Outcomes of COVID-19 in hospitalized solid organ transplant recipients compared to a matched cohort of non-transplant patients at a national healthcare system in the United States.

Data describing outcomes of solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) are variable, and the association between SOT status and mortality remains unclear. In this study, we compare clinical outcomes of SOT recipients hospitalized with COVID-19 between March 10, and September 1, 2020, to a matched cohort of non-SOT recipients at a national healthcare system in the United States (US). From a population of 43 461 hospitalized COVID-19-positive patients, we created a coarsened exact matched cohort of 4035 patients including 128 SOT recipients and 3907 weighted matched non-SOT controls. Multiple logistic regression was used to evaluate association between SOT status and clinical outcomes. Among the 4035 patients, median age was 60 years, 61.7% were male, 21.9% were Black/African American, and 50.8% identified as Hispanic/Latino ethnicity. Patients with a history of SOT were more likely to die within the study period when compared to matched non-SOT recipients (21.9% and 14.9%, respectively; odds ratio [OR] 1.93; 95% confidence interval [CI]: 1.18-3.15). Moreover, SOT status was associated with increased odds of receiving invasive mechanical ventilation (OR [95% CI]: 2.34 [1.51-3.65]), developing acute kidney injury (OR [95% CI]: 2.41 [1.59-3.65]), and receiving vasopressor support during hospitalization (OR [95% CI]: 2.14 [1.31-3.48]).

Prevalence of frailty among kidney transplant candidates and recipients in the United States: Estimates from a National Registry and Multicenter Cohort Study.

Frailty, a measure of physiologic reserve, is associated with poor outcomes and mortality among kidney transplant (KT) candidates and recipients. There are no national estimates of frailty in this population, which may help patient counseling and resource allocation at transplant centers. We studied 4616 KT candidates and 1763 recipients in our multicenter prospective cohort of frailty from 2008-2018 with Fried frailty measurements. Using Scientific Registry of Transplant Recipients (SRTR) data (KT candidates = 560 143 and recipients = 243 508), we projected the national prevalence of frailty (for KT candidates and recipients separately) using standardization through inverse probability weighting, accounting for candidate/recipient, donor, and transplant factors. In our multicenter cohort, 13.3% of KT candidates were frail at evaluation; 8.2% of LDKT recipients and 17.8% of DDKT recipients were frail at transplantation. Projected nationally, our modeling strategy estimated 91 738 KT candidates or 16.4% (95% confidence interval [CI] 14.4%-18.4%) of all KT candidates during the study period were frail, and that 34 822 KT recipients or 14.3% (95% CI 12.3%-16.3%) of all KT recipients were frail (LDKT = 8.2%; DDKT = 17.8%). Given the estimated national prevalence of frailty, transplant programs should consider assessing the condition during KT evaluation to improve patient counseling and resource allocation along with identification of recipients at risk for poor outcomes.

Frailty and Access to Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Frailty, a syndrome distinct from comorbidity and disability, is clinically manifested as a decreased resistance to stressors and is present in up to 35% of patient with ESKD. It is associated with falls, hospitalizations, poor cognitive function, and mortality. Also, frailty is associated with poor outcomes after kidney transplant, including delirium and mortality. Frailty is likely also associated with decreased access to kidney transplantation, given its association with poor outcomes on dialysis and post-transplant. Yet, clinicians have difficulty identifying which patients are frail; therefore, we sought to quantify if frail kidney transplant candidates had similar access to kidney transplantation as nonfrail candidates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied 7078 kidney transplant candidates (2009-2018) in a three-center prospective cohort study of frailty. Fried frailty (unintentional weight loss, grip strength, walking speed, exhaustion, and activity level) was measured at outpatient kidney transplant evaluation. We estimated time to listing and transplant rate by frailty status using Cox proportional hazards and Poisson regression, adjusting for demographic and health factors. RESULTS: The mean age was 54 years (SD 13; range, 18-89), 40% were women, 34% were black, and 21% were frail. Frail participants were almost half as likely to be listed for kidney transplantation (hazard ratio, 0.62; 95% confidence interval, 0.56 to 0.69; P<0.001) compared with nonfrail participants, independent of age and other demographic factors. Furthermore, frail candidates were transplanted 32% less frequently than nonfrail candidates (incidence rate ratio, 0.68; 95% confidence interval, 0.58 to 0.81; P<0.001). CONCLUSIONS: Frailty is associated with lower chance of listing and lower rate of transplant, and is a potentially modifiable risk factor.

The Impact of the mKidney mHealth System on Live Donor Follow-Up Compliance: Protocol for a Randomized Controlled Trial.

