Analysis of Rejection, Infection and Surgical Outcomes in Type I Versus Type II Diabetic Recipients After Simultaneous Pancreas-Kidney Transplantation.

Given the increasing frequency of simultaneous pancreas-kidney transplants performed in recipients with Type II diabetes and CKD, we sought to evaluate possible differences in the rates of allograft rejection, infection, and surgical complications in 298 Type I (T1D) versus 47 Type II (T2D) diabetic recipients of simultaneous pancreas-kidney transplants between 2006-2017. There were no significant differences in patient or graft survival. The risk of biopsy-proven rejection of both grafts was not significantly different between T2D and T1D recipients (HRpancreas = 1.04, p = 0.93; HRkidney = 0.96; p = 0.93). Rejection-free survival in both grafts were also not different between the two diabetes types (ppancreas = 0.57; pkidney = 0.41). T2D had a significantly lower incidence of de novo DSA at 1 year (21% vs. 39%, p = 0.02). There was no difference in T2D vs. T1D recipients regarding readmissions (HR = 0.77, p = 0.25), infections (HR = 0.77, p = 0.18), major surgical complications (HR = 0.89, p = 0.79) and thrombosis (HR = 0.92, p = 0.90). In conclusion, rejection, infections, and surgical complications after simultaneous pancreas-kidney transplant are not statistically significantly different in T2D compared to T1D recipients.

Interplay of Donor-Recipient Relationship and Donor Race in Living Liver Donation in the United States.

INTRODUCTION: Living liver donation improves survival of end-stage liver disease (ESLD) patients. Yet, it continues to represent a small proportion of United States (U.S.) liver transplantation with existing racial disparities. We investigated the interplay of donor-recipient relationship and donor race to understand donor subgroups with no significant increase. METHODS: We studied 4407 living liver donors in the U.S. from January 1, 2012, to December 31, 2022 (median age = 36 years, and 59% were biologically related to the recipient). We quantified the change in the number of donors per 3-year increment using negative binomial regression (incidence rate ratio [IRR]), stratified by donor-recipient relationship and race/ethnicity. RESULTS: Among biologically related donors, the observed annual number of White donors increased from 146 to 253, Hispanic donors from 18 to 53, and Black donors decreased from 11 to 10. Among unrelated donors, White donors increased from 65 to 221, Hispanic donors from 4 to 25, and Black donors from 3 to 11. For the IRR of biologically related donors aged <40 and ≥40 years, White donors increased by 18% and 22%; Hispanic donors increased by 25% and 54%; and Black donors did not change. Likewise, the IRR of unrelated donors aged <40 and ≥40 years, White donors increased by 48% and 55%; Hispanic donors increased by 52% and 65%; and Black donors did not change. CONCLUSIONS: While biologically related donors represent the majority of donors, unrelated donors have substantially risen in recent years, primarily driven by White donors. Although the rate of unrelated donations increased among Hispanic donors, the absolute number remains very small (≤25 donors/year). Interventions are needed to increase education among Hispanic and Black communities to grow unrelated living liver donations across race/ethnicity.

Program Evaluation of Pharmacist-Performed Medication Adherence Assessments in Candidates for Living Donor Kidney Transplant.

Introduction: Medication education and adherence assessments are integral to kidney transplant success. This program evaluation aimed to describe candidate-reported findings using a standardized medication adherence assessment in candidates undergoing living-donor kidney transplantation. Design: This was a single-center retrospective description of medication adherence on adult HIV-negative living-donor candidates from July 1, 2018 to December 1, 2018 who had ≥6 months post-operative follow-up. Medication adherence assessments were performed by a pharmacist at the pre-operative visit within 2 weeks prior to transplant. Candidates were considered to (a) have adherence concerns if they reported missed/late medications within 2 weeks of assessment or ever stopped a medication without medical advice and (b) considered using adherence strategies if they reported active use of pill box, method to keep track of refills/auto-refill use, medication list, or medication reminder(s). Missed medication data were collected at 3- and 6-months posttransplant. Results: Among 181 candidates included, 81 (45%) had adherence concerns and 169 (93%) reported using adherence strategies. There were no significant differences with adherence concerns by age ≤ 29 years, sex, race, prior transplant/dialysis, or less than a high school education. More candidates with greater than a high school education used adherence strategies (96% vs 86%, P = .002). Too few candidates had documentation on missing medications at 3 and 6 months. Conclusions: Over 40% of candidates reported characteristics concerning medication nonadherence despite over 90% reporting adherence strategies used. Medication adherence assessments can assist with identification of medication nonadherence and education individualization.

