B Cell Immunology Lund PI, 1U19AI142737-01– One of the major barriers to successful organ transplantation is the presence of antibodies directed against antigens expressed on the donor allograft. In addition to the ABO blood group antigens, HLA molecules represent the most important cell surface antigens responsible for antibody-mediated rejection (AMR). In humans, HLA-specific antibodies (HLA-Abs) are produced following a sensitizing event, such as pregnancy, blood transfusion, or transplant, that exposes an individual to non-self cells. These antibodies negatively impact thousands of patients both before and after transplant.

Following a sensitizing event, a patient would be expected to carry a cadre of memory B cells or antibody-secreting cells (ASCs) that are specific for non-self HLA antigens and are responsible for the HLA-specific memory and HLA-Abs that harm transplant patients. There are some data that HLA-specific B-lineage cells can be detected at low frequencies circulating in the blood or residing in the bone marrow. A recent report indicates that the mere presence of circulating HLA-specific B cells provides considerable diagnostic and prognostic information for patients with AMR. However, these HLA-specific B-lineage cells have not been well-characterized.

We hypothesize that sensitized individuals retain a heterogenous pool of HLA-specific B-lineage cells and that differences in memory B cell and ASC phenotype are responsible for the variable clinical phenotype following a possibly sensitizing event. As part of a larger U19 program examining tissue and organ-specific B cell immunity, we aim to:

1. Determine the presence, specificity, and phenotype of HLA-specific B lineage cells across a range of tissues in sensitized humans
2. Determine the clonal relationships of these HLA-specific B-lineage cells through B cell receptor cloning and sequencing.

Currently, the lab of David K.C. Cooper, MD, PhD, DSc(Med), FRCS, FACC, FACS, FAST, is spearheading xenotransplatation efforts at UAB.

The work of the laboratory is primarily aimed at trying to resolve the critical shortage of deceased human donor organs for transplantation by developing an alternative source of organs by using pigs. This entails the genetic-engineering of pigs to protect their organs from the human immune response (rejection), which is stronger than against transplanted human organs. The work largely entails testing of cells from genetically-engineered pigs (provided by a small biotechnology company, Revivicor, of Blacksburg, Virginia) using several different laboratory assays that determine the resistance of the cells to injury by the human immune response. These assays include human serum antibody binding to the pig cells, human serum cytotoxicity of the cells, and the mixed lymphocyte reaction (which measures the human cellular response to pig cells).

When the quality of the cells has been well-documented, a pig organ transplant is carried out in a nonhuman primate (as a surrogate for the human recipient) to determine (i) the resistance of the pig organ to the immune response, and (ii) the function of the organ in the foreign environment.

The work of the laboratory has extended to transplantation studies of pig kidneys, hearts, livers, pancreatic islets (for patients with diabetes), and corneas (for patients with corneal blindness), and to the transfusion of pig red blood cells (as an alternative to human red blood cells). In view of the fact that more than 80,000 American patients are presently awaiting kidney transplantation, the current major organ of interest is the kidney.

Caregiver Benefit and Burden among Obese Living Donors (Reed PI, K01 submitted) Caregiver burden is a well-known issue associated with primary caregiving for individuals with chronic disease, including solid organ transplant candidates and recipients, with an estimated 44 million individuals in the United States serving as unpaid caregivers for an adult or child family member.

In addition to financial burdens associating with the caregiving role, caregivers also experience psychological distress, fatigue, and adverse health outcomes, including higher rates of hypertension and heart disease. These burdens are of particular concern to caregivers with their own underlying health issues, such as obesity, which may be further magnified when the caregiver becomes a patient, simultaneously requiring their own care while caring for another (e.g. obese living kidney donors who serve as the primary caregiver for their transplant recipient).

Approximately 20% of living kidney donors are parents and significant others, individuals who likely serve as the primary caregiver of the recipient. Living donors experience their own recovery period post-donation; thus those who are caregivers are simultaneously responsible for ensuring the recovery of the recipient and their own health post-donation. To date, no study of living donors has considered a donor’s physical health at donation in conjunction with their relationship to the recipient.

