4 hours. Animal 2 demonstrated poor indocyanine green (ICG) fluorescence, which was likely due to an inability to identify and preserve venous outflow. The authors noted the outcome may have been influenced by the anatomical differences between pigs and humans.

Fresh cadavers were used in the pulsatile human cadaveric VCBA model. The authors briefly described the method to obtain pulsatile perfusion. After a pulsatile circuit was established, VCBA recovery and autotransplantation were performed.

Two cadavers used in the model showed an improvement in operative time from 8.0 hours to 6.6 hours. One of the cadavers showed adequate perfusion, while the other demonstrated limited perfusion. The authors noted this outcome may have been due to the inability of the perfusion pump to function correctly when in steep Trendelenburg position. It is also possible the cadaveric tissue was unable to tolerate the prolonged pulsatile perfusion.

The heart-beating, brain-dead human research donor model included human donors who were ineligible for organ donation. The authors used robotic dissection, beginning in the rectovesical cul-de-sac posterior to the seminal vesicles to develop the retroprostatic prerectal space and extending laterally along the anterior surface of the rectum toward the endopelvic fascia and pelvic side walls bilaterally, staying posterior to the vascular mesenteric arcade of the bladder. Space of Retzius was developed, radical prostatectomy and seminal vesiculectomy were performed, and the bladder was retracted anteriorly. The bladder with vascular supply, including internal iliac arteries and veins with the bilateral vascular mesenteric apron, was removed en bloc. Deep vascular dissection and hemostasis of deep vessels was achieved.

The specimen was extracted and subsequently underwent extracorporeal back-table hypothermic perfusion and vascular reconstruction of bilateral arteries and veins to create an independent conjoined ostia. Finally, the bladder was robotically transplanted and underwent vascular anastomosis to the recipient’s right common iliac vessels and vesicourethral anastomosis. The authors investigated several hypothermia techniques and recommended ligating the vascular supply only after the bladder, with its mesentery, was completely freed up. Vascular reconstruction included a side-to-side anastomosis of the right and left arteries and the right and left veins. Number 5 polytetrafluoroethylene was used for vascular anastomosis in the transplant. ICG firefly immunofluorescence was used to assess vascular perfusion.

Five heart-beating, brain-dead human research donors were included in this study. Operative time improved from 11.2 hours to 5.3 hours, with a similar decrease in robotic operative time. Vascular perfusion was demonstrated in 3 out of 5 cases. In the second case, the donor became coagulopathic and unstable, which led to cardiac arrest and precluded autotransplantation in the heart-beating state. Successful autotransplantation was still achieved. The third case employed an open approach, and secondary to atherosclerotic disease, arterial re-anastomosis. Autotransplantation was unable to be performed. In the fourth case, the donor was kept on ventilatory support and observed for 12 hours after successful autotransplantation. At re-evaluation, bladder vascularity was “excellent” and viable on physical inspection. The authors confirmed these findings with ICG immunofluorescence and cystoscopy.

This study, as part of a significant effort to prepare for a first-in-human phase 0 trial, attempted to identify and advance the understanding of the appropriate technique for VCBA transplantation. It demonstrated that it is possible to attain adequate and sustained VCBA perfusion for up to at least 12 hours postoperatively. As expected, there was significant improvement in the learning curve involved in performing this procedure. The authors noted that rodent models have been used to assess bladder transplantation and found 30-day mortality rates of 52% and evidence of nerve regeneration and good bladder capacities.⁴ Bladder patches have also been used in rodent models.⁵

Regarding human studies, those studies have been limited to en bloc nonvascularized bladder patches and unsuccessful kidney-bladder transplant secondary to rejection.⁶ In 2008, a successful transplant of bilateral kidneys, ureters, and bladder into a 12-month-old female recipient was reported.⁷ While vascular supply was established, no independent bladder vascular anastomosis was performed. At 6-month follow-up, the patient was doing well.

This study is an “essential preclinical step for assessing feasibility of clinical human bladder transplantation.” The authors qualified that potential candidates for bladder transplantation would be limited to highly selected patients, including those with terminal neurogenic or chronic inflammatory bladder disease, those with refractory or recurrent bladder infections or stones in the post-transplant immunosuppressed setting, and those with future transplantation and imminent immunosuppression. These criteria may be expanded to patients with contraindications to using the small bowel to create a urinary diversion and those with organ-confined bladder cancer who are already on immunosuppression. Patients on dialysis who are scheduled to undergo future kidney transplantation may also be included.

The authors made a careful note to “re-emphasize that the need for immunosuppression restricts broad applicability of VCBA transplantation for the typical patient with nonmetastatic muscle-invasive bladder cancer who requires radical cystectomy.” There are still many unanswered questions in this field, the authors concluded. However, this is the first report of bladder autotransplantation in heart-beating, brain-dead human research donors. This study was a necessary step prior to the next phase—a feasibility trial of human bladder autotransplantation, which is actively recruiting patients.

David Ambinder, MD is a urology resident at New York Medical College/Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

 

References

1. Nassiri N, Cacciamani G, Gill IS. Robotic bladder autotransplantation: preclinical studies in preparation for first-in-human bladder transplant. J Urol. 2023;210(4):600-610. doi:10.1097/JU.0000000000003620
2. Brännström M, Johannesson L, Bokström H, et al. Livebirth after uterus transplantation. Lancet. 2015;385(9968):607-616. doi:10.1016/S0140-6736(14)61728-1
3. Cacciamani GE, Medina L, Lin-Brande M, et al. Timing, patterns and predictors of 90-day readmission rate after robotic radical cystectomy. J Urol. 2021;205(2):491-499. doi:10.1097/JU.0000000000001387
4. Takeuchi K, Takechi S, Ohoka H, Yokoyama M, Iwata H, Takeuchi M, Matsuda S. Histological study of urinary bladder transplantation in rats. 1997;63(7):922-926. doi:10.1097/00007890-199704150-00002
5. Wang K, Yamataka A, Kobayashi H, et al. Transplantation of infantile bladder in rats: an alternative procedure for bladder augmentation. 2001;71(2):199-202. doi:10.1097/00007890-200101270-00005
6. Gutierrez Calzada JL, Martinez JL, Baena V, Laguna G, Arrieta J, Rodriguez J, Moncada A. En bloc kidney and bladder transplantation from an anencephalic donor into an adult recipient. J Urol. 1987;138(1):125-126. doi:10.1016/s0022-5347(17)43017-5
7. Kato T, Selvaggi G, Burke G, et al. Partial bladder transplantation with en bloc kidney transplant—the first case report of a ‘bladder patch technique’ in a human. Am J Transplant. 2008;8(5):1060-1063. doi:10.1111/j.1600-6143.2008.02180.x