Impact of Donor Warm Ischemia Time on Graft Survival for Donation After Circulatory Death Kidney Transplantation.

BACKGROUND: The utilization of kidneys donated after circulatory death (DCD) is an important strategy to address the ongoing shortage of organs suitable for transplantation in the United States. However, the nonuse rate of DCD kidneys remains high compared with kidneys donated after brain death (DBD) because of concerns regarding the injury incurred during donor warm ischemia time (DWIT). Therefore, we investigated the impact of DWIT on the risk of death-censored graft failure after DCD kidney transplantation (KT). METHODS: Retrospective analysis was conducted on DCD KTs using the Standard Transplant Analysis and Research data set. The association of DWIT with death-censored graft failure was evaluated using multivariable Cox proportional hazard regression, with reference to DCD KTs with Kidney Donor Risk Index (KDRI) of ≤0.78 and the median DWIT of 26 min. RESULTS: A total of 28 032 DCD kidney-alone transplants between January 2010 and December 2021 were studied. When stratified by KDRI, increasing DWIT was associated with a clinically significant increased risk for death-censored graft failure only in the subset of kidneys with KDRI >1.14 but not in those with KDRI >0.78-≤0.94 and >0.94-≤1.14, compared with the reference group. CONCLUSIONS: We suggest that clinicians should not decline kidneys on the basis of DWIT in favor of potential offers of DBD or other DCD kidneys with shorter DWIT, provided that their KDRI scores are within an acceptable limit. Our study highlights opportunities for more efficient usage of DCD kidneys and improving the shortage of transplantable organs.

Influence of induction therapy and antiretroviral regimen on outcomes in kidney transplant recipients living with human immunodeficiency.

PURPOSE: Kidney transplantation has a survival benefit for people with human immunodeficiency virus (HIV) and end-stage kidney disease, however increased rates of rejection remain an issue. Questions remain regarding the impact of induction immunosuppression therapy and antiretroviral (ARV) choice on long-term outcomes. METHODS: We performed a multicenter retrospective analysis of outcomes in recipients with HIV who received kidneys from donors without HIV transplanted between 2004 and 2019. The association between induction and ARV regimens and long-term outcomes including rejection, graft, and recipient survival over 5 years was investigated using Cox regression modeling. RESULTS: Seventy-eight kidney transplants (KT) performed in 77 recipients at five US transplant centers were included, with median follow up of 7.1 (4.3-10.7) years. Overall recipient and graft survival were 83% and 67%, respectively. Rejection occurred in 37% (29/78). Recipients with rejection were more likely to be younger, recipients of deceased donor organs, and Black. Receipt of rabbit anti-thymocyte globulin (rATG) induction without protease-inhibitor (PI)-based ARVs was associated with 83% lower risk of rejection (adjusted hazard ratio (aHR) 0.17 (95% CI 0.05-0.63), p =.007) and a non-statistically significantly lower risk of graft failure (aHR 0.18 (0.03-1.16), p =.07) when compared to those who received other induction and ARV combinations. CONCLUSIONS: In this multicenter retrospective study, we found a trend toward lower rejection and improved graft survival among those who received both rATG for induction and PI-sparing ARVs.

Indications, Techniques, and Barriers for Pancreas Transplant Biopsy: A Consensus Perspective From a Survey of US Centers.