It is unknown whether perceived caregiver burden-associated symptoms among living donors are correlated with post-donation outcomes, which is of particular significance among those with excess weight and risk factors for comorbid disease development. We hypothesize that there may be a phenotype of obese caregiver living donors at risk for adverse post-donation outcomes and a subset with increased coping mechanisms who experience a benefit from their simultaneous caregiving and donor roles.

To address this gap in knowledge, we propose to develop an intervention to reduce caregiver burden in this vulnerable population of caregiver living donors in a sequential quantitative to qualitative mixed methods design study with the following unique aims:

1. To assess perceived psychological and physical burden attributable to caregiving among a cohort of living kidney donors who were obese at the time of donation.
2. To explore priorities for self-care and reduction in caregiver burden among obese living donors who have served as the primary caregiver for their transplant recipient.
3. To design and pilot an intervention to alleviate caregiver burden among obese living donor caregivers.

Chronic kidney disease progression in people living with HIV (Locke PI, R01DK117675) – More than 1.1 million people in the United States (US) are living with human immunodeficiency virus (HIV) infection, and an estimated 30% of people living with HIV (PLWH) have evidence of chronic kidney disease (CKD). Compared to the general population, the rate of end-stage renal disease (ESRD) among PLWH is tenfold greater and mortality on dialysis is 19-fold higher.

Contributors to CKD in PLWH include comorbidities shared with the uninfected population, HIV-specific factors, and genetic variants; however, the interplay of these various determinants remains incompletely understood. Existing CKD risk prediction tools for PLWH have low sensitivity and insufficient positive predictive value for clinical decision-making. The ability to risk-stratify PLWH and distinguish those at highest risk for future development of CKD from those at low risk is critical to optimize care and patient outcomes. PLWH at high risk can be targeted for interventions to slow CKD progression and improve survival, including earlier establishment of nephrology care and referral for transplantation; while identification of those at low risk allows for the development of a living donor selection framework specific to PLWH, effectively expanding HIV+ to HIV+ transplantation to include living donors.

We hypothesize that the impact of HIV on CKD risk varies by the interplay between comorbid conditions, HIV-related factors, and genetic variants, and distinct phenotypes of PLWH with high and low CKD risk exist. To better understand this relationship, we will leverage the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a unique prospective clinical cohort with > 34,000 participants, and will address the following unique aims:

1. To explore the association of unique HIV-related processes and clinical characteristics with risk for CKD
2. To explore the association of genetic variants with risk for CKD and correlate histologic findings with genetic risk
3. To develop a tool for predicting CKD risk among PLWH

Stratification by risk for future development of CKD is critical for identifying those PLWH at highest risk that would benefit from early nephrology care and referral for transplantation and those at lowest risk that could be eligible for living kidney donation. Using an existing cohort of PLWH representative of the US HIV population, with time varying data and DNA for genotyping, to inform CKD risk prediction is necessary, practical, and novel. Our findings will contribute new insights into the relationship between HIV and risk for kidney disease.

Establishing Culturally Competent Educational standards for living kidney Donors (ECCEED) (Kale, mentored / Locke, mentor American College of Surgeons Resident Research Scholarship) - Living kidney donors remain a critical source of organs for their loved ones; yet living donor kidney transplant (LDKT) has declined since 2004, particularly in the southeastern US. In addition to geographic disparities, racial disparities in LDKT have also been identified.

Despite the disproportionate number of African Americans (AA) needing transplantation, fewer than 1 in 5 AAs undergo LDKT. Racial concordance between living donors and recipients is 95% and living donation rates are also known to be lower among AAs. Transplant candidate and potential donor factors contribute to this disparity. Difficulty asking family/friends to donate on one’s behalf and lack of knowledge about the donation process, respectively, have been implicated in lower donation rates.

Programs, including the Living Donor Champion model and Smartphone App, were developed to separate the advocacy role from the transplant candidate in order to overcome barriers associated with asking someone to donate on one’s behalf, and have demonstrated increases in living donor inquiries.5,6 These programs were implemented in resource-intense urban settings and close geographic proximity to urban-based transplant centers limiting their generalizability to low-resource areas like rural, southeastern US. These programs also failed to include interventions to improve donor comfort with the donation/evaluation process.

