Higher Rates Of Acute Rejection Research Articles

Association of early post-transplant hyperglycaemia and diabetes mellitus on outcomes following heart transplantation.

Early post-transplant hyperglycaemia (EPTH) and post-transplant diabetes mellitus (PTDM) are common following solid organ transplantation and may be associated with adverse outcomes. We studied the prevalence of EPTH and cumulative 5-year prevalence of PTDM in a modern cohort of heart transplant recipients who were free from diabetes at baseline as well as the association of EPTH, PTDM and pre-transplant T2DM with adverse transplant-related outcomes. Retrospective cohort study of heart transplant recipients followed for 5 years at a single centre in Sydney, Australia. A total of 141 patients were included, of whom 25 had pre-existing type 2 diabetes mellitus (T2DM) and 116 were free from diabetes at baseline. In patients without pre-existing T2DM, 88 of 116 (76%) experienced EPTH, which was associated with higher rates of acute rejection and hospitalizations, and lower 5-year survival. PTDM developed in 45 of 116 (39%) patients, all of whom had experienced EPTH. Both PTDM and pre-existing T2DM were associated with increased rates of graft rejection and hospitalization, and greater than three-fold increased likelihood of death compared to patients that remained free from diabetes. EPTH and PTDM are highly prevalent following cardiac transplantation. EPTH develops within days of transplant and is strongly associated with progression to PTDM. Pre-existing T2DM, PTDM and EPTH are associated with greater hospitalization, increased episodes of rejection and worse 5-year survival compared to patients who remained free from diabetes during follow-up.

Development of a Porcine VCA Model Using an External Iliac Vessel-Based Vertical Rectus Abdominus Myocutaneous Flap.

Vascularized composite allotransplantation (VCA) involves transplanting a functional and anatomically complete tissue graft, such as a hand or face, from a deceased donor to a recipient. Although clinical VCA has resulted in successful outcomes, high rates of acute rejection and increased requirements for immunosuppression have led to significant long-term complications. Of note, immunosuppressed graft recipients are predisposed to infections, organ dysfunction, and malignancies. The long-term success of VCA grafts requires the discovery and implementation of unique approaches that avoid these complications altogether. Here, we describe our surgical technique and initial experience with a reproducible heterotopic porcine VCA model for the preclinical assessment of approaches to improve graft outcomes. Six heterotopic porcine allogeneic vertical rectus abdominis myocutaneous flap transplants were performed using Sinclair donors and Yucatan recipients. Immunosuppressive therapy was not used. Each flap was based on the left external iliac vessel system. Animals were followed postoperatively for surgery-related complications. The six pigs underwent successful VCA and were euthanized at the end of the study. Each flap demonstrated complete survival following vessel anastomosis. For the allogeneic recipients, on average, minimal erythema and healthy flap color were observed from postoperative days 1 to 4. There were no surgery-related animal deaths or complications. We have developed a reproducible, technically feasible heterotopic porcine VCA model based on the left external iliac vessel system. Our results demonstrate this model's potential to improve VCA graft outcomes by exploring tolerance induction and rejection biomarker discovery in preclinical studies.

Successful Extension of Vascularized Composite Allograft Perfusion Cold Storage to 24 h in a Rat Hindlimb Transplant Model.

Vascularized composite allograft transplantation is a treatment option for complex tissue injuries; however, ischemia reperfusion injury and high acute rejection rates remain a challenge. Hypothermic machine perfusion using acellular storage perfusate is a potential solution. This study evaluated the University of Wisconsin Kidney Preservation Solution-1 (KPS-1) compared with normal saline (NS) for preservation of donor rat hindlimbs subjected to 24 h of ex vivo perfusion cold storage. Hindlimbs were subjected to 24-h perfusion cold storage with heparinized KPS-1 (n = 6) or heparinized NS (n = 6). Flow, resistance, and pH were measured continuously. At the end of the 24-h period, tissue was collected for histological analysis of edema and apoptosis. KPS-1 perfused limbs showed significantly less edema than the NS group, as evidenced by lower limb weight gain (P < 0.001) and less interfascicular space (P < 0.001). KPS-perfused muscle had significantly less cell death than NS-perfused muscle based on terminal deoxynucleotidyl transferase dUTP nick-end labeling (P < 0.001) and cleaved caspase-3 staining (P = 0.045). During hypothermic machine perfusion, a significant decrease in pH over time was detected in both groups, with a significantly greater decline in pH in the KPS-1 group than in the NS group. There were no significant differences overall and over time in flow rate or vascular resistance between the KPS and NS groups. Perfusion with KPS-1 can successfully extend vascularized composite allograft perfusion cold storage for 24 h in a rat hindlimb model without significant edema or cell death.