BACKGROUND: Pancreas transplant biopsy practices for the diagnosis of rejection or other pathologies are not well described. METHODS: We conducted a survey of staff at US pancreas transplant programs (March 22, 2022, to August 22, 2022) to assess current program practices and perceptions about the utility and challenges in the performance and interpretation of pancreas allograft biopsies. RESULTS: Respondents represented 65% (76/117) of active adult pancreas transplant programs, capturing 66% of recent pancreas transplant volume in the United States. Participants were most often nephrologists (52%), followed by surgeons (46%), and other staff (4%). Pancreas allograft biopsies were performed mostly by interventional radiologists (74%), followed by surgeons (11%), nephrologists (8%), and gastroenterologists (1%). Limitations in the radiologist's or biopsy performer's comfort level or expertise to safely perform a biopsy, or to obtain sufficient/adequate samples were the two most common challenges with pancreas transplant biopsies. Pancreas transplant biopsies were read by local pathologists at a majority (86%) of centers. Challenges reported with pancreas biopsy interpretation included poor reliability, lack of reporting of C4d staining, lack of reporting of rejection grading, and inconclusive interpretation of the biopsy. Staff at a third of responding programs (34%) stated that they rarely or never perform pancreas allograft biopsies and treat presumed rejection empirically. CONCLUSIONS: This national survey identified significant variation in clinical practices related to pancreas allograft biopsies and potential barriers to pancreas transplant utilization across the United States. Consideration of strategies to improve program experience with percutaneous pancreas biopsy and to support optimal management of pancreas allograft rejection informed by histology is warranted.

Generating strategies for a national comeback in pancreas transplantation: A Delphi survey and US conference report.

In the United States, potential transplant candidates with insulin-dependent diabetes mellitus are inconsistently offered pancreas transplantation (PTx), contributing to a dramatic decline in pancreas allograft utilization over the past 2 decades. The American Society of Transplantation organized a workshop to identify barriers inhibiting PTx and to develop strategies for a national comeback. The 2-day workshop focused on 4 main topics: (1) referral/candidate selection, (2) organ recovery/utilization, (3) program performance/patient outcomes, and (4) enhanced education/research. Topics were explored through expert presentations, patient testimonials, breakout sessions, and strategic planning, including the identification of tasks for immediate focus. Additionally, a modified-Delphi survey was conducted among workshop members to develop and rate the importance of barriers, and the impact and feasibility of workgroup-identified improvement strategies. The panelists identified 16 barriers to progress and 44 strategies for consideration. The steps for a national comeback in PTx involve greater emphasis on efficient referral and candidate selection, better donor pancreas utilization practices, eliminating financial barriers to procurement and transplant, improving collaboration between transplant and diabetes societies and professionals, and increasing focus on PTx training, education, and research. Partnership between national societies, patient advocacy groups, and professionals will be essential to realizing this critical agenda.

Frailty and Kidney Transplant Waitlisting: A Single-Center Experience.

BACKGROUND: Frailty is widely prevalent among kidney transplant (KT) candidates and is associated with poor peri and post-transplant outcomes. Whether frailty is a modifiable risk factor in KT candidates is unknown. Efforts to intervene in frailty have been hindered by a lack of a standardized approach to testing and treating frailty in clinical practice. METHODS: Patients undergoing evaluation for kidney transplantation underwent frailty testing during their clinical visits using a combination of the Short Physical Performance Battery (SPPB) and Groningen Frailty Indicator (GFI) instruments. Scores from the SPPB and GFI were combined to stratify patients into 4 risk groups. Patients in the highest-risk groups were referred to physical therapy (PT) and returned for repeat frailty testing. Pre- and post-PT scores were compared with assessment for improvement. RESULTS: Forty patients met the criteria for PT, of which 16 (40%) completed PT and returned for repeat frailty testing. The mean SPPB score improved from 5.88 to 8.94 after PT (P < .01). The mean GFI score improved from 5.25 to 4.06 after PT but was not statistically significant (P = .081). CONCLUSIONS: Our unique approach of using 2 validated scores, SPPB and GFI, together addressed many components of frailty evaluation, including physical, cognitive, and psychosocial components. We used PT as a targeted intervention for addressing both the physical and non-physical impairments among frail KT candidates. Physical therapy was noted to have a positive impact on each of these components.

Medical and Surgical Management of the Failed Pancreas Transplant.