We have previously shown that lack of comfort with this process is the single greatest barrier to living donation among AAs, and as such, current programs designed to increase living donation have not optimized cultural inclusivity limiting increases in living donation among AAs.4 We utilized the RE-AIM (Reach, Efficacy, Adoption, Implementation, Maintenance) framework to develop and implement a novel Living Donor Navigator Program (LDN). LDN combines advocacy training to overcome barriers in initiating conversations with and identification of potential living donors with the use of non-clinical navigators to guide donors through the evaluation process.

Early results indicate that compared to non-participants there was a 7-fold increase among all LDN participants and an 11-fold increase among AA LDN participants in the likelihood of having an approved donor, suggesting that the effect of the LDN program is greater among AAs. We hypothesize that the success of the LDN program is the result of the program’s enhanced cultural competency.

Our program is the first of its kind to demonstrate increased efficacy among AAs, and assessment of its cultural competency and inclusion is necessary to identify best practices and establish standards of practice for organ donation and transplantation educational materials and programs targeting AAs. To this end, we propose:

1. Conduct qualitative assessments to identify key culturally competent components of the LDN program. We will utilize a novel formative research tool, Nominal Group Technique (NGT), to ascertain the factors most responsible for ensuring the cultural competency of the LDN program. NGT will be conducted among transplant candidates, candidate advocates, potential living kidney donors, and patient navigators.
2. Develop an organizational schema for the development of culturally competent living donor educational programs. We will utilize a card sorting task, multidimensional scaling, and hierarchical cluster analyses to cognitively map the optimal organizational schema for ensuring cultural competency in living donor educational programming.

Glomerular filtration estimation in cirrhosis (Locke PI, R01 submitted) - More than 4.4 million adults have liver disease, 633,323 of whom have end stage disease, or cirrhosis. As Americans have become more obese, non-alcoholic steatohepatitis has eclipsed viral hepatitis as the main etiology of cirrhosis and many have comorbid conditions, such as hypertension and diabetes. Studies estimate that 25% of cirrhotic individuals also have concomitant kidney disease; in addition to hepatorenal syndrome (HRS) and glomerulonephritis, diabetic and hypertensive nephropathies contribute to the renal disease burden.

Renal disease is a known negative prognostic indicator for mortality, but efforts to prospectively identify patients at risk have been limited by the poor performance of renal function estimating equations in the cirrhotic population. The ability to assess and even predict subclinical changes in renal function offers promise for improving care for individuals with cirrhosis, with earlier interventions for HRS, appropriate pharmacokinetic dosing of medications to avoid acute kidney injury (AKI), and timely access to transplantation.

No tool for estimating renal function in cirrhotic patients exists that fully accounts for end-stage liver pathophysiology. Existing equations designed to estimate glomerular filtration rate (eGFR) utilize readily available laboratory and body composition markers (e.g. serum creatinine and weight, respectively) to generate mathematical maps back to the gold standard measure of renal function – measured glomerular filtration rate (mGFR). Renal function, however, reflects the entire nephron mass, filtration (glomeruli) and secretion (tubules).

eGFR equations do not assess the secretory function of the kidney, which is responsible for the clearance of protein- or albumin-bound molecules such as medications. Available GFR equations have all been developed in cohorts of healthy people, with limited ethnic and gender diversity and fail to accurately perform at extremes of renal function; some rely on filtration markers, such as Cystatin C, which are influenced by body composition and adiposity.

Moreover, eGFR formulae rely on serum creatinine which is strongly influenced by muscle mass, such that the muscle wasting typically observed in individuals with liver disease leads to lower creatinine levels and further contributes to an overestimation of renal function in cirrhotics. We hypothesize that accounting for tubular secretory function and measures of muscle wasting will more accurately estimate renal function in cirrhotics than existing estimating equations. To address existing knowledge gaps in the assessment of renal function among cirrhotics, we will answer these unique aims:

1. To establish the relative contributions of the nephron to renal function among individuals with cirrhosis
2. To correlate morphometric and anthropometric measures of muscle wasting with serum creatinine
3. To derive a formula for eGFR that accurately estimates renal function in individuals with cirrhosis