Abstract 12489: Sex Differences in Incidence and Outcomes of Patients With New-Onset Post-Transplant Diabetes Mellitus After Heart Transplantation

Introduction: Post-transplant diabetes mellitus (PTDM) is a common complication following heart transplantation (HT), mostly commonly occurring in the first year after transplant. A few risk factors for the development of PTDM have been identified, including immunosuppressive medications such as calcineurin inhibitors and glucocorticoids. Some studies have suggested that among HT recipients, women have higher rates of acute rejection which may necessitate higher doses of steroids and further hyperglycemia. However, differences between sexes in the incidence of PTDM after HT have not been established. Methods: A retrospective review of patients who underwent HT at a large-volume center between January 1, 2010 and December 31, 2019 was performed. Patients undergoing re-transplantation or dual-organ transplantation were excluded. PTDM was defined as hemoglobin A1C≥6.5% or a random glucose &gt;200 after HT among patients with no prior history of DM. Predictors of PTDM by sex were analyzed with logistic regression, and post-transplant outcomes were analyzed with Chi-Square analysis. Results: Among 317 transplant patients without pre-transplant DM, 71 (22.4%) patients were identified who had PTDM: 24 females (33.7%), 47 males (66.2%). There were no statistically significant differences in baseline characteristics between males and females who developed PTDM including age, race, pre-transplant HTN, calcineurin or steroid dosing at 1 month and 1 year post-transplant. Baseline HTN (OR 2.9, [1.3, 6.7], p=0.009) and mean steroid dose over the first 2 years post-transplant (OR 1.2, [1.0, 1.3], p=0.006) were predictors of PTDM in females but not in males, and mean tacrolimus dose was a predictor in males (OR 1.1, [1.0, 1.2], p=0.001) but not in females. Time to PTDM diagnosis did not differ by sex (log-rank p=0.56). Additionally, post-transplant outcomes in patients with PTDM including acute cellular rejection, antibody-mediated rejection, coronary allograft vasculopathy and death did not differ by sex. Conclusion: PTDM is a common complication of HT. Our study suggests that risk factors for PTDM among HT recipients differ by sex. Future studies should investigate the mechanisms underlying these differences to further guide sex-specific post-HT care.

Deciphering the True Immunologic Risk in Renal Transplantation in Patients With HIV

Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P=.045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated.

Low-dose interleukin-2 promotes immune regulation in face transplantation: A pilot study

Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (∼4-fold to 5-fold) of circulating Tregs and a reduction (∼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.

Treatment of De Novo Renal Transplant Recipients With Calcineurin Inhibitor-free, Belatacept Plus Everolimus-based Immunosuppression.

Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

Unrelated versus related living-donor kidney transplantation is associated with higher acute rejection rate but similar graft survival Running title: Outcomes in living-donor kidney transplantation

Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared with that from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival, between transplant recipients who received a kidney from a living-related donor (LRD) and from a living unrelated donor (LURD). Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time, of 60-65 mL/min (p&lt;0.05 over a 10-year period). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at 5 years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR. Multivariate analysis showed that human leukocyte antigen (HLA) -DR mismatch (MM) was an independent predictor of AR (hazard ratio [HR] 2.256, p&lt;0.05). HLA-A and HLA-B MM did not affect the AR HR between the groups. Graft function and censored-death survival rates were similar between the LURD and LRD KT recipients. HLA-DR MM was an independent risk factor for AR.

Renal Function at Discharge Among Kidney Recipients Experiencing Delayed Graft Function and Its Associations With Long-term Outcomes.

