Spleen Transplant in Solid Organ Transplantation

Study Overview
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Brief Summary
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Although the notions that kidney transplantation is the treatment of choice for patients with end-stage renal disease and that simultaneous kidney and pancreas transplant is the only treatment able to restore euglycemia in patients with type 1 diabetes and selected patients with type 2 diabetes, are now consolidated, rates of transplantation remain low among potential candidates with high levels of preformed anti-HLA antibodies. Most of the data comes from the experience in kidney transplant but can be easily translated to pancreas transplant. Approximately 30% of patients on the transplant waiting list have evidence of sensitization in the form of alloantibodies, generated from exposure to previous transplants, blood transfusions, pregnancy, or other events. The presence of a panel-reactive antibody level of at least 80% (i.e. a high level of sensitization) creates difficulty in finding matched kidneys from compatible donors, leading to lower rates of transplantation in highly sensitized candidates compared to non-sensitized; the longer waiting times translates in an increased mortality rate. Despite the development of desensitization strategies and the advancement in immunosuppression protocols, it is apparent that transplanting these patients carries an increased risk of acute antibody mediated rejection; 25%-50% of transplants will have an early acute antibody mediated rejection . Most of these rejections can be successfully treated, but a high rate of transplant glomerulopathy and chronic antibody mediated rejection (AMR) leading to accelerated allograft failure is common.

Detailed Description
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Although the notions that kidney transplantation is the treatment of choice for patients with end-stage renal disease and that simultaneous kidney and pancreas transplant is the only treatment able to restore euglycemia in patients with type 1 diabetes and selected patients with type 2 diabetes, are now consolidated, rates of transplantation remain low among potential candidates with high levels of preformed anti-HLA antibodies. Most of the data comes from the experience in kidney transplant but can be easily translated to pancreas transplant. Approximately 30% of patients on the transplant waiting list have evidence of sensitization in the form of alloantibodies, generated from exposure to previous transplants, blood transfusions, pregnancy, or other events. The presence of a panel-reactive antibody level of at least 80% (i.e. a high level of sensitization) creates difficulty in finding matched kidneys from compatible donors, leading to lower rates of transplantation in highly sensitized candidates compared to non-sensitized; the longer waiting times translates in an increased mortality rate. Despite the development of desensitization strategies and the advancement in immunosuppression protocols, it is apparent that transplanting these patients carries an increased risk of acute antibody mediated rejection; 25%-50% of transplants will have an early acute antibody mediated rejection . Most of these rejections can be successfully treated, but a high rate of transplant glomerulopathy and chronic antibody mediated rejection (AMR) leading to accelerated allograft failure is common. This protocol has been designed to demonstrate the feasibility and efficacy of spleen transplant as a desensitization strategy for highly sensitized patients, potential candidates of kidney or simultaneous kidney pancreas transplant with (positive cross-match by flow cytometry (T or B) or B positive standard cross-match). After obtaining surgical and research consent at a pre-transplant clinic visit, patients will be receiving spleen transplant followed by spleen removal and kidney or simultaneous kidney pancreas transplant. Duration of the subject participation will begin upon consent and will last for one year after the surgery. Incidence of treated acute rejection (humoral or cellulo-mediated) within the first year (defined as biopsy proven or clinically indicated) will be determined. Graft and patient survival will be monitored and compared with a cohort of highly sensitized patients with similar immunological characteristics, treated with our standard protocol. DSA levels and post-transplant cross-match will be determined.

Official Title
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Spleen Transplant as an Immunomodulatory Strategy in Solid Organ Transplantation

Conditions
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Kidney Transplant Rejection, Positive FCXM (T or B Cell Positive), Positive CDC Cross-Match (B Cell Positive), Kidney/Pancreas Transplant Rejection

Intervention / Treatment
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* Procedure: Spleen Transplantation/Removal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must give written informed consent, and Subject is ≥ 18 years of age, and Subject is eligible for a kidney or simulateous kidney pancreas transplant, and Subjects are highly sensitized (cPRA 98-100%), and Subjects have a positive T flow crossmatch Exclusion Criteria: Severe cardiac disease not amenable to intervention Clinical significant systemic infection within 30 days prior to transplant Life expectancy < 1 Year Positive pregnancy test performed < 1 week prior to enrollment or intention to plan a pregnancy in the following year Current drug or alcohol abuse Uncontrolled, severe psychiatric illness Combined transplantation of kidney and other organs

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The protocol presented a single center, open label, prospective trial in which subjects, highly sensitized recipients with a positive T and B flow or positive B standard crossmatch, will undergo spleen transplant and kidney or simultaneous kidney pancreas transplant at the University of Illinois at Chicago. The expected number of patients is 40. Graft and patient survival will be monitored and compared with an historical cohort of highly sensitized patient which received kidney or simultaneous kidney pancreas transplant alone without spleen.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: highly sensitized patients with either a positive FCXM, or positive CDC cross-match<br>highly sensitized patients that receive a donor offer and have either a positive FCXM (T or B cell positive) or positive CDC cross-match (B cell positive); a positive CDC cross-match (T cell positive) remains a contraindication at this time. | Procedure: Spleen Transplantation/Removal<br>* Spleen transplantation/removal and kidney transplantation alone or simultaneous kidney and pancreas transplantation in highly sensitized patients with either a positive flow cytometry cross-match (FCXM) (T or B cell positive) or a complement-dependent cytotoxicity (CDC) cross-match (B cell positive).<br>|
| No Intervention: historical cohort of highly sensitized patients with a positive FCXM, or positive CDC cross-match<br>The control group, as comparison, will be an historical cohort of highly sensitized patients with positive flow (B and T) or positive B standard crossmatch, which received kidney transplant alone or simultaneous kidney and pancreas transplant and followed our standard protocol | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of successful spleen transplantations/removals that can overcome the immunological barrier of positive T flow crossmatch and allow better results in kidney transplant recipients with high cPRA compared to the standard treatment. | Rate of successful spleen transplantations/removals that can overcome the immunological barrier of positive T flow crossmatch and allow better results in kidney transplant recipients with high cPRA compared to the standard treatment. | 3 years | 
| Rate of graft success | Rate of graft will be monitored and compared with a cohort of highly sensitized patient and positive T flow crossmatch, treated with our standard protocol. | 3 years | 
| Rate of patient survival | Rate of patient survival will be monitored and compared with a cohort of highly sensitized patient and positive T flow crossmatch, treated with our standard protocol. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of T flow crossmatch that becomes negative | Rate of T flow crossmatch that becomes negative, leading to less rejections and consequent improved kidney function. | 3 years |