Perfusion Techniques in Kidney Allograft Preservation to Reduce Ischemic Reperfusion Injury: A Systematic Review and Meta-Analysis.

The limited supply and rising demand for kidney transplantation has led to the use of allografts more susceptible to ischemic reperfusion injury (IRI) and oxidative stress to expand the donor pool. Organ preservation and procurement techniques, such as machine perfusion (MP) and normothermic regional perfusion (NRP), have been developed to preserve allograft function, though their long-term outcomes have been more challenging to investigate. We performed a systematic review and meta-analysis to examine the benefits of MP and NRP compared to traditional preservation techniques. PubMed (MEDLINE), Embase, Cochrane, and Scopus databases were queried, and of 13,794 articles identified, 54 manuscripts were included (n = 41 MP; n = 13 NRP). MP decreased the rates of 12-month graft failure (OR 0.67; 95%CI 0.55, 0.80) and other perioperative outcomes such as delayed graft function (OR 0.65; 95%CI 0.54, 0.79), primary nonfunction (OR 0.63; 95%CI 0.44, 0.90), and hospital length of stay (15.5 days vs. 18.4 days) compared to static cold storage. NRP reduced the rates of acute rejection (OR 0.48; 95%CI 0.35, 0.67) compared to in situ perfusion. Overall, MP and NRP are effective techniques to mitigate IRI and play an important role in safely expanding the donor pool to satisfy the increasing demands of kidney transplantation.

Social network interventions to reduce race disparities in living kidney donation: Design and rationale of the friends and family of kidney transplant patients study (FFKTPS).

INTRODUCTION: Racial/ethnic disparities in living donor kidney transplantation (LDKT) are a persistent challenge. Although nearly all directed donations are from members of patients' social networks, little is known about which social network members take steps toward living kidney donation, which do not, and what mechanisms contribute to racial/ethnic LDKT disparities. METHODS: We describe the design and rationale of the Friends and Family of Kidney Transplant Patients Study, a factorial experimental fielding two interventions designed to promote LKD discussions. Participants are kidney transplant candidates at two centers who are interviewed and delivered an intervention by trained center research coordinators. The search intervention advises patients on which social network members are most likely to be LKD contraindication-free; the script intervention advises patients on how to initiate effective LKD discussions. Participants are randomized into four conditions: no intervention, search only, script only, or both search and script. Patients also complete a survey and optionally provide social network member contact information so they can be surveyed directly. This study will seek to enroll 200 transplant candidates. The primary outcome is LDKT receipt. Secondary outcomes include live donor screening and medical evaluations and outcomes. Tertiary outcomes include LDKT self-efficacy, concerns, knowledge, and willingness, measured before and after the interventions. CONCLUSION: This study will assess the effectiveness of two interventions to promote LKD and ameliorate Black-White disparities. It will also collect unprecedented information on transplant candidates' social network members, enabling future work to address network member structural barriers to LKD.

Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease. Methods: We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort. Results: Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D+ transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell-activating factor and decreased CXCL13 levels in circulation. Conclusions: Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.

APRIL/BLyS deficient rats prevent donor specific antibody (DSA) production and cell proliferation in rodent kidney transplant model.

APRIL (A proliferation inducing ligand) and BLyS (B Lymphocyte Stimulator) are two critical survival factors for B lymphocytes and plasma cells, the main source of alloantibody. We sought to characterize the specific effects of these cytokines in a kidney transplant model of antibody mediated rejection (AMR). We engineered APRIL-/- and BLyS-/- Lewis rats using CRISPR/Cas9. APRIL-/- and BLyS-/- rats were sensitized with Brown Norway (BN) blood (complete MHC mismatch). Twenty-one days following sensitization, animals were harvested and collected tissues were analyzed using flow cytometry, ELISPOT, and immunohistochemistry. Flow cross match and a 3 day mixed lymphocyte reaction (MLR) was performed to assess donor specific antibody (DSA) production and T-cell proliferation, respectively. Sensitized dual knock out Lewis rats (APRIL-/-/BLyS-/-) underwent kidney transplantation and were sacrificed on day 7 post-transplant. Sensitized BLyS-/- had significant decreases in DSA and cell proliferation compared to WT and APRIL-/- (p<0.02). Additionally, BLyS-/- rats had a significant reduction in IgG secreting cells in splenic marginal zone B lymphocytes, and in cell proliferation when challenged with alloantigen compared to WT and APRIL-/-. Transplanted APRIL-/-/BLyS-/- rodents had significantly less DSA and antibody secreting cells compared to WT (p<0.05); however, this did not translate into a significant difference in AMR seen between groups. In summary, our studies suggest that APRIL and BLyS play a greater role in DSA generation rather than AMR, highlighting the role of cellular pathways that regulate AMR.