Despite the continued improvements in pancreas transplant outcomes in recent decades, a subset of recipients experience graft failure and can experience substantial morbidity and mortality. Here, we summarize what is known about the failed pancreas allograft and what factors are important for consideration of retransplantation. The current definition of pancreas allograft failure and its challenges for the transplant community are explored. The impacts of a failed pancreas allograft are presented, including patient survival and resultant morbidities. The signs, symptoms, and medical and surgical management of a failed pancreas allograft are described, whereas the options and consequences of immunosuppression withdrawal are reviewed. Medical and surgical factors necessary for successful retransplant candidacy are detailed with emphasis on how well-selected patients may achieve excellent retransplant outcomes. To achieve substantial medical mitigation and even pancreas retransplantation, patients with a failed pancreas allograft warrant special attention to their residual renal, cardiovascular, and pulmonary function. Future studies of the failed pancreas allograft will require improved reporting of graft failure from transplant centers and continued investigation from experienced centers.

Tixagevimab-Cilgavimab Decreases the Rate of SARS-CoV-2 Infection Among Solid Organ Transplant Recipients.

BACKGROUND: SARS-CoV-2 infection in solid organ transplant (SOT) recipients is associated with high morbidity and mortality. Tixagevimab/cilgavimab monoclonal antibodies were previously authorized for pre-exposure prophylaxis for immunocompromised individuals. We aimed to determine if tixagevimab/cilgavimab could prevent breakthrough SARS-CoV-2 infection in SOT recipients. MATERIAL AND METHODS: We conducted a prospective single-center study of SOT recipients who received tixagevimab/cilgavimab compared with those who did not. Demographics, type of transplant, immunosuppression regimen, COVID-19 vaccination status, and tixagevimab/cilgavimab administration data were collected. Participants were interviewed for 6 months or until they tested positive for SARS-CoV-2, whichever came first. Kaplan-Meier SARS-CoV-2-free survival curves were created based on the tixagevimab/cilgavimab administration date and SARS-CoV-2 infection. The log-rank test was used for comparison. Univariate and multivariate Cox regression models were constructed. RESULTS: The study cohort included 323 patients. Two hundred forty-eight received tixagevimab/cilgavimab, and 75 did not (control). COVID-19 vaccination rate was higher among tixagevimab/cilgavimab recipients than nontixagevimab/cilgavimab recipients (99.6% vs 92.0%; P < .001). Twenty-six patients in the tixagevimab/cilgavimab group (10.5%) and 23 in the control group (30.7%) tested positive for SARS-CoV-2 infection (P < .001). In a multivariate analysis, receipt of tixagevimab/cilgavimab and duration from transplant were both associated with reduced risk of SARS-CoV-2 infection (hazard ratio 0.431; 95% CI 0.224-0.828 and hazard ratio 0.917; 95% CI 0.861-0.978, respectively). CONCLUSION: During the study period, SOT recipients who received tixagevimab/cilgavimab had a significantly lower rate of SARS-CoV-2 infection. There were no differences in symptom frequency, illness severity, hospitalization rate, or treatment of SARS-CoV-2 infection.

The Perspectives of General Nephrologists Toward Transitions of Care and Management of Failing Kidney Transplants.

The management of failing kidney allograft and transition of care to general nephrologists (GN) remain a complex process. The Kidney Pancreas Community of Practice (KPCOP) Failing Allograft Workgroup designed and distributed a survey to GN between May and September 2021. Participants were invited via mail and email invitations. There were 103 respondents with primarily adult nephrology practices, of whom 41% had an academic affiliation. More than 60% reported listing for a second kidney as the most important concern in caring for patients with a failing allograft, followed by immunosuppression management (46%) and risk of mortality (38%), while resistant anemia was considered less of a concern. For the initial approach to immunosuppression reduction, 60% stop antimetabolites first, and 26% defer to the transplant nephrologist. Communicating with transplant centers about immunosuppression cessation was reported to occur always by 60%, and sometimes by 29%, while 12% reported making the decision independently. Nephrologists with academic appointments communicate with transplant providers more than private nephrologists (74% vs. 49%, p = 0.015). There are heterogeneous approaches to the care of patients with a failing allograft. Efforts to strengthen transitions of care and to develop practical practice guidelines are needed to improve the outcomes of this vulnerable population.

Conservative Kidney Management in Kidney Transplant Populations.

