Publications by authors named "Roslyn B Mannon"

116 Publications

Chronic Allograft Injury.

Clin J Am Soc Nephrol 2021 Apr 5. Epub 2021 Apr 5.

Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska

With the incremental improvements in long-term kidney transplant survival, there is renewed focus on what causes failure of the transplanted allograft. Over the past decade, our understanding of the injuries that lead to loss of graft function over time has evolved. Chronic allograft injury includes both immune-mediated and nonimmune-mediated injuries, which may involve the organ donor, the recipient, or both. The targets of injury include the kidney tubular epithelium, the endothelium, and the glomerulus. As a response to injury, there are the expected tissue remodeling and repair processes. However, if inflammation persists, which is not uncommon in the transplant setting, the resulting maladaptive response is matrix deposition and/or fibrosis. This ultimately leads to declining graft function and, finally, failure. With our advancing knowledge of the multiple etiologies and mechanisms, enhanced by more recent cohort studies in humans, there is an opportunity to identify those at greater risk to initiate new strategies to ameliorate the process. Although the most recent studies focus on immune-mediated injuries, there is a critical need to identify both markers of injury and mechanisms of injury. In this review, we highlight the findings of recent studies, highlight the potential therapeutic targets, and identify the continued unmet need for understanding the mechanisms of late graft failure.
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http://dx.doi.org/10.2215/CJN.15590920DOI Listing
April 2021

Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity.

Am J Transplant 2021 Mar 16. Epub 2021 Mar 16.

Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity.
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http://dx.doi.org/10.1111/ajt.16561DOI Listing
March 2021

COVID-19 test result reporting for deceased donors: Emergent policies, logistical challenges, and future directions.

Clin Transplant 2021 Mar 10:e14280. Epub 2021 Mar 10.

University of Iowa, Iowa City, IA, USA.

The coronavirus disease 2019 (COVID-19) pandemic poses unprecedented challenges to the transplant community, including organ procurement organizations (OPOs), transplant centers, regulatory agencies, and recipient candidates. Access to timely, accurate information on the status of deceased donor viral infection is essential in determining organ acceptance. The Organ Procurement and Transplantation Network expeditiously added fields to collect these data; however, use of the data collection fields was not uniform nationally. Standardized, field-defined data capture and reporting are vital to ensure optimal organ utilization during this pandemic, and to prepare the community for subsequent challenges.
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http://dx.doi.org/10.1111/ctr.14280DOI Listing
March 2021

Risk Prediction for Delayed Allograft Function: Analysis of The Deterioration of Kidney Allograft Function (Dekaf) Study Data.

Transplantation 2021 Feb 23. Epub 2021 Feb 23.

University of Minnesota, Department of Surgery, Transplantation Division, Minneapolis, MN; University of Minnesota, School of Public Health, Biostatistics Division, Minneapolis, MN; University of Alabama, Department of Medicine, Birmingham, AL; Hennepin Healthcare, Division of Nephrology, Minneapolis, MN; University of Manitoba, Department of Internal Medicine, Winnipeg, Manitoba. University of Iowa, Department of Internal Medicine, Iowa City, IA; Mayo Clinic, Division of Nephrology & Hypertension, Department of Internal Medicine, Rochester, MN; Mayo Clinic, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Rochester, MN; University of California, UCLA Immunogenetics Center, Los Angeles, CA Univeristy of Nebraska Medical Center and Nebraska-Western Iowa Veterans Affairs Medical Center, Omaha, NE.

Background: Delayed graft function (DGF) of a kidney transplant results in increased cost and complexity of management. For clinical care or a DGF trial, it would be ideal to accurately predict individual DGF risk and provide preemptive treatment. A calculator developed by Irish et al has been useful for predicting population, but not individual risk.

Methods: We analyzed the Irish calculator (IC) in the DeKAF prospective cohort (incidence of DGF= 20.4%) and investigated potential improvements.