Discrepant subtyping of blood type A2 living kidney donors: Missed opportunities in kidney transplantation.

BACKGROUND: Despite the institution of a new Kidney Allocation System in 2014, A2/A2B to B transplantation has not increased as expected. The current Organ Procurement and Transplantation Network policy requires subtyping on two separate occasions, and in the setting of discrepant results, defaulting to the A1 subtype. However, there is significant inherent variability in the serologic assays used for blood group subtyping and genotyping is rarely done. METHODS: The National Kidney Registry, a kidney paired donation (KPD) program, performs serological typing on all A/AB donors, and in cases of non-A1/non-A1B donors, confirmatory genotyping is performed. RESULTS: Between 2/18/2018 and 9/15/2020, 13.0% (145) of 1,111 type A donors registered with the NKR were ultimately subtyped as A2 via genotyping. Notably, 49.6% (72) of these were subtyped as A1 at their donor center, and in accordance with OPTN policy, ineligible for allocation as A2. CONCLUSION: Inaccurate A2 subtyping represents a significant lost opportunity in transplantation, especially in KPD where A2 donors can not only facilitate living donor transplantation for O and highly sensitized candidates, but can also facilitate additional living donor transplants. This study highlights the need for improved accuracy of subtyping technique, and the need for policy changes encouraging optimal utilization of A2 donor kidneys.

Voucher-Based Kidney Donation and Redemption for Future Transplant.

Importance: Policy makers, transplant professionals, and patient organizations agree that there is a need to increase the number of kidney transplants by facilitating living donation. Vouchers for future transplant provide a means of overcoming the chronological incompatibility that occurs when the ideal time for living donation differs from the time at which the intended recipient actually needs a transplant. However, uncertainty remains regarding the actual change in the number of living kidney donors associated with voucher programs and the capability of voucher redemptions to produce timely transplants. Objective: To examine the consequences of voucher-based kidney donation and the capability of voucher redemptions to provide timely kidney allografts. Design, Setting, and Participants: This multicenter cohort study of 79 transplant centers across the US used data from the National Kidney Registry from January 1, 2014, to January 31, 2021, to identify all family vouchers and patterns in downstream kidney-paired donations. The analysis included living kidney donors and recipients participating in the National Kidney Registry family voucher program. Exposures: A voucher was provided to the intended recipient at the time of donation. Vouchers had no cash value and could not be sold, bartered, or transferred to another person. When a voucher was redeemed, a living donation chain was used to return a kidney to the voucher holder. Main Outcomes and Measures: Deidentified demographic and clinical data from each kidney donation were evaluated, including the downstream patterns in kidney-paired donation. Voucher redemptions were separately evaluated and analyzed. Results: Between 2014 and 2021, 250 family voucher-based donations were facilitated. Each donation precipitated a transplant chain with a mean (SD) length of 2.3 (1.6) downstream kidney transplants, facilitating 573 total transplants. Of those, 111 transplants (19.4%) were performed in highly sensitized recipients. Among 250 voucher donors, the median age was 46 years (range, 19-78 years), and 157 donors (62.8%) were female, 241 (96.4%) were White, and 104 (41.6%) had blood type O. Over a 7-year period, the waiting time for those in the National Kidney Registry exchange pool decreased by more than 3 months. Six vouchers were redeemed, and 3 of those redemptions were among individuals with blood type O. The time from voucher redemption to kidney transplant ranged from 36 to 155 days. Conclusions and Relevance: In this study, the family voucher program appeared to mitigate a major disincentive to living kidney donation, namely the reluctance to donate a kidney in the present that could be redeemed in the future if needed. The program facilitated kidney donations that may not otherwise have occurred. All 6 of the redeemed vouchers produced timely kidney transplants, indicating the capability of the voucher program.

Early detection of SARS-CoV-2 and other infections in solid organ transplant recipients and household members using wearable devices.

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.

Cytomegalovirus antiviral stewardship in the COVID-19 Era: Increasing complexity of prophylaxis and treatment and potential mitigation strategies.

Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid organ transplant (SOT). Severe acute respiratory coronavirus 2 (SARS-CoV-2), which causes the novel betacoronavirus 2019 disease (COVID-19), has become the first global pandemic in 100 years. The world's attention has turned to address this unanticipated development; however, the viral infection that has long plagued outcomes after solid organ transplantation still requires vigilance. With physical distancing as the key intervention to reduce the healthcare burden, and the unease related to healthcare contact within the transplant population given the associated morbidity and mortality of COVID-19 in transplant recipients, providers have struggled to evaluate and streamline essential in-person healthcare contact, including laboratory visits. Owing to this, the COVID-19 pandemic has placed a significant strain on the delivery of CMV prophylaxis and treatment after solid organ transplantation. In this piece, we will describe issues our CMV antiviral stewardship service has encountered in the care of the transplant recipient with CMV during the this unprecedented time and share our expert opinion to approaches to providing optimal, evidenced based care during a pandemic associated with a seemingly unrelated viral infection.

