Deceased Donor Bladder or Combined Kidney-bladder Transplantation: a Phase 0 First-in-human Study

Vascularized Composite Bladder Allograft Transplantation: a Phase 0 (First-in-human) Study for Deceased Donor Bladder or Combined Kidney-bladder Transplantation

The goal of this clinical trial is to demonstrate the feasibility of bladder transplantation in patients with terminal bladder diseases who would benefit from a new bladder or a combined kidney and bladder transplant. The main questions it aims to answer are:

• Is human bladder transplantation feasible and safe?
• How will the new bladder function in terms of storage and emptying?

Participants will undergo a bladder-only or combined kidney and bladder transplantation. They will then be followed for two years to evaluate the efficacy, safety, and functionality of the bladder transplant.

Inclusion Criteria:

• Age 18-70 years

• Positive history of one of the following:

  1. Terminal bladder pathology resulting in poor compliance, recurrent refractory infections, and/or and resultant upper tract (kidney and ureteral) pathology, with possible resultant kidney disease.
  2. Localized, non-metastatic, bladder cancer requiring radical cystectomy. In this protocol, the only patients with a history of urothelial cell carcinoma that has already been treated, with an appropriate disease-free interval would be considered. Moreover, only candidates requiring a joint kidney and bladder transplantation or patients with a pre-existing transplant, on standard immunosuppression, will be considered.

• Patients that are on immunosuppression for pre-existing solid organ transplantation will be included in this study.

• Patient agrees to comply with the protocol and states a dedication to the immunomodulatory treatment regime.

• Patient has been previously fully vaccinated and boosted against COVID-19, or is willing to undergo timely vaccination.

  (a) Caretakers of the recipient will be strongly encouraged to be vaccinated.

• Patients must demonstrate appropriate manual dexterity or sufficient assistance at home to perform clean intermittent catheterizations as needed. The patient (or assistant) must demonstrate proficiency in performing clean intermittent catheterization during pre-transplant workup.

• No co-existing medical condition which, in the opinion of the study team, could affect the immunomodulatory protocol, surgical procedure, or functional results. If the condition is amenable to treatment, the study team must agree that said condition should not significantly enhance the surgical risks of genitourinary transplantation. Examples of such medical conditions would include burden of atherosclerotic disease that would preclude vascular anastomosis, and psychiatric disorders that would preclude reliable adherence to medications.

• No active co-existing psychosocial problems (i.e., alcoholism, drug abuse).

• Negative crossmatch with donor.

Exclusion Criteria:

• Positive history of one of the following medical co-morbidities:

  1. HIV (active or seropositive), active hepatitis B or C, viral encephalitis, untreated sepsis, active tuberculosis, viral encephalitis, toxoplasmosis, varicella zoster virus
  2. Conditions that may impact the success of the surgical procedure or increase the risk of postoperative complications including inherited coagulopathies like hemophilia, Von-Willebrand's disease, protein C and S deficiency, thrombocythemia, thalassemia, sickle cell disease.
  3. Mixed connective tissue diseases and collagen disorders (can result in poor wound healing after surgery), including: mixed connective tissue disorder; severe deforming rheumatoid arthritis; infectious, post-infectious, or inflammatory (axonal or demyelinating) neuropathy; Ehlers-Danlos syndrome;
  4. lipopolysaccharidosis or amyloidosis (effects nerve regeneration)
  5. Impaired liver function as evaluated by liver function panel, including the presence of hyperbilirubinemia, elevated AST/ALT, and the presence of secondary coagulopathy, measured by prothrombin, international normalized ratio, and partial thromboplastin time.
  6. Severe anemia (hemoglobin < 7 g/dL), leukopenia (WBC < 3 x 109 cell/L), or thrombocytopenia (platelets < 20 x109 cells/L).

• Patient is either not vaccinated or is unwilling to undergo vaccination against COVID-19 prior to transplantation.

• Oncology patient specific:

  1. History of non-urothelial malignancy in past 5 years, with the exception of non-melanomatous skin cancer
  2. History of malignancy involving metastases

• Patients unable to receive adequate follow-up care and/or unable to receive immunosuppression due to geographic, financial or other reasons.

• Patients with a smoking history who cannot demonstrate smoking cessation for a period of 6 months prior to listing and a desire to abstain from post-operative smoking will be excluded.

• Records of poor medical compliance, documented psychological disorder(s), substance abuse or incomplete psychological clearance.

• Particular attention will be paid to the candidate's compliance and their desire to undergo the offered procedure. While there is no "score" on any particular evaluation that would rule out a patient, certain factors can aid in the identification of patients who for example may not have the ability to comply with the medical directives necessary to care for a genitourinary transplant, or psychologically are not prepared for transplant, or who have unrealistic expectations about the transplant. The decision on eligibility is a team decision. All members of the team will discuss each candidate in a multidisciplinary meeting and reasons for concern over eligibility will be discussed at a Selection Committee Meeting. In circumstances where the candidate is considered to be less suitable, they could be given an opportunity to address these issues either through individual counseling or further education and then be reconsidered as a potential candidate. Every effort to prevent a request for allograft removal will be made.