Liver

Kidney (Locke PI, R01DK113980) - Living kidney donors continue to be a critical source of organs facilitating timely transplantation and excellent outcomes. Historically, living donors were healthy and free of baseline abnormalities. In response to the organ shortage, transplant centers now commonly approve donors classified as obese (body mass index (BMI) ≥ 30kg/m2), and currently, more than 25% of all living donors are considered obese at donation. Relaxation of selection criteria to include obese living donors has occurred despite a paucity of safety data. Determining candidacy for living donation among obese individuals remains challenging, as the appropriate BMI cutoff above which donation is no longer safe is unknown. Most centers have implemented a “one size fits all” approach to setting BMI limits (e.g. individuals with BMI > 35kg/m2 are excluded from donation) rather than a personalized approach that accounts for individual baseline differences. In the general population, obese individuals have a 3.57-fold higher risk for ESRD compared to individuals with normal weight (BMI 18.5-24.9 kg/m2).

Donors are not drawn from the general population, but are very carefully screened, and the impact of obesity might be different in these healthier individuals. In a recent multi-cohort study of individuals healthy enough to be potential donors (healthy non-donors), the adjusted risk for ESRD associated with obesity was only 1.16-fold higher but varied significantly based on other baseline comorbidities. The true risk among obese living donors likely falls somewhere in between these estimates: obese living donors are otherwise healthy at baseline but lose half their nephron mass. Our preliminary findings suggest that risk for post-donation ESRD is significantly higher among obese compared with non-obese donors. However, it remains unclear if this risk is modified by other baseline comorbidities or obesity-related characteristics (e.g. BMI trajectory, metabolic syndrome), reflective of underlying differences between obese and non-obese persons, or directly attributable to donation itself.

We hypothesize that the impact of obesity on post-donation ESRD risk varies significantly by obesity-related characteristics and other comorbidities, and an obese phenotype exists in whom living kidney donation is safe. To better understand the relationship between obesity and risk for post-donation kidney failure, we will leverage and build upon an existing NIH-funded retrospective cohort study of live donors to assemble the largest cohort of obese living donors and will:

1. Explore the association of baseline health characteristics with risk for post-donation kidney failure among obese living kidney donors
2. Explore the association of obesity-specific risk factors with risk for post-donation kidney failure
3. Develop a tool for kidney failure risk among obese living donors; estimate risk for post-donation kidney failure among obese living donors directly attributable to donation.

Our findings will have a major impact on the practice of living donation among obese persons, informing critical aspects of donor selection, informed consent, and post-donation care.

Geographic Variation in Non-HCC MELD Exceptions and Its Effect on Liver Transplant Waitlist Outcomes, Cannon PI, K08 submitted)

Geographic variation in the model for end stage liver disease (MELD) score at transplant across donation service areas has fueled a major public policy debate over allocation of donor livers. An important caveat to this perceived disparity is the focus in allocation MELD, in which patients with lower calculated MELD scores may be assigned a higher score if their calculated MELD is thought to underestimate the risk of waitlist mortality. Analysis of calculated MELD at transplant demonstrates much less variation between regions. Indeed, some high allocation MELD regions actually have low calculated MELD scores relative to the rest of the country. The different picture painted by consideration of allocation versus calculated MELD scores highlight the critical role MELD exception points play in geographic differences in access to transplantation. A national liver review board was recently implemented to impose national standardization of MELD exception scores in an effort to mitigate geographic disparity.

A major potential flaw in this strategy is that it treats MELD scores and exception diagnoses as stationary risk factors, meaning that the risk of mortality associated with a given MELD score or exception diagnosis is assumed to be the same across geographic areas. We know that social determinants of health and access to care vary widely across the country, however, and that these differences have a significant impact on health outcomes. Imposing a geographically uniform MELD exception scoring policy that does not account for these important differences may have the unintended effect of overestimating the risk of waitlist mortality for exception patients (and thus awarding too much priority for transplantation) in some geographic regions while underestimating that risk in others, thus worsening geographic disparity rather than mitigating it.