Impact and outcomes of primary cytomegalovirus disease in seronegative abdominal solid organ transplant recipients of cytomegalovirus unexposed donors (D-/R-).

BACKGROUND: Primary cytomegalovirus (CMV) disease in high-risk (D+/R-) abdominal solid organ transplant recipients (aSOTRs) is well described, however, little is known of primary CMV disease in low-risk (D-/R-) patients. METHODS: Observational study of adult aSOTRs between 1/1/2009 and 9/1/2019 screened based on serostatus at transplant; D-/R- and D+/R- patients were included. PRIMARY OBJECTIVE: Describe epidemiology of primary CMV in D-/R- aSOTRs. SECONDARY OBJECTIVE: Compare infectious and transplant-related outcomes of primary CMV disease in the first 90 days (early CMV) between D-/R- and D+/R-. RESULTS: Of 782 D-/R- aSOTRs in the study period, 13 developed CMV at any time after transplant to last follow-up. Of 671 D+/R- patients, 186 developed CMV. Early CMV disease was significantly more common in the D-/R- group (54% vs 15.6%, P = .0005) despite populations being similar demographically, including allograft subtype. D-/R- patients with early CMV disease had median viral load >100 000 IU/mL and 42.9% had end-organ manifestations; 71.4% required hospital admission. Immunosuppressive therapy was adjusted in 100% of patients, there was an approximately 14.3% rate of antiviral resistance and 28.6% had concomitant opportunistic infection. These findings were similar to D+/R- patients. There was no difference in risk of rejection or all-cause mortality associated with early CMV disease, however, graft loss was significantly higher in D-/R-. CONCLUSION: D-/R- aSOTRs infrequently develop CMV, however, when it occurs, they present with disease manifestations similar to and graft outcomes inferior to D+/R- with CMV. Additionally, the majority of CMV disease in D-/R- occurs in the first 90 days after transplant, suggesting possible donor subclinical infection or transfusion source. The complicated course in D-/R- is likely caused by low clinical suspicion. Awareness of disease severity and aggressive upfront management may promote positive outcomes.

Single center results of simultaneous pancreas-kidney transplantation in patients with type 2 diabetes.

Studies have found similar outcomes of Simultaneous Pancreas-Kidney transplantation (SPKT) in patients with Type 2 (T2D) and Type 1 diabetes (T1D). However, there are scarce data evaluating the association of recipient factors such as age, BMI, or pretransplant insulin requirements with outcomes, thus the criteria for the optimal recipient selection remains unclear. In this study, 284 T1D and 39 T2D patients, who underwent SPKT between 2006 and 2017 with 1 year of follow-up at minimum, were assessed for potential relationship of pretransplant BMI and insulin requirements with posttransplant diabetes and pancreatic graft failure. Kaplan-Meier analysis showed similar rates of freedom from posttransplant diabetes (94.7% T2D vs. 92.3% T1D at 1 yr, and 88.1% T2D vs. 81.1% T1D at 5 yrs) and graft survival (89.7% T2D vs. 90.4% T1D at 1 yr, and 89.7% T2D vs. 81.2% T1D at 5 yrs). There was no significant association between BMI or pretransplant insulin requirements with posttransplant diabetes occurrence in either T1D (p = .10, .43, respectively) or T2D (p = .12, .63) patients in the cohort; or with graft failure (T1D: p = .40, .09; T2D: p = .71, .28). These observations suggest a less restricted approach to selective use of SPKT in patients with T2D.

B-cell Deficiency Attenuates Transplant Glomerulopathy in a Rat Model of Chronic Active Antibody-mediated Rejection.