BACKGROUND: Every year, more than 5500 healthy people in the United States donate a kidney for the medical benefit of another person. The Organ Procurement and Transplantation Network (OPTN) requires transplant hospitals to monitor living kidney donors (LKDs) for 2 years postdonation. However, the majority (115/202, 57%) of transplant hospitals in the United States continue to fail to meet nationally mandated requirements for LKD follow-up. A novel method for collecting LKD follow-up is needed to ease both the transplant hospital-level and patient-level burden. We built mKidney-a mobile health (mHealth) system designed specifically to facilitate the collection and reporting of OPTN-required LKD follow-up data. The mKidney mobile app was developed on the basis of input elicited from LKDs, transplant providers, and thought leaders. OBJECTIVE: The primary objective of this study is to evaluate the impact of the mKidney smartphone app on LKD follow-up rates. METHODS: We will conduct a two-arm randomized controlled trial (RCT) with LKDs who undergo LKD transplantation at Methodist Specialty and Transplant Hospital in San Antonio, Texas. Eligible participants will be recruited in-person by a study team member at their 1-week postdonation clinical visit and randomly assigned to the intervention or control arm (1:1). Participants in the intervention arm will receive the mHealth intervention (mKidney), and participants in the control arm will receive the current standard of follow-up care. Our primary outcome will be policy-defined complete (all components addressed) and timely (60 days before or after the expected visit date) submission of LKD follow-up data at required 6-month, 1-year, and 2-year visits. Our secondary outcome will be hospital-level compliance with OPTN reporting requirements at each visit. Data analysis will follow the intention-to-treat principle. Additionally, we will collect quantitative and qualitative process data regarding the implementation of the mKidney system. RESULTS: We began recruitment for this RCT in May 2018. We plan to enroll 400 LKDs over 2 years and follow participants for the 2-year mandated follow-up period. CONCLUSIONS: This pilot RCT will evaluate the impact of the mKidney system on rates of LKD and hospital compliance with OPTN-mandated LKD follow-up at a large LKD transplant hospital. It will provide valuable information on strategies for implementing such a system in a clinical setting and inform effect sizes for future RCT sample size calculations. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11000.

Early Changes in Kidney Distribution under the New Allocation System.

The Kidney Allocation System (KAS), a major change to deceased donor kidney allocation, was implemented in December 2014. Goals of KAS included directing the highest-quality organs to younger/healthier recipients and increasing access to deceased donor kidney transplantation (DDKT) for highly sensitized patients and racial/ethnic minorities. Using national registry data, we compared kidney distribution, DDKT rates for waitlist registrants, and recipient characteristics between January 1, 2013, and December 3, 2014 (pre-KAS) with those between December 4, 2014, and August 31, 2015 (post-KAS). Regional imports increased from 8.8% pre-KAS to 12.5% post-KAS; national imports increased from 12.7% pre-KAS to 19.1% post-KAS (P<0.001). The proportion of recipients >30 years older than their donor decreased from 19.4% to 15.0% (P<0.001). The proportion of recipients with calculated panel-reactive antibody =100 increased from 1.0% to 10.3% (P<0.001). Overall DDKT rate did not change as modeled using exponential regression adjusting for candidate characteristics (P=0.07). However, DDKT rate (incidence rate ratio, 95% confidence interval) increased for black (1.19; 1.13 to 1.25) and Hispanic (1.13; 1.05 to 1.20) candidates and for candidates aged 18-40 (1.47; 1.38 to 1.57), but declined for candidates aged >50 (0.93; 0.87 to 0.98 for aged 51-60 and 0.90; 0.85 to 0.96 for aged >70). Delayed graft function in transplant recipients increased from 24.8% pre-KAS to 29.9% post-KAS (P<0.001). Thus, in the first 9 months under KAS, access to DDKT improved for minorities, younger candidates, and highly sensitized patients, but declined for older candidates. Delayed graft function increased substantially, possibly suggesting poorer long-term outcomes.

Histocompatibility considerations for kidney paired donor exchange programs.

PURPOSE OF REVIEW: To highlight the role of histocompatibility testing in kidney paired donor (KPD) exchange programs as well as the new technological advances that may have an effect on KPD. RECENT FINDINGS: Technological advances in human leukocyte antigen (HLA) antibody identification using the Luminex single-antigen bead multiplexing platform have facilitated virtual cross-matching and the ability to accurately match donor/recipient pairs through KPD. A knowledge of the limitations of this assay is the key to proper interpretation of the data and maximization of this new technology. Novel assays such as C1q and Ig subclass identification may be useful in further determining which HLA antibodies are clinically relevant. SUMMARY: KPD is an established method for increasing access to transplantation for patients with incompatible live donors. Advances in histocompatibility testing have played a role in the success of KPD.

A virtual crossmatch protocol significantly increases access of highly sensitized patients to deceased donor kidney transplantation.