Results: We found that the predictive performance of the calculator in those meeting Irish inclusion criteria was comparable to that reported by Irish et. al. For cohorts excluded by Irish: a) in pump-perfused kidneys the IC over-estimated DGF risk; b) in simultaneous pancreas kidney (SPK) transplants, the DGF risk was exceptionally low. For all 3 cohorts, there was considerable overlap in IC scores between those with and those without DGF. Using a modified definition of DGF - excluding those with a single dialysis in the first 24 hours posttransplant - we found that the calculator had similar performance as with the traditional DGF definition. Studying whether DGF prediction could be improved, we found that recipient cardiovascular disease was strongly associated with DGF even after accounting for IC predicted risk.

Conclusions: The IC can be a useful population guide for predicting DGF in the population for which it was intended, but has limited scope in expanded populations (SPK, pump) and for individual risk prediction. DGF risk prediction can be improved by inclusion of recipient cardiovascular disease.
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http://dx.doi.org/10.1097/TP.0000000000003718DOI Listing
February 2021

Banff and ABMR: Are we going in the right direction?

Am J Transplant 2021 Feb 23. Epub 2021 Feb 23.

Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

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http://dx.doi.org/10.1111/ajt.16546DOI Listing
February 2021

Precision Dosing for Tacrolimus Using Genotypes and Clinical Factors in Kidney Transplant Recipients of European Ancestry.

J Clin Pharmacol 2021 Jan 29. Epub 2021 Jan 29.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra- and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin-induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate-release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed-effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted.
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http://dx.doi.org/10.1002/jcph.1823DOI Listing
January 2021

Impact of Subclinical Borderline Inflammation on Kidney Transplant Outcomes.

Transplant Direct 2021 Feb 26;7(2):e663. Epub 2021 Jan 26.

Department of Medicine, University of Alabama School of Medicine, Birmingham, AL.

Background: Surveillance biopsies permit early detection of subclinical inflammation before clinical dysfunction, but the impact of detecting early subclinical phenotypes remains unclear.

Methods: We conducted a single-center retrospective cohort study of 441 consecutive kidney transplant recipients between 2015 and 2018 with surveillance biopsies at 6 months post-transplant. We tested the hypothesis that early subclinical inflammation (subclinical borderline changes, T cell-mediated rejection, or microvascular injury) is associated with increased incidence of a composite endpoint including acute rejection and allograft failure.

Results: Using contemporaneous Banff criteria, we detected subclinical inflammation in 31%, with the majority (75%) having a subclinical borderline phenotype (at least minimal inflammation with mild tubulitis [>i0t1]). Overall, subclinical inflammation was independently associated with the composite endpoint (adjusted hazard ratio, 2.88; 1.11-7.51;  = 0.03). The subgroup with subclinical borderline inflammation, predominantly those meeting the Banff 2019 i1t1 threshold, was independently associated with 5-fold increased hazard for the composite endpoint ( = 0.02). Those with concurrent subclinical inflammation and subclinical chronic allograft injury had worse outcomes. The effect of treating subclinical inflammation was difficult to ascertain in small heterogeneous subgroups.

Conclusions: Subclinical acute and chronic inflammation are common at 6 months post-transplant in kidney recipients with stable allograft function. The subclinical borderline phenotype with both tubulitis and interstitial inflammation was independently associated with poor long-term outcomes. Further studies are needed to elucidate the role of surveillance biopsies for management of allograft inflammation in kidney transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000001119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837932PMC
February 2021

Sex matters: COVID-19 in kidney transplantation.

Kidney Int 2021 03 5;99(3):555-558. Epub 2021 Jan 5.

Canadian Donation and Transplantation Research Program, Edmonton, Alberta, Canada; Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada; Centre for Outcomes Research, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783460PMC
March 2021

Practicing With Uncertainty: Kidney Transplantation During the COVID-19 Pandemic.

Am J Kidney Dis 2021 Jan 1. Epub 2021 Jan 1.

Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic required transplant nephrologists, surgeons, and care teams to make decisions about the full spectrum of transplant program operations and clinical practices in the absence of experience or data. Initially, across the country, there was a reduction in kidney transplant procedures and a striking pause in the conduct of living donation and living-donor transplant surgeries. Aspects of candidate evaluation and follow-up rapidly converted to telehealth. Months into the pandemic, much has been learned from experiences worldwide, yet many questions remain. In this Perspective, we reflect on some of the practice decisions made by the transplant community in the initial response to the pandemic and consider lessons learned, including those related to the risks, benefits, and logistical considerations of proceeding with versus delaying deceased-donor transplantation, living donation, and living-donor transplantation during the pandemic. We review the evolution of therapeutic strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their use in transplant recipients, current consensus related to immunosuppression management in infected transplant recipients, and emerging information on vaccination against SARS-CoV-2. We share our thoughts on research priorities, discuss the areas in which we are still practicing with uncertainty, and look ahead to the next phase of the pandemic response.
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http://dx.doi.org/10.1053/j.ajkd.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946342PMC
January 2021

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Kidney Int 2020 Dec 24. Epub 2020 Dec 24.

Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA. Electronic address:

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.
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http://dx.doi.org/10.1016/j.kint.2020.12.015DOI Listing
December 2020

Industry partnerships in transplantation: How should AJT manage the inevitable conflict of interest?

Am J Transplant 2020 Dec 14. Epub 2020 Dec 14.

Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.1111/ajt.16447DOI Listing
December 2020

Survey of Clinician Opinions on Kidney Transplantation from Hepatitis C Virus Positive Donors: Identifying and Overcoming Barriers.

Kidney360 2020 Nov 25;1(11):1291-1299. Epub 2020 Nov 25.

University of Iowa, Iowa City, IA.

Background: Transplant practices related to use of organs from Hepatitis C virus infected donors (DHCV+) is evolving rapidly.

Methods: We surveyed U.S. kidney transplant programs by email and professional society listserv postings between 7/19-1/20 to assess attitudes, management strategies, and barriers related to use of viremic (nucleic acid testing (NAT)+) donor organs in HCV uninfected recipients.

Results: Staff at 112 unique programs responded, representing 54% of U.S. adult kidney transplant programs and 69% of adult deceased donor kidney transplant volume in 2019. Most survey respondents were transplant nephrologists (46%) or surgeons (43%). Among responding programs, 67% currently transplant DHCV antibody+/NAT- organs under a clinical protocol or as standard of care. By comparison, only 58% offer DHCV NAT+ kidney transplant to HCV- recipients, including 35% under clinical protocols, 14% as standard of care, and 9% under research protocols. Following transplant of DHCV NAT+ organs to uninfected recipients, 53% start direct acting antiviral agent (DAA) therapy after discharge and documented viremia. Viral monitoring protocols after DHCV NAT+ to HCV uninfected recipient kidney transplantation varied substantially. 56% of programs performing these transplants report having an institutional plan to provide DAA treatment if declined by the recipient's insurance. Respondents felt a mean decrease in waiting time of ≥18 months (range 0-60) justifies the practice. Program concerns related to use of DHCV NAT+ kidneys include insurance coverage concerns (72%), cost (60%), and perceived risk of transmitting resistant infection (44%).

Conclusions: Addressing knowledge about safety and logistical/financial barriers related to use of DHCV NAT+ kidney transplantation for HCV uninfected recipients may help reduced discards and expand the organ supply.
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http://dx.doi.org/10.34067/KID.0004592020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695231PMC
November 2020

Avoiding surveillance biopsy: Use of a noninvasive biomarker assay in a real-life scenario.

Clin Transplant 2021 Jan 24;35(1):e14145. Epub 2020 Nov 24.

Division of Nephrology, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Purpose: TruGraf™ blood test measures a specific gene expression signature in peripheral blood mononuclear cells for noninvasive assessment of kidney transplant recipients (KTRs) with stable renal function, excluding subclinical acute rejection (subAR) with high degree of confidence. Study objective was to correlate TruGraf™ test with 6-month surveillance biopsy (SBx).

Methods: Prospective, single-center study of 116 consecutive KTRs with SBx performed at 6 months post-transplant..TruGraf™ done at time of SBx; results compared with histology (Banff 2017) for concordance.

Results: Of 116 enrollees, 26 excluded, absent biopsy (n = 17), test quality control issues (n = 9), leaving 90 KTRs-66% deceased donor kidneys, 58% African American, and 59% male. TruGraf™ result negative in 67 subjects; 54 had normal biopsy, indicating SBx could have been avoided. Eight subjects had true positive result where biopsy justified. Unnecessary biopsy would have been performed in 15 subjects with false-positive TruGraf™, and subAR missed in 13 subjects with false-negative test. In overall population of 90 patients, SBx would have been avoided in 54 (60%).

Conclusions: Implementation of TruGraf™ testing in a "real-world" cohort at the time of SBx identified a significant proportion of KTRs that could have avoided SBx.
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http://dx.doi.org/10.1111/ctr.14145DOI Listing
January 2021

Is It Time for Operation Warp Speed in Transplant Research?

Authors:
Roslyn B Mannon

Transplant Direct 2020 Nov 20;6(11):e619. Epub 2020 Oct 20.

Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Nebraska-Western Iowa VA Medical Center, Omaha, NE.

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http://dx.doi.org/10.1097/TXD.0000000000001073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581020PMC
November 2020

Apolipoprotein L1: role in the evaluation of kidney transplant donors.

Curr Opin Nephrol Hypertens 2020 Nov;29(6):645-655

Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Purpose Of Review: To summarize the current state of evidence regarding the role of apolipoprotein L1 (APOL1) genotyping in evaluating donors for kidney transplantation.

Recent Findings: African ancestry is associated with an increased risk of kidney failure following living donation. Moreover, kidney transplants from African ancestry deceased donors have an increased risk of graft failure. Preliminary evidence suggests that APOL1 genotype may mediate at least a portion of this racial variation, with high-risk APOL1 genotypes defined by presence of two renal risk variants (RRVs). A pilot study 136 African ancestry living donors found that those with APOL1 high-risk genotypes had lower baseline kidney function and faster rates of kidney function decline after donation. To date, three retrospective studies identified a two-to-three times greater risk of allograft failure associated with kidneys from donors with high-risk APOL1 genotype. Active research initiatives seek to address unanswered questions, including reproducibility in large national samples, the role of 'second hits' injuries, and impact of recipient genotype, with a goal to build consensus on applications for policy and practice.

Summary: As evidence evolves, APOL1 genotyping may have applications for organ quality scoring in deceased donor kidney allocation, and for the evaluation and selection of living donor candidates.
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http://dx.doi.org/10.1097/MNH.0000000000000653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7741488PMC
November 2020

Survey of US Living Kidney Donation and Transplantation Practices in the COVID-19 Era.

Kidney Int Rep 2020 Nov 25;5(11):1894-1905. Epub 2020 Aug 25.

Organ Transplant Center, University of Iowa, Iowa City, Iowa, USA.

Introduction: The scope of the impact of the coronavirus disease 2019 (COVID-19) pandemic on living donor kidney transplantation (LDKT) practices is not well defined.

Methods: We surveyed US transplant programs to assess practices, strategies, and barriers to living LDKT during the COVID-19 pandemic. After institutional review board approval, the survey was distributed from 9 May 2020 to 30 May 2020 by e-mail and postings to professional society list-servs. Responses were stratified based on state COVID-19 cumulative incidence levels.

Results: Staff at 118 unique centers responded, representing 61% of US living donor recovery programs and 75% of LKDT volume in the prepandemic year. Overall, 66% reported that LDKT surgery was on hold (81% in "high" vs. 49% in "low" COVID-19 cumulative incidence states). A total of 36% reported that evaluation of new donor candidates had paused, 27% reported that evaluations were very much decreased (>0% to <25% typical), and 23% reported that evaluations were moderately decreased (25% to <50% typical). Barriers to LDKT surgery included program concerns for donor (85%) and recipient (75%) safety, patient concerns (56%), elective case restrictions (47%), and hospital administrative restrictions (48%). Programs with higher local COVID-19 cumulative incidence reported more barriers related to staff and resource diversion. Most centers continuing donor evaluations used remote strategies (video, 82%; telephone, 43%). As LDKT resumes, all programs will screen for COVID-19, although timeframe and modalities will vary. Recommendations for presurgical self-quarantine are also variable.

Conclusion: The COVID-19 pandemic has had broad impacts on LDKT practice. Ongoing research and consensus building are needed to reduce barriers, to guide optimal practices, and to support safe restoration of LDKT across centers.
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http://dx.doi.org/10.1016/j.ekir.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445484PMC
November 2020

The COVID-19 pandemic: A community approach.

Clin Transplant 2020 11 28;34(11):e14059. Epub 2020 Sep 28.

Transplanation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

An unprecedented global pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has quickly overwhelmed the health care systems worldwide. While there is an absence of consensus among the community in how to manage solid organ transplant recipients and donors, a platform provided by the American Society of Transplantation online community "Outstanding Questions in Transplantation," hosted a collaborative multicenter, multinational discussions to share knowledge in a rapidly evolving global situation. Here, we present a summary of the discussion in addition to the latest published literature.
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http://dx.doi.org/10.1111/ctr.14059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435543PMC
November 2020

A glossary for patient care and scientific dialogue from KDIGO.

Am J Transplant 2021 02 4;21(2):458-459. Epub 2020 Sep 4.

Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

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http://dx.doi.org/10.1111/ajt.16226DOI Listing
February 2021

Pharmacogenomics in kidney transplant recipients and potential for integration into practice.

J Clin Pharm Ther 2020 Dec 14;45(6):1457-1465. Epub 2020 Jul 14.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

What Is Known And Objective: Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice.

Methods: From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome-wide association study were included.

Results: Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton-pump inhibitors.

What Is New And Conclusion: Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants.

Clinical Trial: Genomics of Transplantation, clinicaltrials.gov (NCT01714440).
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http://dx.doi.org/10.1111/jcpt.13223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719579PMC
December 2020

The Advancing American Kidney Health (AAKH) Executive Order: Promise and Caveats for Expanding Access to Kidney Transplantation.

Kidney360 2020 Jun;1(6):557-560

Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, NE.

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http://dx.doi.org/10.34067/KID.0001172020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316167PMC
June 2020

Avoidance of CNI and steroids using belatacept-Results of the Clinical Trials in Organ Transplantation 16 trial.

Am J Transplant 2020 12 13;20(12):3599-3608. Epub 2020 Jul 13.

Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA.

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.
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http://dx.doi.org/10.1111/ajt.16152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710570PMC
December 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report.

Am J Transplant 2020 10 27;20(10):2652-2668. Epub 2020 May 27.

Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

The purpose of the STAR 2019 Working Group was to build on findings from the initial STAR report to further clarify the expectations, limitations, perceptions, and utility of alloimmune assays that are currently in use or in development for risk assessment in the setting of organ transplantation. The goal was to determine the precision and clinical feasibility/utility of such assays in evaluating both memory and primary alloimmune risks. The process included a critical review of biologically driven, state-of-the-art, clinical diagnostics literature by experts in the field and an open public forum in a face-to-face meeting to promote broader engagement of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics membership. This report summarizes the literature review and the workshop discussions. Specifically, it highlights (1) available assays to evaluate the attributes of HLA antibodies and their utility both as clinical diagnostics and as research tools to evaluate the effector mechanisms driving rejection; (2) potential assays to assess the presence of alloimmune T and B cell memory; and (3) progress in the development of HLA molecular mismatch computational scores as a potential prognostic biomarker for primary alloimmunity and its application in research trial design.
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http://dx.doi.org/10.1111/ajt.15937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586936PMC
October 2020

Use of Checkpoint Inhibitors in a Kidney Transplant Recipient with Metastatic Cancer.

Clin J Am Soc Nephrol 2020 Aug 23;15(8):1190-1192. Epub 2020 Mar 23.

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

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http://dx.doi.org/10.2215/CJN.15941219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409757PMC
August 2020

Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

Kidney Int Rep 2020 Mar 13;5(3):278-288. Epub 2019 Dec 13.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient genotypes.

Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys.

Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses.

Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.
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http://dx.doi.org/10.1016/j.ekir.2019.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056919PMC
March 2020

Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report.

Am J Transplant 2020 06 17;20(6):1495-1502. Epub 2020 Mar 17.

Critical Path Institute, Tucson, Arizona, USA.

On September 27-28, 2018 the Food and Drug Administration (FDA) and the Critical Path Institute's Transplant Therapeutics Consortium convened a public workshop titled "Evidence-Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment." The workshop facilitated cooperative engagement of transplant community stakeholders, including pharmaceutical industry, academic researchers, clinicians, patients, and regulators to discuss methods to advance the development of novel immunosuppressive drugs for use in solid organ transplantation. Day 1 focused on the utility of biomarkers in drug development with considerations for seeking regulatory endorsement for use in clinical trials. Biomarkers add value to drug development by improving patient selection criteria, safety monitoring, endpoint selection, and more. Regulatory endorsement through the FDA Biomarker Qualification Program encourages the use of biomarkers in drug development by instilling confidence and consistency in biomarker interpretation across trials. Public-private partnerships or consortia allow stakeholders to share expertise, resources, and data in pursuit of biomarker qualification. Biomarkers relevant to pretransplant risk assessment, early posttransplant care, and assessment of immune response, immunosuppressive drug efficacy, and graft function as discussed on day 1 of the workshop are described.
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http://dx.doi.org/10.1111/ajt.15833DOI Listing
June 2020

Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective, randomized clinical trial.

Am J Transplant 2020 06 8;20(6):1668-1678. Epub 2020 Mar 8.

Emory University, Atlanta, Georgia, USA.

In a phase 2 multicenter open-label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)-based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low-dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time, the rate of biopsy-proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.
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http://dx.doi.org/10.1111/ajt.15817DOI Listing
June 2020

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group.

Transplantation 2020 05;104(5):911-922

Centre for Transplant and Renal Research, Westmead Institute of Medical Research, University of Sydney and Renal Unit, Westmead Hospital, NSW, Australia.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
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http://dx.doi.org/10.1097/TP.0000000000003095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176344PMC
May 2020

CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients.

Pediatr Transplant 2019 08 24;23(5):e13494. Epub 2019 May 24.

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear.

Methods: We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant.

Results: The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers.

Conclusions: Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.
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http://dx.doi.org/10.1111/petr.13494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009482PMC
August 2019

Acute Kidney Injury in Kidney Transplants: New Insights.

Authors:
Roslyn B Mannon

Nephron 2019 16;143(3):193-196. Epub 2019 May 16.

Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA,

Delayed allograft function (DGF) is defined as dialysis treatment in the kidney transplant recipient in the first week following transplantation. With the demand for kidney transplants growing and the supply limited, as well as implementation of a national allocation scheme for deceased donor kidneys, rates of DGF remain high, on average, 30% for recipients of deceased donor kidneys. DGF is associated with inferior allograft outcomes, and there are no FDA-approved therapies to mitigate this disorder. There is renewed interest in this therapeutic arena, and there are several recent clinical trials that have considered interventions within the recipient to reduce injury. A critical issue is that of trial design and end points as well as translating from acute kidney injury (AKI) trials in cardiac bypass to the more complicated kidney transplant scenario. DGF is a significant clinical outcome after kidney transplantation without known approved therapy beyond clinical support. This mini-review highlights our presentation at the 24th International Conference on Advances in Critical Care Nephrology and UAB/UCSD O'Brien Center AKI Pre-Meeting.
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http://dx.doi.org/10.1159/000500550DOI Listing
July 2020