Graft Failure In Recipients Research Articles

Impact of deceased organ donor marijuana use on donor culture positivity and solid organ transplant recipient outcomes

With the increasing prevalence of marijuana use in the US, many deceased organ donors have a history of marijuana use, raising concerns about infectious risks to transplant recipients. We performed a multicenter retrospective cohort study in which exposed donors were those with recent marijuana use (in the prior 12 months) and unexposed donors were those with no recent marijuana use. Primary outcomes included the following: (1) positive donor cultures for bacteria or fungi, (2) recipient infection due to bacteria or fungi within 3 months posttransplant, and (3) recipient graft failure or death within 12 months posttransplant. Multivariable regression was used to evaluate the relationship between donor marijuana use and each outcome. A total of 658 recipients who received organs from 394 donors were included. Recent marijuana use was not associated with donor culture positivity (aOR: 0.84, 95% CI: 0.39-1.81, P = .65), recipient infection (aHR: 1.02, 95% CI: 0.76-1.38, P = .90), or recipient graft failure or death (aHR: 1.65, 95% CI: 0.90-3.02, P = .11). Our data suggest that organs from donors with a history of recent marijuana use do not pose significant infectious risks in the early posttransplant period.

Superiority of Single-Antigen Bead Study in Donor-Specific Antibodies: Determination in Highly Sensitized Patients.

The presence of donor-specific antibodies against HLA before kidney transplant has been variably associated with decreased long-term graft survival. Data on the association between pretransplant donor-specific antibodies and rejection and cause of graft failure in recipients of donor kidneys are scarce. For this study of HLA antibody levels, we analyzed serum samples from 76 patients (48 women and 28 men) who were prepared for kidney transplant at the Baskent University İstanbul Hospital between 2017 and 2022. Levels were determined by using Lifecodes panel reactive antibody class I and II identification kits and Lifecodes LSA class I and II identification kits by the Luminex assay method. Multiple antigen tests showed more than 70% sensitization detected against both class I and class II antigens in our patient group. When some samples were reevaluated with the single-antigen bead method, desensitization values were shown to be considerably reduced compared with values from multiple antigen methods. The single-antigen-coated bead method can be useful in determining the risk of donor-specific antibodies in highly sensitized patients.

Association of sex-specific donor skeletal muscle index with surgical outcomes in living donor liver transplantation recipients.

A recent study reported a correlation between the muscle mass of male donors and graft failure in living donor liver transplantation (LDLT) recipients. We investigated the association of sex-specific donor skeletal muscle index (SMI) with mortality and graft failure in LDLT recipients. We retrospectively analysed 2750 sets of donors and recipients between January 2008 and January 2018. The recipient outcomes were analysed by dividing the data according to donor sex. Cox regression analyses were performed to evaluate the association between donor SMI by sex and 1-year mortality and graft failure in recipients. In the male donor group, robust donor (increased SMI) was significantly associated with higher risks for mortality (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.00-1.06, p=.023) and graft failure (HR: 1.04, 95% CI: 1.01-1.06, p=.007) at 1year. In the female donor group, the robust donor was significantly associated with lower risks for mortality (HR: 0.92, 95% CI: 0.87-0.97, p=.003) and graft failure (HR: 0.95, 95% CI: 0.90-1.00, p=.032) at 1year. Donor SMI was associated with surgical outcomes in recipients. Robust male and female donors were a significant negative and protective factor for grafts respectively.

Impact of deceased organ donor injection drug use on donor culture positivity and recipient outcomes.