Conservative kidney management (CKM) has been increasingly accepted as a therapeutic option for seriously ill patients with advanced chronic kidney disease. CKM is active medical management of advanced chronic kidney disease without dialysis, with a focus on delaying the worsening of kidney disease and minimizing symptom burden. CKM may be considered a suitable option for kidney transplant recipients with poorly functioning and declining allografts, defined as patients with low estimated glomerular filtration rate (<20 mL/min per 1.73 m2) who are approaching allograft failure. CKM may be a fitting option for transplant patients facing high morbidity and mortality with or without dialysis resumption, and it should be offered as a choice for this patient population. In this review, we describe clinical considerations in caring for patients with poorly functioning and declining kidney allografts, especially the unique decision-making process around kidney replacement therapies. We discuss ways to incorporate CKM as an option for these patients. We also discuss financial and policy considerations in providing CKM for this population. Patients with poorly functioning and declining kidney allografts should be supported throughout transitions of care by an interprofessional and multidisciplinary team attuned to their unique challenges. Further research on when, who, and how to integrate CKM into existing care structures for patients with poorly functioning and declining kidney allografts is needed.

Impact of Blood Pressure Control on Graft Survival in Kidney Transplant Recipients.

BACKGROUND: Cardiovascular disease is the primary driver of morbidity and mortality in kidney transplant recipients. Hypertension is an important risk factor for development of cardiovascular disease in this population. Despite its important role in post-transplant outcomes, the blood pressure goals for kidney transplant recipients remain elusive. Current guidelines are based on observational data or data extrapolated from the chronic kidney disease population. METHODS: We followed 5-year blood pressure control of 378 kidney-alone transplant recipients at a single center and evaluated patient survival, graft survival, proteinuria, and rate of decline of kidney graft function. RESULTS: We found that a mean systolic blood pressure (BP) of 121 to 130 mm Hg was associated with better graft survival, slower decline of kidney allograft function, and lower degree of proteinuria when compared with a mean systolic BP ≤120 or >130 mm Hg. CONCLUSION: This study provides evidence for strict blood pressure control, systolic BP between 121 and 130 mm Hg, and also cautions against intensive control of systolic BP <120 mm Hg in kidney transplant recipients.

Comprehensive review: Frailty in pancreas transplant candidates and recipients.

Well-selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney-pancreas transplantation often experience dramatic improvements in quality of life and long-term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well-validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter.

Past and Present Policy Efforts in Achieving Racial Equity in Kidney Transplantation.

Purpose of Review: Inequities in transplant access for underrepresented minorities and people of low socioeconomic status persist. The central principle to organ allocation, the "Final Rule" is grounded on "equitable allocation of cadaveric organs," regardless of background, including race/ethnicity, gender, and socioeconomic status, and there have been ongoing previous and current efforts in achieving the goal of equity in access to transplantation. Recent Findings: Some of these disparities are caused by impeded access to the transplant waiting list (i.e., lack of referral to transplantation, socioeconomic constraints) and are somewhat beyond the purview of Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) policy. This paper examines past and present OPTN/UNOS policy efforts that strive to make access to kidney transplantation more racially equitable. Summary: Past and current policy efforts have brought the transplant community closer to the goal of achieving equity in access to transplantation. More comprehensive data collection may aid in further understanding existing challenges.

Willingness of Kidney and Liver Transplant Candidates to Receive HCV-Infected Organs.

INTRODUCTION: Transplantation of organs exposed to hepatitis C virus (HCV) into uninfected patients has yielded excellent outcomes and more widespread adoption may lead to fewer discarded organs and more transplants. Patient perceptions may shed light on acceptability and likely the uptake of HCV+/HCV- transplantation, gaps in understanding, and perceived benefits/risks. METHODS: We surveyed 435 uninfected kidney and liver transplant candidates at four centers about their attitude towards HCV-infected organs. RESULTS: The percentage of patients willing to accept HCV-infected organs increased from 58% at baseline, to 86% following education about HCV, direct-acting antiviral agents (DAAs), and HCV+/HCV- transplantation benefits/risks. More willingness to accept an organ from an intravenous drug user (P < 0.001), age >50 y old (P = 0.02), longer waiting time (P = 0.02), more trust in the transplant system (P = 0.03), and previous awareness of DAAs (P = 0.04) were associated with higher willingness to accept an HCV-infected organ. The most important reasons for accepting an HCV-infected organ were a decrease in waiting time (65%), lower mortality and morbidity risk while on the waiting list (63%), effectiveness of DAAs (54%), and a quicker return to higher functional status (51%). CONCLUSIONS: Presenting patients with information about HCV+/HCV- transplantation in small doses that are calibrated to account for varying levels of health and numerical literacy is recommended.