Using Organ Procurement and Transplantation Network data, we examined DGF, and used recipient serum creatinine at discharge as a correlate of renal function and DGF severity (mild: <2.5 mg/dL; severe: ≥2.5 mg/dL). The associations between donor and recipient factors and DGF severity were quantified using logistic regression. We also examined the associations between DGF severity and long-term recipient outcomes, adjusting for potential confounders. A predictive model using donor and recipient factors had a reasonably good ability to discriminate mild (low creatinine) versus severe (high creatinine) DGF (c-statistic of 0.70). In Cox regression, DGF and creatinine at discharge were both independently associated with long-term outcomes, yet their effects differed depending on the outcome (graft function, death-censored graft function, recipient mortality). Our findings suggest that having DGF, but with relatively good renal function (creatinine <2.5) at discharge, may be less deleterious on graft and recipient survival compared with severe, prolonged DGF, which was associated with a decreased median graft survival of ~2.6 y compared with no DGF with low creatinine at discharge. Our novel DGF severity stratification identified unique factors associated with DGF severity, along with DGF's association with long-term graft and patient survival. The adverse cost and outcome implications of severe DGF warrant additional investigation to improve kidney transplantation practice.

Post-transplant mortality and graft failure after induction immunosuppression among Black heart transplant recipients in the United States

Black heart transplant recipients are more likely to receive induction immunosuppression compared to other races because of higher rates of acute rejection, graft failure, and mortality. However, it is not known whether contemporary induction immunosuppression improves their post-transplant outcomes. To evaluate whether Black patients who were prescribed induction immunosuppression therapy have lower all-cause mortality or graft-failure rates compared to those who were not, we studied Black U.S. adult heart transplant recipients in the Scientific Registry of Transplant Recipients database (2008-2018). We used multivariable Cox proportional hazards regression analysis to compare the hazards of all-cause mortality or graft failure as a composite, for patients who were prescribed induction immunosuppression and those who were not. Among 5160 recipients, 2787 (54.0%) were prescribed induction immunosuppression and 2373 (46.0%) were not. There was no evidence of survival differences according to induction immunosuppression for the composite of all-cause mortality or graft failure (aHR=1.13, 95% CI 0.96-1.32), mortality (aHR=1.14, 95% CI 0.97-1.34), graft failure (aHR=1.05, 95% CI 0.82-1.34) and acute rejection (aHR=1.00, 95% CI 0.89-1.12). Given the side effects of treatment, future guidelines should reconsider the recommendation for induction immunosuppression among Black patients.

Biologically Unrelated Living Donor for Kidney Transplantation Associated With Higher Acute Rejection Rate but With Similar Graft Survival of a Related Living Donor.

Kidney transplantation (KT) from living donors has been shown to have multiple benefits compared to those from deceased donors. We sought to compare significant graft outcomes, namely acute rejection (AR), graft function, and survival between transplant recipients who received a kidney from living related donor (LRD) and living unrelated donor (LURD). Our cohort comprised 198 donor and recipient pairs undergoing living-donor KT at our center over 10 years. The LRD recipients were compared with LURD recipients according to demographic and clinical characteristics, transplant variables (including immunosuppression), graft function, survival, and AR rate. The estimated glomerular filtration rate (eGFR) was similar in both groups over the follow-up time i.e.,60-65 mL/min (p>0.05 over 10 years). Censored graft survival was similar between LRD and LURD recipients (96.9% vs. 98.0% at five years and 87.8% vs. 79.4% at 10 years, respectively; p=0.837). The LURD recipients had a higher incidence of AR, although LURD recipient status was not an independent risk factor for AR.Multivariate analysis showed that human leukocyte antigen (HLA)-DR mismatch (MM) was an independent predictor of AR (hazard ratio (HR) 2.256, p<0.05). Both HLA-A and HLA-B MM did not affect the AR HR between the groups. Graft function and censored graft survival rates were similar between LURD and LRD KT recipients in our study. The AR was higher in LURD recipients, although the LURD recipient status was not an independent risk factor for AR. The HLA-DR MM was an independent predictor of AR, while HLA-A and HLA-B MM did not affect AR HR between groups of patients.

Preoperative CD52 Level Predicts Graft Survival following Kidney Transplantation.