BACKGROUND: Patients with preexisting antihuman leukocyte antigen (HLA) antibodies (sensitized patients) are more likely to have a positive crossmatch with possible donors and have a lower likelihood of receiving a renal transplant with longer wait times. A virtual crossmatch protocol using solid-phase technology to determine the specificity of anti-HLA antibodies may improve the probability of identifying a crossmatch-negative compatible donor and increase access of sensitized patients to kidney transplantation. METHODS: A virtual crossmatch protocol was implemented on October 1, 2006 with solid-phase HLA antibody characterization for all sensitized patients on the waiting list. Transplant rates for the period from October 2006 to June 2008 were compared with Scientific Registry of Transplant Recipients (SRTR) data from 2006 to determine national transplant rates for sensitized patients. RESULTS: SRTR data for 2006 showed that nationally 590 of 10,659 transplants (5.5%) were in-patients with panel reactive antibody (PRA) more than or equal to 80%. During 2006 to 2008, after initiation of the virtual crossmatch protocol, we performed 122 deceased donor kidney transplants, of which 15 (12.3%) sensitized patients (PRA>or=80%) received transplants (P=0.004 compared with SRTR national data), with 9 (7.4%) patients having a PRA more than 90%. The virtual crossmatch protocol was predictive of a negative-final crossmatch and eliminated the use of preliminary cross-matching with attendant cost savings of more than $100,000. CONCLUSION: Initiation of a virtual crossmatch protocol using solid-phase histocompatibility techniques significantly increased access of sensitized patients to kidney transplantation and was more cost effective. Usage of a virtual crossmatch may facilitate greater sharing of kidneys to improve access to transplantation for sensitized recipients.

Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway.

The CD28/B7 costimulatory pathway is generally considered dispensable for memory T cell responses, largely based on in vitro studies demonstrating memory T cell activation in the absence of CD28 engagement by B7 ligands. However, the susceptibility of memory CD4 T cells, including central (CD62L(high)) and effector memory (T(EM); CD62L(low)) subsets, to inhibition of CD28-derived costimulation has not been closely examined. In this study, we demonstrate that inhibition of CD28/B7 costimulation with the B7-binding fusion molecule CTLA4Ig has profound and specific effects on secondary responses mediated by memory CD4 T cells generated by priming with Ag or infection with influenza virus. In vitro, CTLA4Ig substantially inhibits IL-2, but not IFN-gamma production from heterogeneous memory CD4 T cells specific for influenza hemagglutinin or OVA in response to peptide challenge. Moreover, IL-2 production from polyclonal influenza-specific memory CD4 T cells in response to virus challenge was completely abrogated by CTLA4Ig with IFN-gamma production partially inhibited. When administered in vivo, CTLA4Ig significantly blocks Ag-driven memory CD4 T cell proliferation and expansion, without affecting early recall and activation. Importantly, CTLA4Ig treatment in vivo induced a striking shift in the phenotype of the responding population from predominantly T(EM) in control-treated mice to predominantly central memory T cells in CTLA4Ig-treated mice, suggesting biased effects of CTLA4Ig on T(EM) responses. Our results identify a novel role for CD28/B7 as a regulator of memory T cell responses, and have important clinical implications for using CTLA4Ig to abrogate the pathologic consequences of T(EM) cells in autoimmunity and chronic disease.

Novel phenotypes and migratory properties distinguish memory CD4 T cell subsets in lymphoid and lung tissue.

Memory T cells are heterogeneous in expression of lymph node homing receptors, delineating "central-memory" (TCM, CD62Lhi/CCR7+) and "effector-memory" (TEM, CD62Llo/CCR7-) subsets that migrate to lymphoid and non-lymphoid tissues, respectively. It is not known how these subsets arise or how homing receptor expression and tissue origin determine their functional and migratory properties. Here, we investigated the role of CD62L expression in the generation, function, distribution and migration of heterogeneous memory CD4 T cells specific for influenza hemagglutinin (HA). We found that CD62Lhi and CD62Llo memory subsets are generated independent of CD62L expression by the activated precursor, and both subsets distribute into spleen and lung. Functionally, spleen- and lung-derived CD62L memory subsets produce effector cytokines at similar kinetics but differ strikingly in cell surface phenotype and migration: the CD62Llo memory subset expresses a classic memory phenotype (CD45RBlo/CD44hi/CD11a(hi)), while the CD62Lhi subset expresses an unconventional phenotype (CD45RBhi/CD44int/CD11a(int)), defining a new polyclonal memory subset. The CD62Lhi subset also trafficked more efficiently than CD62Llo cells into lymph nodes; however, only lung but not spleen CD62Llo memory T cells homed to lung. Our results reveal novel phenotypic heterogeneity of memory CD4 T cells co-segregating with CD62L expression and tissue-specific tropism of non-lymphoid memory CD4 T cells.

