Fall 2023 Research Internship

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http://hdl.handle.net/1920/13587

These papers are published as part of the Center for Biomedical Science and Policy (CBSP) Young Scholars Research Internship completed during Fall 2023. The program mentored elite high school students interested in pursuing study and/or career in the fields of biology or medical science with emphasis on advanced data analytics.

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Evaluation of Antithymocyte Globulin and Basiliximab as Induction Therapy in Kidney Transplant Recipients
(George Mason University, 2023-12) Bhalla, Arnav; Katasani, Hamsini; Herdrich, Kyle
Background The roles of induction and maintenance therapies are becoming increasingly critical in promoting the long-term success of renal transplants and the reduction of post-surgery acute rejection. From 1998 to 2007, 78% of kidney transplant recipients (KTR) in the U.S. received immunosuppressive induction therapy [1]; fast forward to 2014, that percentage increased to 90%. [2] The three most popular antibodies used in induction therapy for KTRs in the U.S. are Antithymocyte Globulin (“Thymo”), Basiliximab (“Simulect”), and Alemtuzumab (“Campath”). According to Koyawala, et al., rabbit Thymo is used in approx. 50% of indication therapies for KTRs, Basiliximab 20%, and Campath 15%. [2] Thymo is a polyclonal antibody and lymphocytedepleting agent sourced from rabbits or horses that were immunized with human thymocytes. [3] By reducing the count of T cells, Thymo prevents KTRs’ white blood cells from rejecting the transplanted organs. Rabbit Thymo was approved in 2017 for KTRs’ induction therapy. Before then, Basiliximab was the only FDA approved induction agent for KTRs in the U.S. Basiliximab is a chimeric mouse-human antibody and an interleukin-2 receptor antagonist (IL2RA) agent that decreases patients’ T cell production by blocking certain receptors on T cells. On the other hand, Campath is a lab-produced humanized rat monoclonal antibody that works to deplete capable immune cells, T and B cells. [4] In terms of efficacy, outcomes, and side effects after renal transplantation, Thymo and Campath are found to be most effective at preventing rejection among high-risk kidney recipients; however, Thymo is also correlated with higher rate of infections, cancer, and lymphoproliferative disease incidents. [3, 5, 6] In contrast, Basiliximab recipients showed the lowest rate of infections and side effects. Cost-wise, Basiliximab is a more cost-effective alternative to Thymo for standard and low-risk KTRs. [3, 5] An analysis of ten randomized controlled trials (over 1200 patients included) compared the efficacy of Campath relative to IL2RAs (Basiliximab and Daclizumab) and Thymo. [4] The 2012 study found that Campath resulted in a lower rate of biopsy-proven acute rejection than the induction using IL2Ras, but there was no significant difference when compared to rabbit Thymo. The study also found no apparent difference in terms of graft loss, patient death, and new-onset diabetes mellitus among the induction agents. On the other hand, a 2019 study by Alloway et.al. examined the results of two international randomized trials (508 KTRs included) to compare the efficacy of rabbit Thymo vs. Basiliximab. [7] The study found that 1 year and 5 years after transplantation, the rate of reported treatment failures was nearly 11% lower in rabbit Thymo recipients compared to the Basiliximab recipients. Furthermore, the 10-year data of the rabbit Thymo recipients showed a 10% lower acute rejection rate than the Basiliximab recipients. One new development in renal induction therapy is the combined use of Thymo and Basiliximab. The combined therapy has been used as a feasible alternative for patients who could not take full dosage of Thymo due to various health reasons such as thrombocytopenia, leukopenia, or cytokine release syndrome. Since Basiliximab on its own was sometimes considered too weak to prevent graft failure, an induction therapy consisting of both Thymo and Basiliximab became a plausible option. A 2023 retrospective study of 80 KTRs showed that one-year graft survival rate was not significantly different between the Basiliximab recipients and the Thymo-Basiliximab combined recipients, suggesting a positive support for the dual induction therapy consisted of low-dosage Thymo and Basiliximab. [8] On the other hand, a national study published in 2021 by Lam et. al [9] concluded that patients who received the Thymo-Basiliximab combined induction therapy have an increased risk of graft loss and mortality five years after transplantation when compared to those who received Thymo-only induction therapy. This study analyzed data of over 150,000 KTRs from a national registry between 2005 and 2018. The other new trend worth noting is the exclusion of steroids from maintenance therapy. Due to their anti-inflammatory and immunosuppressive properties, steroids have historically been used to prevent acute rejection after renal surgeries. However, long-term steroid use could cause adverse side effects such as osteoporosis, cataract, and higher cardiovascular and infection risks. A 2016 study by Haller et al. found that the acute rejection risk was noticeably higher for patients who were subjected to steroid reduction or withdrawal. [10] However, a couple other studies found steroid reduction techniques to be safe and effective as steroid-based maintenance therapy, and that steroid withdrawal are especially beneficial to certain patient groups, including African American recipients, sensitized patients, and pediatric patients. [11, 12] The purpose of this study is two-fold: One is to evaluate whether the combined Thymo-Basiliximab induction therapy is as effective as other regimens (Thymo, Simulect, Campath) in preventing graft failures and patient death. The other is to examine whether the steroid-free maintenance therapy is as effective as the steroid-included maintenance therapy in graft failures and patient mortality.