Due to the ongoing opioid epidemic in the United States, deceased organ donors increasingly have a history of injection drug use (IDU), raising concerns about infectious risks to solid organ transplant (SOT) recipients. We sought to determine how recent IDU among deceased organ donors impacted donor culture results and recipient outcomes. A retrospective cohort study was performed at three transplant centers. Exposed donors were those with "recent IDU" (in the prior 12 months). Primary outcomes included (1) positive donor cultures for bacteria or Candida species, (2) recipient bacterial or Candida infection within 3 months posttransplant, and (3) recipient graft failure or death within 12 months posttransplant. Mixed effects multivariable regression models were used to evaluate the relationship between recent donor IDU and each outcome. A total of 658 SOT recipients who received organs from 394 donors were included. Sixty-six (17%) donors had a history of recent IDU. Recent IDU in donors was associated with a significantly increased odds of donor culture positivity (aOR 3.65, 95% CI 1.06-12.60, p = .04) but was not associated with SOT recipient infection (aHR 0.98, 95% CI 0.71-1.36, p = .92) or graft failure or death (aHR 0.67, 95% CI 0.29-1.51, p = .33). Donors with recent IDU are more likely to have positive cultures, but their recipients' outcomes are unaffected, suggesting organs from donors with recent IDU may be safely utilized.

Outcomes of liver transplant recipients with high MELD scores: an experience from a Canadian centre.

Background:The frequency with which patients with high Model for End-Stage Liver Disease (MELD) scores undergo liver transplantation has been increasing. Canadian literature regarding the outcomes of liver transplantation in recipients with high MELD scores is limited. The primary objective of this study was to assess patient and graft survival among recipients with high (> 35) and low (≤ 35) MELD scores. Secondary objectives were to potentially identify independent predictors of graft failure and patient mortality.Methods:We conducted a retrospective chart review of patients undergoing liver transplantation at a single Canadian centre from 2012 to 2017.Results:A total of 332 patients were included in the study: 280 patients had a MELD score of 35 or lower, and 52 had a MELD score above 35. Patients with high MELD scores had higher rates of pretransplant acute kidney injury and dialysis (p < 0.001), admission to the intensive care unit (ICU) or intubation (p < 0.001), intraoperative blood product transfusions (p < 0.001) and post-transplantation acute kidney injury and dialysis (p < 0.001), as well as longer ICU (p < 0.001) and hospital stays (p = 0.002). One- and 3-year patient survival in recipients with MELD scores of 35 or lower was 93.1% and 84.9% versus 85.0% and 80.0% in recipients with MELD scores above 35 (p = 0.37). One- and 3-year graft survival in recipients with MELD scores of 35 or lower was 91.7% and 90.9% versus 77.2% and 72.8% in recipients with MELD scores above 35 (p < 0.001). Prior liver transplant was an independent predictor of patient mortality, and no independent predictors of graft failure were identified. When MELD was replaced with D-MELD (donor age × recipient MELD), it predicted graft failure but not patient survival.Conclusion:No difference in patient mortality was found between MELD groups. Graft survival was significantly lower in recipients with MELD scores above 35. D-MELD may potentially be used as an adjunct in determining risk of graft failure in recipients with high MELD scores.

MO954: Older Living Donors—is it A Feasible Alternative For Kidney Transplantation?

