Nima Nassiri, MD, was one of the recipients of the 2024 Urology Care Foundation™ Research Scholar Awards. These awards provide $40,000 annually for mentored research training for clinical and postdoctoral fellows or early-career faculty. Societies for Pediatric Urology Sushil Lacy MD Award sponsored Dr Nassiri’s award.

Background

The current gold standard for patients with terminal bladder pathology involves urinary reconstruction using a vascularized segment of intestine, which carries an inherent predisposition to a variety of early and late metabolic,¹ infectious,² nutritional,^1,3 and renal complications.^2,4 These are common and carry significant morbidity and mortality.^5,6 The incidence of 1 or more of these complications ranges from 40% to 80%, and readmission rates range from 25% to 30% within 3 months after surgery.^5-7 Replacement of the diseased bladder with a more normal urinary reservoir could circumvent these complications. Recently, the necessary preclinical work, including robotic bladder autotransplantation in brain-dead but heart-beating human research donors was described.^8,9 In these studies, the technique for vascularized composite bladder allograft (VCBA) recovery and transplantation was described. This represents the first such study to demonstrate the technical feasibility of bladder transplantation. Based on this work, 2 United Network for Organ Sharing–approved VCBA programs have been established, and 2 first-in-human clinical trials have been initiated (NCT#05462561; NCT#06337942).

Central Question

A central immunological question remains: can immune tolerance protocols employing mixed chimerism be utilized in vascularized composite allografts (VCAs) obtained from deceased donors, including VCBAs? The need for immunosuppression must be deemed a necessary and acceptable tradeoff for the functional gain afforded by any VCA. Like most VCA transplants, a bladder transplant necessitates lifelong immunosuppression, which predisposes patients to various complications and side effects, including infections, cancers, nephrotoxicity, cardiomyopathy, and diabetes, among others. Current protocols for immunological tolerance establish mixed chimerism through engraftment of donor-derived hematopoietic progenitor stem cells (HPSCs). While these protocols liberate some patients from immunosuppression, they are mostly limited to solid organ transplants and most successful in living donor kidney transplants.^10,11

A key first step to expanding the application of immune tolerance to VCA transplant recipients is to determine if cellular yields sufficient for immune tolerance can be obtained from deceased donors. Ideally, an HPSC yield adequate for inducing mixed chimerism could be recovered from the peripheral blood of deceased donors. Answers to this question are central to the long-term success of bladder transplantation as a viable treatment option for patients with terminal bladder pathology.

Hypothesis

This study seeks to take the first steps toward demonstrating the feasibility of immune tolerance protocols employing mixed chimerism in VCA-bladder transplants. We hypothesize that appropriate HPSC yields can be obtained in timely fashion from brain-dead deceased donors without sacrificing allograft viability. Our objective will be to demonstrate that HPSC yields sufficient for immune tolerance protocols can be obtained through a process of peripheral mobilization and apheresis. Biospecimens obtained from both the VCBA and solid organs will be interrogated before, during, and after HPSC recovery to describe the immune landscape and demonstrate intact graft viability.

Experimental Design in Brief

In this study, HPSCs will be peripherally mobilized using a combination of granulocyte colony-stimulating factor and plerixafor and collected through large-volume apheresis, followed by cellular selection, processing, and evaluation (Figure). After the cellular product is obtained, the VCBA will be recovered, cystoscopically evaluated, and biopsied for histologic and immunohistochemical analysis. Findings will be compared to prerecovery controls obtained as part of the VCBA transplant protocol. We will compare blood, urine, and tissue obtained before and after HPSC collection to controls, with a goal end point of demonstrating no difference after HPSC recovery.

Specific Aims

There are 3 specific aims to this study: (1) demonstrate successful peripheral mobilization and collection of HPSCs from brain-dead deceased human donors; (2) evaluate the impact of HPSC recovery on the histopathological integrity of the VCBA and other solid organs; and (3) describe how the molecular landscape of VCBA and lung changes after HPSC recovery.

Impact

We seek to demonstrate that tolerogenic protocols for mixed chimerism that employ deceased-donor HPSC collection may be tenable after VCBA (and by proxy any VCA or deceased-donor organ transplant). These outcomes would have broad implications for all VCA recipients. Unlike solid organ transplantation, VCA transplants dramatically improve quality of life, but generally, are not lifesaving. Consequently, every effort should be made to minimize the deleterious side effects of immune-suppressing medications. Immunological tolerance through mixed chimerism has demonstrated tremendous success after living kidney transplantation, liberating patients from antirejection medications and increasing the lifespan of the transplanted kidney. Demonstrating readily available and adequate HPSC yields without a negative impact on organ viability would be a critical first step and tremendous leap forward in the potential application of tolerance protocols to recipients of deceased-donor bladder transplants. The achievement of immune tolerance might make possible the ultimate goal of a lifelong durable single organ transplant and the elimination of immunosuppression and its attendant risks.