Evaluation of Pancreatic Re-transplantation Outcomes
(George Mason University, 2023-12) Sharma, Grace; Yallapragada, Vinay
Background In this literature review, we will cover details of prior research. This review includes studies published after 2012. There is extremely limited information available about the outcomes of pancreas retransplants. Most studies in this field are single-center reports with small datasets. This literature review can be divided into three main areas: 1. Analysis of graft survival in different forms of pancreas transplants 2. Analysis of patient survival in different forms of pancreas transplants 3. Review of recommendations to consider pancreas retransplants for patients Several studies have identified the graft survival rates of retransplant patients and compared them with graft survival rates for other pancreas transplant patients. In [7], authors compared the graft survival between 187 primary transplant and 26 retransplant patients, noting that graft survival rates were lower amongst retransplants than primary transplants. In 2018, Gasteiger et al. [4] concluded that graft survival in first-time retransplant patients was similar to graft survival amongst patients that received more than one retransplant. In [1], Hollinger determined that graft survival was similar amongst patients who received an early retransplant and a delayed retransplant. Most studies analyzing graft survival rates in pancreas retransplants are single-center reports studying less than 50 patients each. In 2015, Siskind et al. [6] reviewed more than a thousand retransplants in a larger database, UNOS; the authors determined that graft survival in retransplant patients was significantly lower than primary transplant patients. Most studies determining graft survival rates of retransplant patients also studied patient survival rates. In [2], the authors conducted an in-depth analysis of retransplants done after 2003 and determined that there was no significant difference between the patient survival rates of primary transplant and retransplant patients. In [7], the authors concluded that patient survival was not different for primary transplant patients and retransplant patients. The analysis on the UNOS database revealed that patient survival was greater in the retransplant group than the primary transplant group [6]. Most work in this field has concluded by supporting pancreas retransplants as a viable option for patients. In [5], the authors state that retransplants are feasible and that it should be considered for diabetic patients who have lost their first pancreas. In [3], where the authors analyzed 18 retransplant patients, the study concluded by determining that retransplants are a safe and effective procedure. In [7], the authors had determined that retransplants had lower graft survival than primary transplants yet concluded that it can be offered to diabetic patients. However, in [6], the authors analyzed over 1,000 retransplants and concluded that retransplants should not be considered for all patients.
Evaluation of Transplanting Organs from Drowned Donors
(George Mason University, 2023-12) Han, Caleb; Ho, Seraphina; Jung, Isaac
Background Donor-derived infections, transmitted from organ donor to organ recipient, while infrequent, often lead to the death of the organ recipient because of their compromised immune systems. A recent CDC publication reported that organ transplants from drowned organ donors potentially exposed to environmental molds (e.g. Scedosporium) through the aspiration of water may lead to invasive mold infections (IMIs) in the recipients of the exposed organs [1]. Scedosporium, a pathogenic soil-dwelling saprophyte often found in polluted water bodies, has emerged as the most common cause of drowned donor derived invasive fungal infections (IFIs), and can manifest as pneumonia, CNS disease, and dissemination [2]. Despite the significant developments made in regards to understanding IMIs from drowned donors, between 2000 and 2016, out of the 61 published cases of scedosporiosis following solid organ transplantation (SOT), 36 of these cases resulted in death, a high mortality rate of 59% [3]. Furthermore, in 2023, Xiaoli Lin and colleagues analyzed the perioperative infections, microbiological results, early transplant outcomes, and first-year clinical outcomes of 38 drowned donor renal recipients. The analyses revealed that when compared to the control group, drowned donors exhibited a significantly higher rate of positive fungal cultures (36.84% vs.13.15%,), and recipients displayed an increased prevalence of gram-negative bacteria (23.68% vs.5.26%) as well as multidrug-resistant GNB infections (18.42% vs. 3.95%) [4]. Additionally, studies regarding IMIs have identified a correlation between the necessary immunosuppressive medications taken by SOT recipients required to prevent organ rejection, and increased risks of contracting invasive mold infections (IMIs) [1, 5]. Currently, one of the most pressing issues in transplantation is the shortage of organs. To address this challenge, there is a growing emphasis on promoting the use of deceased donors, including drowned donors, in organ transplantation, despite the risk of IMIs. Due to persistent shortage of kidneys and livers for transplantation, most transplant centers have been considered to obtain and use the organs even from drowned donors [6]. However, there has been no report on the effects of kidney and/or liver transplants from drowned donors in light of graft failure and recipients’ mortality rates. Thus, studies on the outcomes of drowned donor kidney and liver transplants are required in comparison to other common accidents and injuries (i.e. Drug intoxication, Gunshot wound, Blunt injury, and Asphyxiation) to understand potentials of the drowned donor kidney and liver transplantation as another transplant resource. OBJECTIVE We aimed to investigate differences in graft failure and patient mortality rate between drowning, gunshot, drug intoxication, asphyxiation, and blunt injury.

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