Abstract BACKGROUND AND AIMS Kidney transplantation (KT) improves survival and quality of life of patients with end-stage renal disease. However, there is still an unbalance between supply and demand for kidneys. To increase the number of available grafts and reduce the waiting list for transplantation, recruitment of older living donors has expanded. This approach remains controversial for several reasons, including the impact of kidney function decline on long-term graft and recipient survival. We aimed to evaluate the impact of living donor (LD) age on recipient graft survival and on graft function decline over time. METHOD This is a Unicenter retrospective observational study that included kidney transplants of LD between 2008 and 2017. Several clinical data were analyzed, including donors’ comorbidities, immunological features of the transplant, induction immunosuppression, number of acute rejections (AR) at the first year, and the graft glomerular filtration rate (eGFR) during the follow-up period. The eGFR was calculated using the CKD-EPI equation. The LDs were classified as young (&amp;lt;60 years) and old (≥60 years) for analysis purposes. The Kaplan–Meier curves and Cox proportional hazards multivariable regression were used for survival analysis and linear mixed regression was used to evaluate the annual slope of recipient eGFR, comparing both groups. RESULTS We observed 210 LD kidney transplants: 86% (n = 181) from young (D &amp;lt; 60) and 14% (n = 29) from old donors (D ≥60). The average age was 41.3 ± 13.3 years for recipients and 48.0 ± 10.6 years for donors. The pre-donation eGFR was significantly higher in D &amp;lt; 60 than D ≥60 (101.7 ± 14.0 versus 90.2 ± 11.0 mL/min/1.73 m2; P &amp;lt; 0.001). There was no significant difference in AR in the first year between both groups. (Table 1) The censored recipient graft survival was similar for D &amp;lt; 60 and D ≥60 (86% versus 84%, P = 0.144) (Figure 1) and the older donors’ age was not a predictor of censored graft failure [hazard ratio (HR): 2.689 (95% CI: 0.832–8.690; P = 0.098)]. Although not statistically significant, the overall recipient graft survival was lower in D ≥60 (67% versus 86%, P = 0.071) (Figure 1) and donors’ age ≥60 years was an independent predictor of global recipient graft failure (HR: 3.303, 95% CI: 1.102–9.899; P = 0.033). Linear mixed regression showed that recipient eGFR from D ≥60 was lower than D &amp;lt; 60 at 12 months [46.5 mL/min/1.73 m2 (95% CI: 41.4–51.5) versus 58.6 mL/min/1.73 m2 (95% CI: 56.4–60.8); P = 0.026] and, beyond 1-year, eGFR slope annual decline was steeper in older donor recipients by −1.4 mL/min/1.73 m2 each year [95% CI: (−2.4) to (−0.4); P = 0.005] than in those from younger donors. CONCLUSION Although the greater eGFR graft decline in the first 12 months and beyond, we demonstrated that kidneys from older living donors did not significantly compromise the censored recipient graft survival. We did not evaluate the age match between donor and recipient, as has been done in other studies, but even so, these results support the importance of increasingly encouraging KT from older living donors. It can improve the quality of life, compared to the time on dialysis and, especially for old candidates, can be the only chance to get transplanted.

Associations of sarcopenia with graft failure and mortality in patients undergoing living donor liver transplantation.

Recent studies have reported that sarcopenia influences morbidity and mortality in surgical patients. However, few studies have investigated the associations of sarcopenia with short-term and long-term graft failure in recipients after living donor liver transplantation (LDLT). In this study, we investigated the associations between sarcopenia and graft failure/mortality in patients undergoing LDLT. We retrospectively examined 2816 recipients who underwent LDLT between January 2008 and January 2018. Cox regression analysis was performed to evaluate the associations between sarcopenia and graft failure/mortality in recipients at 60 days, 180 days, and 1 year and overall. Sarcopenia in the recipient was significantly associated with 60-day graft failure (adjusted hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.09-3.61; p=0.03), 180-day graft failure (HR, 1.85; 95% CI, 1.19-2.88; p=0.01), 1-year graft failure (HR, 1.45; 95% CI, 1.01-2.17; p=0.05), and overall graft failure (HR, 1.42; 95% CI, 1.08-1.87; p=0.01). In addition, recipient sarcopenia was associated with 180-day mortality (HR, 1.88; 95% CI, 1.17-3.01; p=0.01), 1-year mortality (HR, 1.53; 95% CI, 1.01-2.29; p=0.04), and overall mortality (HR, 1.43; 95% CI, 1.08-1.90; p=0.01). Preoperative sarcopenia was associated with high rates of graft failure and mortality in LDLT recipients. Therefore, preoperative sarcopenia may be a strong predictor of the surgical prognosis in LDLT recipients.

Heart Transplant Recipients of Donors with Intracranial Hemorrhage Have Worse Survival