Protocol-based donor-derived cell-free DNA surveillance in kidney transplant recipients: A single-center experience.

AIMS: Donor-derived cell-free DNA (dd-cfDNA) surveillance testing has never been studied in comparison with other surveillance tests. In this study we aim to describe our center's clinical experience with routine dd-cfDNA monitoring and to assess whether monitoring dd-cfDNA by protocol provides additional information that aids in detection of acute rejection. MATERIALS AND METHODS: We implemented the dd-cfDNA (Allosure) surveillance protocol in addition to measurements of serum creatinine, proteinuria, and donor-Specific antibody. We retrospectively reviewed all kidney recipients transplanted from July 2018 to April 2020. 366 dd-cfDNA test results were reviewed from 82 patients. RESULTS: There were 13/366 positive dd-cfDNA tests in 8/82 patients. Five of the 8 patients had kidney biopsy which showed: 3 rejections (1 antibody-mediated rejection, 1 T-cell-mediated rejection, and 1 mixed), 1 acute tubular necrosis, and 1 transplant glomerulopathy. The remaining 3 patients did not undergo a biopsy and repeat dd-cfDNA testing improved without intervention. In the 353/366 negative dd-cfDNA tests in 74 patients: 7 patients underwent a biopsy: 1 patient with increased creatinine showed borderline cellular rejection, 3 had recurrent disease (membranoproliferative glomerulonephritis, diabetes mellitus, immunoglobulin A nephropathy), and 3 showed interstitial fibrosis and tubular atrophy. dd-cfDNA levels were not elevated in recipients with infection (BK viruria/viremia, CMV viremia, or urinary tract infection (UTI). CONCLUSION: The addition of surveillance dd-cfDNA testing resulted in marginal added benefit. Whether this offsets the cost of testing needs to be further explored. In our cohort of low-risk patients, the cost of protocol dd-cfDNA testing may not be justified by its limited benefits.

Apolipoprotein L1 Opinions of African American Living Kidney Donors, Kidney Transplant Patients, and Nonpatients.

INTRODUCTION: The discovery of apolipoprotein L1 (ApoL1) has raised important ethical and clinical questions about genetic testing in the context of living and deceased kidney donation. Largely missing from this discussion are the perspectives of those African Americans (AA) most likely to be impacted by ApoL1 testing. METHODS: We surveyed 331 AA potential and former living kidney donors (LKDs), kidney transplant candidates and recipients, and nonpatients at three United States transplant programs about their ApoL1 testing attitudes. RESULTS: Overall, 72% felt that transplant programs should offer ApoL1 testing to AA potential LKDs. If a potential LKD has the high-risk genotype, 79% felt that the LKD should be allowed to make their own donation decision or participate in shared decision-making with transplant doctors. More than half of the potential LKDs (58%) would undergo ApoL1 testing and 81% of former LKDs would take the test now if offered. Most transplant candidates expressed a low likelihood of accepting a kidney from a LKD (79%) or a deceased donor (67%) with the high-risk genotype. CONCLUSIONS: There is strong support among LKDs and transplant patients for ApoL1 testing when evaluating potential kidney donors of African ancestry. Inclusion of AA stakeholders in developing guidelines and educational programs for ApoL1 testing is critical.

Coronavirus Disease 2019 Messenger RNA Vaccine Immunogenicity in Immunosuppressed Individuals.

Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals.