The Impact of Ethnicity on Research Authorization at the Time of Organ Donation: A Single-Center Experience Among Deceased Donor Kidney Transplantation.

Objective: Research on deceased organ donors is needed to expand the donor organ supply. Little is known about the rate of research authorization among various groups. We aimed to determine the percentage of research authorization by the deceased donor family across different donor characteristics. Materials and Methods: We performed a retrospective review of deceased donors referred to one U.S. institution for kidney transplantation over a 12-month period. Organs were offered from multiple organ procurement organizations (OPO) across the United States. Stepwise logistic regression was performed to determine the predictors of research authorization. Results: From 10/2018 to 10/2019, 437 deceased donors were accepted for transplantation. 81.5% came from OPOs outside our donor service area and 18.5% from our local OPO. Overall, research authorization was declined in 24.0% of donors. Declined authorization was highest among Black donors (42.0%) compared to Whites (16.3%) and Hispanics (26.9%); p=0.000006. Donors <35 years had highest declined research authorization at 42.9% compared to older donors. There were no significant differences between individual OPOs. Conclusion: Deceased donor research authorization declined at the time of organ donation is higher among Black and younger donors. There is an immediate need for the transplant and donor community to develop best-practices to eliminate barriers to research in organ transplantation.

A Pilot Single-Blinded, Randomized, Controlled Trial Comparing BNT162b2 vs. JNJ-78436735 Vaccine as the Third Dose After Two Doses of BNT162b2 Vaccine in Solid Organ Transplant Recipients.

Solid Organ Transplant (SOT) recipients are at significant higher risk for COVID-19 and due to immunosuppressive medication, the immunogenicity after vaccination is suboptimal. In the previous studies, booster method showed significant benefit in this population. In the current study, we compared using a mix-and-match method vs. same vaccine as a third dose in SOT recipients. This was a patient-blinded, single center, randomized controlled trial comparing BNT162b2 vs. JNJ-78436735 vaccine as the third dose after two doses of BNT162b2 vaccine. We included adult SOT recipients with functional graft who had received two doses of BNT162b2 vaccine. Participants were randomly assigned to receive either BNT162b2 or JNJ-78436735 in one-to-one ratio. Primary outcome was SARS-CoV-2 IgG positivity at 1 month after the third dose. Sixty SOT recipients, including 36 kidney, 12 liver, 2 lung, 3 heart, and 5 combined transplants, were enrolled, and 57 recipients were analyzed per protocol. There were no statistically significant differences between the two vaccine protocols for IgG positivity (83.3% vs. 85.2% for BNT162b2 and JNJ-78436735, respectively, p = 0.85, Odds Ratio 0.95, 95% Confidence Interval 0.23-4.00). Comparison of the geometric mean titer demonstrated a higher trend with BNT162b2 (p = 0.09). In this pilot randomized controlled trial comparing mix and match method vs. uniform vaccination in SOT recipients, both vaccines were safely used. Since this was a small sample sized study, there was no statistically significant difference in immunogenicity; though, the mix and match method showed relatively lower geometric mean titer, as compared to uniform vaccine. Further studies need to be conducted to determine duration of this immunogenicity. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05047640?term=20210641&draw=2&rank=1, identifier 20210641.

Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal.

BACKGROUND: Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial. METHODS: From 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1. RESULTS: Nine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8-56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07-3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept. CONCLUSIONS: Podocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept. A higher resolution version of the Graphical abstract is available as Supplementary information.

Graft Failure Due to Nonadherence among 150 Prospectively-Followed Kidney Transplant Recipients at 18 Years Post-transplant: Our Results and Review of the Literature.

Background: We previously reported that graft failure due to nonadherence (GFNA) was a major cause of graft loss in kidney transplantation. Here, among 150 prospectively-followed kidney transplant recipients at 18 years post-transplant, we provide: updated (longer-term) estimates of cause-specific graft loss probabilities, risk factors for developing GFNA, and detailed characterizations of patients' overt nonadherent (NA) behavior, including timing, extent, and clinical consequences. Methods: Determination of the patient becoming NA in taking his/her immunosuppressive medications, and the underlying cause of graft loss, were determined prospectively by the attending physicians. For never-functioning-graft, GFNA, GF due to causes other than NA (Other GF), and death with a functioning graft (DWFG), cumulative incidence functions were used to estimate the cumulative probabilities of cause-specific graft loss. Cox stepwise regression was used to determine significant multivariable predictors for the hazard rate of developing GFNA. Results: GFNA was a major cause of graft loss (22/150 patients), particularly among African-American and Hispanic recipients <50 years of age-at-transplant (20/56 experienced GFNA), with estimated percentages of such patients ever developing GFNA ranging between 36.9 and 41.5%. These patients were also at a higher risk of developing Other GF. For the remaining patients (2/94 experienced GFNA), estimated percentages of ever-developing GFNA were much lower (range: 0.0−6.7%). The major cause of graft loss among recipients ≥50 years of age was DWFG; GFNA rarely occurred among older recipients. In 21/22 GFNA patients, NA behavior lasted continuously from the time of developing NA until GFNA. In total, 28/150 patients became NA, and 67.9% (19/28) occurred beyond 36 months post-transplant. A total of 25 of 28 NA patients (89.3%) developed biopsy-proven acute rejection and/or chronic rejection that was directly attributed to the NA behavior. Lastly, 25/28 admitted to NA behavior, with financial and psychological components documented in 71.4% (20/28) and 96.4% (27/28) of NA cases, respectively. Conclusions: These results highlight the importance of performing serial monitoring of patients for overt NA behavior throughout their post-transplant follow-up. Financial and psychological components to NA behavior need to be simultaneously addressed with the goal of achieving complete avoidance/elimination of NA behavior among higher risk patients.

Disparities in Deceased Organ Donor Research Authorization: Experience at One Organ Procurement Organization and Call for National Conversations.

INTRODUCTION: Research with deceased donor organs can provide an important platform for studying interventions to improve organ use and outcomes after authorization from the next-of-kin (NOK) or before death by the decedent (i.e., first-person authorization [FPA]). To date, information on authorization rates across donor subgroups is lacking. METHODS: We performed a retrospective chart review of all 690 deceased organ donors from January 2017 to December 2019 at a midsized Midwestern organ procurement organization (OPO). Multivariable logistic regression was used to assess associations between donor factors and research decline (adjusted odds ratio [aOR], 95% confidence interval [CI]). RESULTS: Electronic records for all 690 deceased donors were reviewed. Of these, 659 (95.5%) yielded at least one transplanted organ. Overall, research was declined in 10.8% of donations. Compared to White donors, research decline was higher for Black (16.0% vs. 8.9%; aOR, 1.87; 95% CI, 1.03-3.40; P = 0.04) and other non-White donors (24.0% vs. 8.9%; aOR, 4.21; 95% CI, 1.02-17.39; P = 0.05). Unadjusted research decline trended higher for Hispanic donors versus non-Hispanic donors (23.1% vs. 10.5%; P = 0.14). Compared to donors age <40 years, research decline trended higher for donors age ≥65 years (16.7% vs. 11.8%; aOR, 4.87; 95% CI, 1.12-21.05; P = 0.03), whereas research decline was 55% lower when donors provided FPA (7.3% vs 15.0%; aOR, 0.45; 95% CI, 0.27-0.76; P = 0.003). CONCLUSIONS: Deceased donor research authorization decline is higher for Black, other non-White, and older donors, but lower when the descendent provides FPA. Identification of disparities in research authorization may stimulate educational strategies to reduce barriers to scientific investigations directed at optimizing the outcomes of organ donation.

When is it safe to perform abdominal transplantation in patients with prior SARS-CoV-2 infection: A case series.

BACKGROUND: The Coronavirus disease 2019(COVID-19) pandemic has negatively impacted worldwide organ transplantation. However, there is limited information on recipients transplanted after SARS-CoV-2 infection. A full understanding of this scenario is required, as transplantation is a life-saving procedure and COVID-19 remains an ongoing threat. METHODS: Abdominal organ transplant recipients diagnosed with COVID-19 prior to transplantation were identified by chart review and clinical data were collected. The primary outcome was the transplant outcome including graft loss, rejection and death, and reactivation of infection post-transplant. RESULTS: We identified 14 patients who received abdominal organ transplants after symptomatic PCR confirmed SARS-CoV-2 infection; four patients had a positive PCR at the time of admission for transplantation. The median time of follow-up was 79 (22-190) days. One recipient with negative PCR before transplant tested positive 9 days after transplant. One of 14 transplanted patients developed disseminated mold infection and died 86 days after transplant. During the follow-up, only one patient developed rejection; thirteen patients had favorable graft outcomes. CONCLUSIONS: We were able to perform abdominal transplantation for patients with COVID-19 before transplant, even with positive PCR at the time of transplant. Larger studies are needed to determine the time to safe transplant after SARS-CoV-2 infection.

Donor Family History of ESKD and Long-term Outcomes Among African American Living Kidney Donors: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Live kidney donation is associated with a small increased risk for kidney disease and hypertension in African American donors. We investigated a possible association between donor family history of end-stage kidney disease (ESKD) and their postdonation kidney function and the development of hypertension. We tested whether this association was modified by kidney donation. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: Former African American live kidney donors between 1993 and 2010. Healthy nondonors were selected from the Coronary Artery Disease in Young Adults (CARDIA) Study. EXPOSURE: Family history of ESKD in a first-degree relative. OUTCOMES: Kidney function and blood pressure ≥ 140/90 mm Hg or use of antihypertensive medications at follow-up. ANALYTICAL APPROACH: Donors were grouped based on family history of ESKD. Outcomes were first compared between donor groups and then between donors and healthy nondonors matched for demographics, follow-up time, and family history. A mixed-effect model was used to compare outcomes. RESULTS: Of 179 donors, 139 (78%) had a first degree relative with ESKD. Predonation characteristics were similar between the 2 groups. At a median follow-up of 11 years postdonation, there was no difference in postdonation estimated glomerular filtration rates (68 ± 19 vs 69 ± 13 mL/min/1.73 m2; P = 0.71) and the presence of albuminuria (P = 0.16). There was a trend toward a higher incidence of hypertension (51% vs 35%; P = 0.08) among donors with a family history of ESKD than for those without. Although there was no difference in annual change in estimated glomerular filtration rate (P = 0.17), the risk for hypertension was higher in donors than nondonors (relative risk, 2.44 [95% CI, 1.56-3.84]), but there was no interaction by family history (P = 0.11). LIMITATIONS: Retrospective small study. Lack of data across donor-recipient specific biological relationship. CONCLUSIONS: Family history of ESKD is not associated with postdonation kidney function among African American kidney donors. Live kidney donation is associated with an increased risk for hypertension among African Americans, independent of donor family history of ESKD.

Deceased donor kidney transplant in a 70-year-old Jehovah's Witness patient: to transplant or not to transplant-a case report.

While Jehovah's Witness (JW) patients refuse transfusions of blood or blood products, they are willing to accept renal allograft transplantation. We describe here a case of what we believe is the oldest (a 70-year-old) JW candidate to undergo a deceased donor kidney transplant reported in the literature. Prior to transplantation, discussions ensued amongst the multidisciplinary transplant team, weighing the potential benefits vs. risks of performing a kidney transplant on this patient due to her refusal (due to religion) to accept any blood transfusions or blood products combined with her advanced age and having longstanding insulin-dependent, type 2 diabetes mellitus with extensive peripheral vascular disease. Preoperatively, we believed that the odds were in favor of performing the kidney transplant safely without the need for any blood product usage. However, her post-operative course was complicated by severe anemia, which developed by post-transplant day 4. The anemia incapacitated the patient's physical and psychological state, creating medical, social and financial burdens on the patient, family, medical team and hospital. Both family and patient grew concerned about her overall condition. Blood transfusion was offered in order to improve her weakness and shortness of breath that developed due to the severe anemia, but the patient (along with her family) refused such treatment. During the 17 days of hospitalization, it was a continuous struggle between the transplant team, patient, and family for her to continue with the recovery process; at times we had even considered that performing the transplant had been a mistake. While organ transplantation can be performed safely in Jehovah's Witnesses, there are multiple factors seen in this particular case that warrant analyzing: (I) the potential use of stricter transplant exclusionary criteria, given the recipient's advanced age and preexisting co-morbidities, which likely increased her risk of developing severe anemia post-operatively, and (II) the recipient's emotional/psychological post-operative state of high anxiety, which developed while she was experiencing the severe anemia; in hindsight, her anxiety level may have been reduced if we had offered daily post-operative psychological counseling sessions. While the patient's allograft is currently doing well, we probably did not have strict enough criteria for proper selection of a JW candidate for kidney transplantation.

Randomized trial of 3 maintenance regimens (TAC/SRL vs. TAC/MMF vs. CSA/SRL) with low-dose corticosteroids in primary kidney transplantation: 18-year results.

A randomized trial of 150 primary kidney transplant recipients, initiated in May 2000, compared tacrolimus (TAC)/sirolimus (SRL) vs. TAC/mycophenolate mofetil (MMF) vs. cyclosporine microemulsion (CSA)/SRL (N = 50/group). All patients received daclizumab induction and maintenance corticosteroids. With current median follow-up of 18 years post-transplant, biopsy-proven acute rejection (BPAR) occurred less often in TAC/MMF (26% (13/50)), vs. the TAC/SRL (36% (18/50)) and CSA/SRL (34% (17/50)) arms combined (p = .23), with statistical significance favoring TAC/MMF (p = .05) after controlling for the multivariable (Cox model) effects of recipient age, recipient race/ethnicity, and donor age. First BPAR rate was clearly more favorable for TAC/MMF after stratifying patients by having 0-1 (N = 72) vs. 2-3 (N = 78) unfavorable baseline characteristics (recipient age <50 years, African American or Hispanic recipient, and donor age ≥50 years) (p = .02). Mean estimated glomerular filtration rate (eGFR), using the CKD-EPI formula, was consistently higher for TAC/MMF, particularly after controlling for the multivariable effect of donor age, throughout the first 96 months post-transplant (p ≤ .008). These differences were translated into an observed more favorable graft failure due to immunologic cause (CAI/TG) rate for TAC/MMF (p = .06), although no significant differences in overall death-uncensored graft loss were observed. Previously reported significantly higher study drug discontinuation and requirement for antilipid therapy rates in the SRL-assigned arms were maintained over time. Overall, these results at 18 years post-transplant more definitively show that TAC/MMF should be the gold standard for achieving optimal, long-term maintenance immunosuppression in kidney transplantation.

APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

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 (APOL1). 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 APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 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 APOL1 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.

Clinical outcomes in HIV+/HCV+ coinfected kidney transplant recipients in the pre- and post-direct-acting antiviral therapy eras: 10-Year single center experience.

BACKGROUND: Previous studies have demonstrated inferior patient and graft survival following kidney transplant (KT) in HIV+/HCV+ coinfected patients compared to HIV+/HCV- recipients. However, these studies were conducted prior to the availability of direct-acting antiviral (DAA) agents and data in the modern era are lacking. METHODS: Single center retrospective study of HIV+/HCV+ coinfected KT recipients (2007-2017). Outcomes were assessed for the pre-DAA and post-DAA (ie, after December 2013) eras including 1-year patient survival, death-censored graft survival, and acute rejection; and serious infections (defined as infections requiring admission to the intensive care unit during initial transplant hospitalization or re-admission to the hospital after discharge) within the first 6 months post-transplant. RESULTS: A total of 13 consecutive HIV+/HCV+ recipients were identified. Median time of post-transplant follow-up was 722 days. Seven patients were transplanted in the DAA era; five of them had anti-HCV Ab+ donors, with two donors being HCV NAT positive; all received DAA therapy, six of them post-transplant (median time from KT to DAA: 83 days; IQR, 54-300). All the patients in the pre-DAA era were on a protease inhibitor-containing ART regimen. One-year patient and death-censored graft survivals were 83% and 67%, respectively, for the patients transplanted in the pre-DAA era, and 100% for both outcomes in the subgroup of patients transplanted in the post-DAA era (P > 0.05). Compared to patients in the post-DAA era, those in the pre-DAA era had higher incidence of serious infections (0 vs 67%; P = 0.02). Acute rejection exclusively occurred in the pre-DAA group (n = 1; 17%). CONCLUSIONS: Outcomes of HIV+/HCV+ KT recipients, including HIV-/HCV+ to HIV+/HCV+ transplants, in the DAA era were excellent in this small cohort. Larger studies are needed.

APOL1 Genotype and Renal Function of Black Living Donors.

Black living kidney donors are at higher risk of developing kidney disease than white donors. We examined the effect of the APOL1 high-risk genotype on postdonation renal function in black living kidney donors and evaluated whether this genotype alters the association between donation and donor outcome. We grouped 136 black living kidney donors as APOL1 high-risk (two risk alleles; n=19; 14%) or low-risk (one or zero risk alleles; n=117; 86%) genotype. Predonation characteristics were similar between groups, except for lower mean±SD baseline eGFR (CKD-EPI equation) in donors with the APOL1 high-risk genotype (98±17 versus 108±20 ml/min per 1.73 m2; P=0.04). At a median of 12 years after donation, donors with the APOL1 high-risk genotype had lower eGFR (57±18 versus 67±15 ml/min per 1.73 m2; P=0.02) and faster decline in eGFR after adjusting for predonation eGFR (1.19; 95% confidence interval, 0 to 2.3 versus 0.4; 95% confidence interval, 0.1 to 0.7 ml/min per 1.73 m2 per year, P=0.02). Two donors developed ESRD; both carried the APOL1 high-risk genotype. In a subgroup of 115 donors matched to 115 nondonors by APOL1 genotype, we did not find a difference between groups in the rate of eGFR decline (P=0.39) or any statistical interaction by APOL1 status (P=0.92). In conclusion, APOL1 high-risk genotype in black living kidney donors associated with greater decline in postdonation kidney function. Trajectory of renal function was similar between donors and nondonors. The association between APOL1 high-risk genotype and poor renal outcomes in kidney donors requires validation in a larger study.

Outcome of low-dose ganciclovir for cytomegalovirus disease prophylaxis in renal-transplant recipients.

To assess the outcome of low-dose-ganciclovir prophylaxis (500 mg twice a day for 3 months) in renal-transplant recipients, a retrospective analysis of 185 patients transplanted between 1998 and 2001 was performed. There were 29 (15.6%) patients who belonged to the highest risk group, donor cytomegalovirus (CMV) positive, recipient negative (D + R-), and 37 (20%) patients in the lowest risk group, D-R-. Induction immunosuppression consisted of polyclonal antibody or OKT3 (n = 62, 33.5%), interleukin-2 receptor antibody (n = 61, 33%), and no induction (n = 62, 33.5%). CMV disease occurred in 13 (7%) patients. Highest incidence was in D + R- group (17.2%), with no cases in D-R- group (P = 0.03). Tissue-invasive CMV occurred in 4 of these 13 patients. In patients developing CMV disease, there was no evidence of ganciclovir resistance and no mortality over a mean follow-up of 42 months. Low-dose ganciclovir was found to be as effective in decreasing the incidence of clinical CMV disease as high-dose ganciclovir (1 gm three times a day for 3-6 months) in previous studies.