Anti-CD3 priming generates heterogeneous antigen-specific memory CD4 T cells.

Anti-CD3 activation of peripheral T cells is used in adoptive immunotherapy for cancer and HIV infection, but the long-term fate of anti-CD3-primed T cells in vivo is not known. In this study, we demonstrate that anti-CD3-mediated activation of influenza hemagglutinin (HA)-specific TCR-transgenic CD4 T cells results in generation of a long-lived HA-specific memory CD4 T cell population when transferred into lymphocyte-deficient and intact mouse hosts. This anti-CD3-primed memory population is indistinguishable from HA peptide-primed memory CD4 T cells in terms of phenotype, rapid recall function, and enhanced proliferative capacity. Moreover, anti-CD3 priming generates phenotypically heterogeneous memory subsets in lymphoid and non-lymphoid sites. Our results suggest that anti-CD3 has potential efficacy in generating memory responses in adoptive immunotherapies and vaccines and that the tissue distribution and maintenance of heterogeneous lymphoid and non-lymphoid memory T cell subsets are a stochastic process that can occur independent of antigen or TCR specificity.

Long-term islet graft survival in NOD mice by abrogation of recurrent autoimmunity.

Islet transplantation has great potential for curing type 1 diabetes; however, long-term islet survival using conventional immunosuppression remains elusive. We present a novel strategy for inducing long-lasting islet graft survival in diabetic NOD mice in the absence of posttransplant immunosuppression by initial treatment with antilymphocyte serum (ALS) followed by coadministration of donor pancreatic lymph node cells (PLNCs). When treated with ALS/PLNC, diabetic NOD mice become normoglycemic and tolerated minor antigen-disparate islet grafts for >100 days and syngeneic islet grafts indefinitely. Donor T-cells are required for graft prolongation, and tolerant hosts have long-term donor T-cell chimerism. Strikingly, host autoreactive T-cells from mice with long-surviving islet grafts predominantly produce interleukin-4, whereas autoreactive T-cells from mice that rejected their islet grafts predominantly produce interferon-gamma. We thus demonstrate a clinically relevant approach for ablation of recurrent autoimmunity in islet transplantation, involving donor lymphocyte-driven alteration of pathogenic autoreactive T-cells.

Memory T cells in transplantation: generation, function, and potential role in rejection.

The adaptive immune system is endowed with long-lived memory to recall previous antigen encounters and respond more effectively to them. Memory immune responses are mediated by antigen-specific memory T lymphocytes that exhibit enhanced function compared with naïve T cells that have never encountered antigen. While the generation of memory T cells specific for pathogens is beneficial in providing protective immunity, memory T cells specific for alloantigens can be deleterious to the recipient of a transplanted organ. In graft rejection, memory T cells mediate accelerated, "second-set" rejection and their presence has been associated with increased propensity for early rejection. Recent findings have demonstrated that alloreactive memory T cells can be generated via exposure to alloantigens, as well as stimuli that are cross-reactive with alloantigens, and are therefore likely present in "naïve" individuals. This review focuses on the characteristics of memory T cells which make them of special interest to the transplant community, including differential activation requirements, broad homing properties, and resistance to tolerance induction. The multiple ways in which memory T cells can contribute to early and late graft rejection are discussed, as well as potential targets for combating alloreactive memory to be considered in the future design of tolerance induction strategies.

Allogeneic parenchymal and hematopoietic tissues differ in their ability to induce deletion of donor-reactive T cells.

The establishment of immune tolerance to self antigen expressed exclusively in the periphery is a crucial yet incompletely understood feature of the immune system. A dominant concept of peripheral tolerance has been that exposure of T cells to signal one, the TCR-MHC interaction, in the absence of signal two, or costimulation, is a major mechanism of peripheral tolerance. This model suggests that any cell type that expresses MHC-peptide complexes, be they of self or foreign origin, should have the capacity to tolerize antigen-specific T cells when critical costimulatory interactions are interrupted. However, a spectrum of responses, from permanent engraftment to rapid rejection, has been observed in various transplantation models utilizing costimulatory blockade. Therefore we undertook a series experiments to directly assess the tolerogenic potential of donor hematopoietic and parenchymal cells. We find that allogeneic tissues differ profoundly in their ability to promote peripheral tolerance concurrent with combined blockade of B7-CD28 and CD40-CD40L pathways. Non-vascularized and vascularized parenchymal grafts as well as donor-specific transfusions promote varying degrees of donor-specific hyporesponsiveness, but fail to induce donor-reactive T-cell deletion; whereas establishment of stable hematopoietic chimerism promotes specific tolerance mediated by deletion of donor-reactive cells in the periphery.