Several factors have been reported to affect graft survival following kidney transplantation. CD52 molecules may increase T cell proliferation and activation, which may contribute to acute graft rejection and graft survival. In the current study, we studied the possible value of preoperative CD52 levels in predicting graft survival following renal transplantation. Ninety-six patients with end-stage renal disease who had kidney transplantation were included in the study from our prospective cohort. Blood samples were taken one day before surgery, and plasma CD52 levels were measured using ELISA (Cloud-Clone Corp., Houston, TX, USA). Acute rejection, acute tubular necrosis, delayed graft function, graft loss, BK infection, cytomegalovirus infection, and graft survival were evaluated. The mean age of recipients was 50.08 ± 12.82 years, and 64.6% were male. The incidence of delayed graft function, acute rejection, graft loss (p < 0.01), BK virus infection, and serum creatinine levels were significantly higher in recipients with high preoperative CD52 levels six months after transplantation (p < 0.05). Kaplan-Meier analysis revealed that three-year graft survival was significantly higher in patients with low preoperative CD52 levels (p < 0.0001). Univariate and multivariate Cox regression analyses showed that serum creatinine levels (hazard ratio [HR] = 1.7, p < 0.05), acute rejection (HR = 2.919, p < 0.05), and preoperative CD52 levels (HR = 3.114, p < 0.05) were independent prognostic factors for graft survival after kidney transplantation. We showed that high preoperative CD52 levels are associated with higher rates of acute rejection, delayed graft function, and BK virus infection and lower rates of graft survival after kidney transplantation.

Outcomes in AB0 Incompatible Living Donor Kidney Transplantation: A Case - Control Study.

BackgroundPatients waiting for a kidney transplant by far exceed available organs. AB0 incompatible living donor kidney transplantation (AB0i LDKT) represents an additional therapeutic strategy, but with higher risk for complications. We aimed at evaluating outcomes of AB0i LDKTs compared to compatible (AB0c) controls at our Institution.MethodsRetrospective matched case – control study (1:2) comparing AB0i vs. AB0c LDKTs from March 2012 to September 2021. Considered outcomes: graft function, acute rejection, sepsis, CMV infection, BK virus reactivation, death-censored graft survival, patient survival.ResultsSeventeen AB0i LDKTs matched to 34 AB0c controls. We found excellent graft function, comparable in the two groups, at all considered intervals, with an eGFR (ml/min/1.73 m2) of 67 vs. 66 at 1 year (p = 0.41), 63 vs. 64 at 3 years (p = 0.53). AB0i recipients had a statistically significant higher incidence of acute rejection, acute antibody-mediated rejection and sepsis within 30 days (p = 0.016; p = 0.02; p = 0.001), 1 year (p = 0.012; p = 0.02; p = 0.0004) and 3 years (p = 0.004; p = 0.006; p = 0.012) after surgery. There was no difference in CMV infection, BK virus reactivation, death-censored graft survival between the two groups. Patient survival was inferior in AB0i group at 1 and 3 years (88.2 vs. 100%; log-rank p = 0.03) due to early death for opportunistic infections. AB0i LDKTs spent longer time on dialysis (p = 0.04) and 82.3 vs. 38.3% controls had blood group 0 (p = 0.003).ConclusionsAB0i LDKT is an effective therapeutic strategy with graft function and survival comparable to AB0c LDKTs, despite higher rates of acute rejection and sepsis. It is an additional opportunity for patients with less chances of being transplanted, as blood group 0 individuals.

Risk Factors of Rejection in Renal Transplant Recipients: A Narrative Review.

Multiple factors influence graft rejection after kidney transplantation. Pre-operative factors affecting graft function and survival include donor and recipient characteristics such as age, gender, race, and immunologic compatibility. In addition, several peri- and post-operative parameters affect graft function and rejection, such as cold and warm ischemia times, and post-operative immunosuppressive treatment. Exposure to non-self-human leucocyte antigens (HLAs) prior to transplantation up-regulates the recipient’s immune system. A higher rate of acute rejection is observed in transplant recipients with a history of pregnancies or significant exposure to blood products because these patients have higher panel reactive antibody (PRA) levels. Identifying these risk factors will help physicians to reduce the risk of allograft rejection, thereby promoting graft survival. In the current review, we summarize the existing literature on donor- and recipient-related risk factors of graft rejection and graft loss following kidney transplantation.