BACKGROUND: Transplant glomerulopathy (TG) is a pathological feature of chronic active antibody-mediated rejection (cAMR) and is associated with renal allograft failure. The specific role of B cells in the pathogenesis of TG is unclear. METHODS: We used a minor mismatched rat kidney transplant model with B cell-deficient recipients, generated by clustered regularly interspaced short palindromic repeats/Cas9 technology, to investigate the impact of B-cell depletion on the pathogenesis of TG. We hypothesized that B-cell deficiency would prevent TG in the rat kidney transplant model of cAMR. Treatment groups included syngeneic, allogeneic, sensitized allogeneic, and B cell-deficient allogeneic transplant recipients. RESULTS: B cell-deficient recipients demonstrated reduced TG lesions, decreased microvascular inflammation, reduced allograft infiltrating macrophages, and reduced interferon gamma transcripts within the allograft. Allograft transcript levels of interferon gamma, monocyte chemoattractant protein-1, and interleukin-1ß correlated with numbers of intragraft macrophages. B cell-deficient recipients lacked circulating donor-specific antibodies and had an increased splenic regulatory T-cell population. CONCLUSIONS: In this model of cAMR, B-cell depletion attenuated the development of TG with effects on T cell and innate immunity.

Significant Improvement in Rat Kidney Cold Storage Using UW Organ Preservation Solution Supplemented With the Immediate-Acting PrC-210 Free Radical Scavenger.

Ischemia-reperfusion injury, including injury from warm- and cold-ischemia (CI) organ storage, remains a significant problem for all solid organ transplants. Suppressing CI damage would reduce delayed graft function and increase the donor organ pool size. PrC-210 has demonstrated superior prevention of damage in several preclinical studies as an immediate-acting free-radical scavenger. Here, we describe its profound efficacy in suppressing CI injury in a rat kidney model. METHODS: Kidneys in 300 gm Sprague-Dawley rats were perfused in situ with UW solution with or without added PrC-210 and then stored at 4°C in the same solution for 0 to 48 hours. When procured, kidney-activated caspase-3 level (a marker of cell death) was measured, and direct histological analysis of kidneys was performed to assess PrC-210 protective efficacy. In vitro analyses of PrC-210-conferred protection to isolated rat kidneys or naked DNA were also performed. RESULTS: A single 15 seconds in situ perfusion of kidneys with 20 mmol/L PrC-210 in UW solution resulted in significant reductions in (1) 30-hour CI-induced kidney-activated caspase level (P < 0.0001); activated caspase was reduced to levels not significantly different than control activated caspase levels seen in unperturbed kidneys, (2) 30-hour CI-induced renal Tubular Injury Scores (P = 0.0004) where brush border and tubular necrosis were markedly reduced, (3) PrC-210 conferred 100% protection against ·OH damage to naked DNA and isolated kidney mitochondria while current UW solution antioxidants were without protective effect. CONCLUSIONS: A single PrC-210-UW solution perfusion of rat kidneys upon removal from the rat profoundly reduced caspase and renal tubular injury in kidneys exposed to 30 hours of CI organ storage. These findings support further development of the PrC-210 molecule to suppress or to prevent ischemia-reperfusion injury in organ transplant and other ischemia-reperfusion injury settings.

Pre-transplant AT1R antibodies and long-term outcomes in kidney transplant recipients with a functioning graft for more than 5 years.

BACKGROUND: There is conflicting data regarding the association of pre-transplant AT1R antibody levels and long-term outcomes following kidney transplantation. MATERIALS AND METHODS: We examined the association between pre-transplant antibodies and long-term graft outcome by assaying pre-transplant sera from 125 kidney transplant recipients from 1999 to 2009. RESULTS: The mean age at transplant was 55.7 ± 13 years; 67.2% were male, 87.2% were Caucasian, and 67.2% received a deceased donor transplant. Induction therapy included 44.8% thymoglobulin. Human leukocyte antigen (HLA) donor-specific antibodies (DSA) were present in 22 (17.6%) patients, while AT1R antibodies > 17 U/mL were present in 24 (19.2%). The mean AT1R antibodies level was 13 ± 7.2 U/mL. Patients were followed-up for 7.1 ± 1.9 years after transplant. Pre-transplant AT1R antibodies were associated with rejection (p < 0.0001), antibody-mediated rejection (ABMR) (p < 0.0001), and death-censored graft failure (DCGF) (p = 0.01). This was confirmed by univariate Cox regression analyses for AT1R antibodies > 10 U/mL (HR 2.64, 95% Cl 1.35 - 5.17, p = 0.04) and AT1R antibodies > 17 U/mL (HR = 1.74, 95% Cl 1.061 - 2.98, p = 0.04). Multivariable analyses did not retain AT1R antibodies as independent predictors of DCGF; however, pre-transplant HLA, DSA, and acute rejection during the first year were associated with DCGF (HR 2.07, 95% Cl 1.13 - 3.78, p = 0.02 and HR 3.03, 95% Cl 1.13 - 3.78, p = 0.0002, respectively). CONCLUSION: Our study indicates that in patients with a functioning kidney allograft > 5 years, pre-transplant AT1R antibodies may be associated with a greater risk of rejection and late graft failure.