Despite an abundance of literature regarding geographic disparity in liver transplantation, there is a shortage of studies that actually apply formal geospatial analytic techniques to geographically based questions facing the field. I propose to utilize such techniques to accomplish the following unique aims:

1. Determine the prevalence and appropriateness of MELD exceptions on a county level and diagnose the presence of geographic clusters where these exceptions provide an inappropriate advantage to transplant candidates with MELD exception scores.
2. Determine appropriate MELD exception scores which would mitigate disparities in waitlist mortality between exception and non-exception patients in each geographic area.
3. Simulate waitlist outcomes under an alternative allocation scenario where MELD exception points are assigned according to geographic region as determined in Aim 2. This study will provide a more granular and personalized approach to the estimation of waitlist mortality and prioritization for liver transplantation.

Kidney

Recently, attention has been re-focused on the geographic disparities in organ transplantation in the United States. While the geographic disparities have been known for all transplantable organs for many years, the United Network of Organ Sharing (UNOS) has recently proposed and approved organ allocation/redistribution policies for heart, lung, liver and kidney transplants in an attempt to create geographic equity. For kidney transplantation, the data and research for geographic disparities largely revolves around the chief metrics used for evaluation of kidney transplant program performance – transplant rate and time to transplant. Both of these metrics are very heavily influenced by the size of a centers kidney transplant waitlist. How patients are evaluated and added the kidney transplant waitlist is variable and dependent on center preference and practice. We evaluated these metrics in the United States by studying data on End Stage Renal Disease (from the United States Renal Data System/USRDS) and kidney transplantation (from the Scientific Registry of Transplant Recipients/SRTR) during 2014.

One goal of this study was to determine how well each state was able to use kidney transplantation as a modality of treatment in patients with kidney disease within their borders. This focused on waitlist additions and transplants performed within a state’s End Stage Renal Disease (ESRD) population. Waitlist rate varied 3.5 fold across states in the US in 2014. ESRD Burden (ESRD prevalence) in 2014 was greatest in the Southeast (contiguous states of LA, MS, AL, GA and SC). Despite the need in this area, the percentage of ESRD patients added to kidney transplant waitlists was lower than average. Kidney transplants performed per state ESRD population was lower in the Southeast than areas of lower ESRD prevalence, indicating the Southeast represents and area of great demand and lower organ supply. Future metrics and allocation proposals should be required to consider ESRD patient density, rather than waitlisted patients, in center performance.

ENGAGE (Locke- sitePI, R01DK111966) - As the kidney transplant waiting list continues to grow, the need for living kidney donors remains a priority within transplantation. The Epidemiology Research Group in Organ Transplantation (ERGOT) at Johns Hopkins University, led by Dr. Dorry Segev, has developed a program whereby community members are trained to fill the role of “Living Donor Champion”. These trained individuals act as coaches for kidney transplant candidates and assist them in identifying individuals who may be eligible to serve as their living kidney donor. Preliminary work as part of a pilot study (5KL2RR025006-04) recruited 15 participants who identified 25 individuals who were evaluated for organ donation. Additionally, once LDCs are in the door for the first session, retention is over 60%. In collaboration with Facebook, Dr. Segev’s group has also developed a smart phone application, called the Donor App, to encourage and facilitate conversations about end-stage renal disease (ESRD) and possible living donation by leveraging a patient’s online social network. The patient describes their ESRD experience to their network of Facebook friends, who are provided with links to learn about ESRD, dialysis, and the live donation process, including the associated risks. Friends can respond to the post, share it with their friends, and get information about becoming a live donor.

In a pilot study, 52 candidates were provided with the Donor App, resulting in the identification of 14 potential live donors. Therefore, under the leadership of Dr. Andrew Cameron, the Hopkins research team seeks to expand upon this early success and implement the Living Donor Champion program in other institutions. They hypothesize that the app may lower the activation energy necessary to initiate discussions about live donation and result in identification of potential donors similar to the success of the LDC program but with fewer resources required. UAB has been asked to participate as a subaward site in a multicenter randomized controlled trial which addresses the following aims:

1. To develop implementation protocols for the LDC program and the Facebook App that can later be used to deliver these interventions to diverse audiences
2. To compare the incidence of LDKT among waitlist candidates receiving the LDC intervention, the Facebook App intervention, and standard of care
3. To quantify treatment heterogeneity among different transplant centers and candidate racial/ ethnic subgroups and to refine implementation protocols based on this heterogeneity