Abstract 11003: Racial Disparities in Induction Immunosuppression Use Among Heart Transplant Recipients in the United States

Introduction: Black heart transplant recipients have higher rates of acute rejection, graft failure, and mortality compared to other races. Induction immunosuppression in the immediate peri-transplant period may lower the risk of acute rejection among high-risk patients, including Black transplant recipients. However, it is not known whether the odds of receiving this treatment are different across races. Therefore, we evaluated whether there are disparities in the use of induction immunosuppression following heart transplants among Black patients compared to other races. Methods: We conducted a cross-sectional study of U.S. adults in the Scientific Registry of Transplant Recipients who received their first heart transplant between 2008 - 2018. We used mixed-effects logistic regression to compare the odds of receiving induction immunosuppression agents (IL-2 receptor antagonists, polyclonal anti-lymphocyte antibodies, and CD52 monoclonal antibodies) across different races. Results: Among 23,935 adult heart transplant recipients, 5,160 (21.6%) were Black, including 2,797 (54.2%) who received induction immunosuppression, and 18,775 (78.4%) were non-Black, including 9,499 (50.6%) who received induction immunosuppression. After accounting for demographic and clinical characteristics and treatment center, Black race was associated with 28% higher odds (Odds Ratio=1.28, 95% CI 1.17-1.40) of induction immunosuppression use compared to other races. Similar results were observed when race was further stratified (Table 1). Conclusions: In our study, Black heart transplant recipients were more likely to receive induction immunosuppression than transplant recipients of other races. However, further research on post-transplant clinical outcomes including survival following induction immunosuppression among Black patients is needed to formulate treatment guidelines.

MO975INFLUENCE OF THE TYPE OF DIALYSIS ON SHORT-TERM KIDNEY TRANSPLANT RESULTS. EXPERIENCE OF OUR CENTER

Abstract Background and Aims Kidney transplantation (KT) is considered to be the best option for renal replacement therapy (RRT) in patients with advanced chronic kidney disease, surpassing any dialysis technique in quality and life expectancy. However, results in terms of how pre-KT dialysis technique influences graft and recipient survival are mixed. Some studies show a higher incidence of vascular complications in the immediate post-transplant period and higher rates of acute rejection in patients coming from peritoneal dialysis (PD) versus those coming from hemodialysis (HD) while others observe a lower incidence of delayed graft function in the PD group of patients versus those on HD. Our objective is to analyze if there are differences in immediate post-kidney transplantation and at 6 months of follow-up depending on the pre-KT dialysis technique, PD versus HD. Method Observational study of all patients with KT of cadaveric donor from the beginning of the KT program in our Center, from August 2011 to August 2019. We analyzed the characteristics of donors and recipients according to the technique (PD/HD), the evolution and complications in the immediate post-KT, as well as results at 6 months of follow-up in terms of complications, renal function and survival of the recipient and the graft. For statistical analysis we used SPSS 25. We compared qualitative variables by means of Xi2 test, and quantitative variables by t of Student, or U of Mann-Whitney if the variables did not follow a normal distribution. A value of p &amp;lt;0.05 was considered significant. Results 121 patients were included, 71 of whom were in the HD group, versus 50 who were in the PD group. The recipients in the HD group were significantly older (57.2 vs 51.6 years, p 0,02) and stayed on dialysis longer (33.8 vs 26.8 months). We observed no difference in the recipient's cardiovascular history, except for increased smoking in the HD group (52.1% vs. 24%). The donor-recipient immune profile was similar in both groups. As for the incidence of delayed graft function, it was significantly lower in the PD group (14.9% vs 34.3%), finding no difference in renal function at hospital discharge or in days of admission. In the first 6 months of follow-up, we found no differences in terms of vascular, urological or infectious complications. There were also no differences in the incidence of acute rejection, renal function measured by creatinine (HD 1.47 vs DP 1.50 mg/dl) and proteinuria (HD 200 vs DP 216 mg/24 hours). Graft and recipient survival at 6 months of TR follow-up were similar in both groups. Conclusion In our experience, we have not found differences in the evolution at 6 months of the KT according to the modality of dialysis , nor greater incidence of vascular, immunological or other complications, with a survival of graft and receptor superimposable between both groups, PD or HD.

Cardiac Allograft Injury in Patients of African Ancestry: Trends of Donor-Derived Cell-Free DNA Based on Genetic Ancestry

Purpose Higher rates of acute rejection in African American transplant recipients are reported across multiple organ types. Mechanisms underlying poorer outcomes vs. other races are poorly defined. Because race is a social construct, most studies use self-identified race to categorize patients. Reports of genetic unique to individuals of African ancestry (AA) led us to hypothesize that ancestry markers might enhance the precision of race categorization in studies of transplant injury and rejection. Methods Using the Genomic Research for Transplantation (GRAfT) cohort, we performed whole-genome genotyping assay and measured the donor-derived cell-free DNA (dd-cfDNA), a biomarker of graft injury. We genotyped 171 heart recipients and estimated the genetic ancestry proportions by GRAF-pop software referencing 1000Genome data. Applying the filters for African genetic ancestry proportion (AGAP), patients were categorized as AA if AGAP was > 85%, and not of AA if AGAP 15%. Serial post-transplant plasma samples were analyzed for dd-cfDNA by Illumina HiSeq3500. We consolidated the highest dd-cfDNA level along the time series to represent each individual; data are presented as median + the standard error. To assess potential relationship between AGAP and dd-cfDNA, we selected patients at two extremes: 31 AAs (>85% AGAP) and 97 non-AAs ( Results Among the 171 recipients, 69 self-reported as AAs (40%), while the AGAP reported 72 AAs (42 %). The consistence between self-reported and AGAP was 97.7% (167/171). AAs at the estimated extremes ( > 85% AGAP) had significantly higher dd-cfDNA level than non-AAs ( 15% AGAP): 3.64 + 0.73 vs. 1.79 + 0.41, p=0.03). Self-reported race showed a non-significant trend towards higher dd-cfDNA levels in AAs compared to non-AAs: 2.91 + 0.48 vs. 1.79 + 0.40, p=0.074). Conclusion This study documents a high consistence between self-reported race and genetic ancestry markers. It also confirms our prior reports of increased graft injury reflected as higher levels of dd-cfDNA in AAs at the extremes of genetic ancestry proportion. Supporting our hypothesis, ancestry markers might augment self-reported race data, warranting further studies on the interaction genetic heterogeneity with social determinants of health.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25mg would be tested, starting with 10mg in cohort 1. No significant difference between Mirococept at 10mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80mg (equivalent to 120mg in human kidney) that provides a basis for further clinical development.

Phenotype of immunosuppression reduction after kidney transplantation.

Immunosuppressive regimens are delivered without direct measure of the net state of immunosuppression. Besides therapeutic drug monitoring, adjustments in immunosuppressive medications are largely event-driven. We studied the clinical phenotype of immunosuppression reduction (ISR) among kidney transplant recipients from 2005 to 2012. Patients were grouped into: no ISR, ISR for infection, or ISR for intolerance. Outcome measures were rejection, rejection-free survival, and IFTA-free survival. 1114 adult kidney transplant recipients were included: 57% had no ISR, 16% had ISR for infection, and 27% had ISR for intolerance. ISR for infection was mainly on MMF, while ISR for intolerance was mainly on FK. ISR was associated with higher rates of acute rejection. The Kaplan-Meier analysis showed increased prevalence of rejection among patients with ISR due to infection (P=.003) or intolerance (P=.05). The risk of interstitial fibrosis and tubular atrophy was increased in patients with ISR due to infection (P=.001) or intolerance (P=.018). Immunosuppression reduction is associated with increased prevalence of rejection. The clinical phenotype of ISR is dominated by IFTA remote from theonset of ISR. Solely focusing on acute rejection may underestimate effects of ISR on long-term graft function and survival.

Relevance of KDPI value and acute rejection on kidney transplant outcomes in recipients with delayed graft function - a retrospective study.

Delayed graft function (DGF) is associated with poorer graft survival and higher rate of acute rejection (AR). It is unknown whether this negative influence relies on the increased risk of AR or the DGF itself. The different Kidney Donor Profile Index (KDPI) values may also play a role in this interaction. Retrospective study aimed to evaluate the impact of DGF on graft function and graft survival in a subset of KT recipients (2004-2017). We also analyzed the relationship between KDPI and DGF. The study includes 601 KT, 226 of them (37%) developed DGF. Graft survival was lower in patients with DGF compared with non-DGF patients. Multivariable analysis revealed DGF as risk factor for graft loss, independently of the presence or not of acute rejection. Between DGF patients, we observed poorer graft survival in patients with higher KDPI value (>85%). We observed a trend of a greater impact of KDPI in patients with DGF, although this interaction was not statistically significant. Additionally, we observed poorer 12-month graft function in DGF patients. DGF is related to poorer graft survival independently of the developed acute rejection. This negative impact might be influenced by high KDPI values.