Social network interventions to reduce race disparities in living kidney donation (Locke Site PI, R01DK114888) - End stage renal disease (ESRD) is among the ten leading causes of death for Americans, and its incidence and prevalence are rising, especially among non-white groups. Kidney transplantation is the most effective treatment option for many Americans with ESRD, but the number of Americans needing kidneys is currently much larger and rising much faster than the current number of transplants performed. Patients who seek transplants have one of two options: wait for a kidney from a deceased donor to become available or obtain a transplant from a living kidney donor. Deceased donor kidney transplant (DDKT) levels are projected to grow little over time, constrained by population aging and mortality patterns, but living donor kidney transplantation (LDKT) holds the prospect of substantial growth if healthy population members are willing and able to donate.

Unfortunately, there are large and persistent racial and ethnic disparities in LDKT rates that compound disparities in rates of ESRD. In a 2010 review, Waterman and colleagues wrote that a critical future direction to overcome racial/ethnic disparities in living donor kidney transplantation is “an exploration of the effectiveness of different strategies for involving patients’ families and social networks in learning about LDKT and locating potential living donors”. Subsequent research has answered this call by testing interventions to address these disparities by designing donor-facing interventions. For instance, the House Calls intervention (Rodrigue et al. 2014) compared the effectiveness of potential donor education efforts based in patient homes, transplant centers, and with the individual patient alone, and found that house calls were associated with elevated rates of LDKT. On the candidate-facing front, the TALK study (Boulware et al. 2013) exposed transplant candidates to videos and brochures in which kidney transplant candidates discussed their experiences discussing living donation with family and friends, focusing on the procedures involved in the evaluation and donation process. However, we believe that transplant candidates could benefit from additional guidance on key matters besides educating members of their family and friendship circles. With whom should they discuss donation? What should they say when they do? Previous interventions have offered little guidance on these critical matters.

LIVING DONOR NAVIGATOR (AMC21 – LOCKE PI) - The demand for kidney transplantation continues to greatly exceed the supply, and living kidney donors remain a critical source of organs for their loved ones. Living donor kidney transplantation (LDKT) has decreased in the US since 2004, and importantly, significant geographic disparities in likelihood of LDKT have been identified, with the southeastern US having the lowest rates. Transplant candidate-related and potential living donor-related factors, including difficulty asking family/friends to donate on one’s behalf and lack of knowledge about the donation process, respectively, have been implicated in lower donation rates. Programs have been developed to separate the advocacy role from the transplant candidate in order to overcome barriers associated with asking someone to donate on one’s behalf, and have demonstrated increases in living donor inquiries. Importantly, these programs were developed and implemented in resource-intense urban settings that afforded ready access to high-speed internet, cell phone service and close geographic proximity to urban-based transplant centers, limiting their generalizability to low-resource settings like the rural, southeastern US. Moreover, these programs failed to include targeted interventions to improve potential living donor comfort with the evaluation process, impeding sustained increases in LDKT. Living donor selection is a comprehensive process that begins with potential donor inquiry, screening of potential donors for absolute contraindications to donation (e.g. solitary kidney), evaluation, and ultimately approval. This process is time-consuming, overwhelming, and involves complex and frequent interactions with the healthcare system.

Not surprisingly, many potential living donors withdraw from the process prior to approval and donation. Multiple studies have demonstrated the feasibility and efficacy of patient navigator programs in improving outcomes, including more efficient use of healthcare systems. In order to address knowledge gaps within existing programs designed to increase living donation, we utilized the RE-AIM framework to develop and implement a novel Living Donor Navigator Program (LDN). LDN combines advocacy-training to overcome barriers in initiating conversations with and identification of potential living donors with the use of non-clinical navigators to guide donors through the evaluation process. Early results indicate a 7-fold increase in likelihood of an approved donor among LDN participants compared to non-participants; however, assessment of LDN reach and adoption demonstrated that geographic disparities among participants exist. We hypothesize that expansion of the LDN program to include telehealth delivery will overcome geographic disparities in access and facilitate sustained increases in living donation. To this end, we will address the following aims:

1. Conduct qualitative assessments to identify facilitators for LDN telehealth participation
2. Implement a LDN telehealth program
3. Compare the effectiveness of telehealth LDN model vs. standard of care for increasing living kidney donation