<h3>Purpose</h3> A significant proportion of heart transplant donors suffer death from intracranial hemorrhage. We sought to determine if recipients of donors who die due to intracranial hemorrhage have worse outcomes post heart transplant. <h3>Methods</h3> The United Network for Organ Sharing database was queried from 2006 to 2020 for all adult recipients who underwent heart transplant. Survival was compared for recipients of donors with intracranial hemorrhage versus all other causes of death. Recipients were then identified if the donor cause of death was cerebrovascular, stroke or head trauma. Survival was compared for recipients of donors with intracranial hemorrhage and donors with nonhemorrhagic stroke or head trauma within this sub-group. <h3>Results</h3> A total of 31,599 patients underwent heart transplant during the study time period, with 6362 patients whose donor died due to intracranial hemorrhage. A total of 15,914 patients received a heart from a donor with an intracranial cause of death. Demographic information is shown in table 1. Survival was significantly worse for recipients of donors who died from intracranial hemorrhage (Figure 1, p<0.001). When survival was compared for recipients whose donor had an intracranial cause of death, intracranial hemorrhage resulted in worse survival compared with a nonhemorrhagic cause of death (p<0.001). Analysis of the cause of death showed a higher rate of graft failure in recipients of donors with intracranial hemorrhage (N=257, 13.4% vs. N=699, 11.9%, p<0.001). <h3>Conclusion</h3> Donors who die from intracranial hemorrhage should be considered with caution and should be matched carefully with the appropriate recipient.

Occurrence of Herpes Viruses in Morphologically Normal Corneas.

The purpose of this study was to detect the occurrence of herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV) DNA in transplanted corneas using polymerase chain reaction (PCR) and to determine the relationship between latent HSV and VZV and herpetic eye disease in recipients. This was a retrospective, interventional case series. Samples from 88 donor corneoscleral buttons (CSBs) were collected from the conjunctiva, iris, and endothelium and tested for HSV-1, HSV-2, and VZV DNA using PCR. All transplanted eyes were evaluated and followed up. The main outcome measures were HSV-1, HSV-2, and VZV DNA positivity rates in donor CSBs and the occurrence of herpetic eye disease or graft failure in recipients of positive corneas. HSV-1 DNA was detected in 5 (5.7%) of 88 CSBs. HSV-2 was not detected in any CSBs, and VZV was found in 1 (1.2%) of the 82 examined CSBs. One recipient (16.7%) developed dendritic epitheliopathy and keratouveitis typical of HSV 12 months after transplantation, although the graft remained clear after treatment. One cornea was used for a tectonic graft and stayed edematous at the 20-month follow-up. The remaining corneas remained clear. Morphologically normal donor corneas may be PCR-positive for herpes viruses, especially HSV-1. Recipients of herpes-positive corneal grafts could be at risk for herpetic eye disease. Further studies using viral RNA by reverse transcriptase PCR are needed to provide more information on HSV and VZV latency and active replication in donor corneas.

Prophylactic Foscarnet for Human Herpesvirus 6: Effect on Hematopoietic Engraftment after Reduced-Intensity Conditioning Umbilical Cord Blood Transplantation

The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.

Impact of warm ischemia time on outcomes for kidneys donated after cardiac death Post-KAS.

Prolonged warm (WIT) and cold (CIT) ischemia times are often important considerations in the discard of DCD kidneys, but their impact on post-transplant outcomes in the post-KAS era is unclear. We examined the association of ischemia time on delayed graft function (DGF) and death-censored graft failure for DCD kidneys. The 2018 SRTR SAF was utilized to identify post-KAS DCD kidney transplants occurring from 2015 to 2018. Relative risk and Cox regression were used to calculate risk of delayed graft function and hazard of death-censored graft failure, respectively. We identified 4,680 kidneys from DCD donors transplanted from 2015 to 2018 with recorded WIT and CIT times. Median WIT was 21.0minutes (IQR 14.0-28.0), and CIT was 18.5hours (IQR 13.9-23.5). The overall incidence of DGF was 42.7%. In a univariable relative risk regression model, extended CIT (24-30hours:RR 1.37, 95% CI 1.15-1.77; >30hours:RR 1.47, 95% CI 1.22-1.77) and WIT (20-40minutes:RR 1.10, 95% CI 1.03-1.17) were associated with increased risk of DGF. When included in a multivariable model, neither prolonged CIT nor WIT were significantly associated with death-censored graft failure. Prolonged WIT and CIT are associated with increased DGF but not death-censored graft failure in recipients of DCD kidney transplants in the post-KAS era. Extended ischemia alone should not be used as a basis for discard or non-utilization of these organs.

Association Between Living Kidney Donor Postdonation Hypertension and Recipient Graft Failure.

Recipients of kidneys from living donors who subsequently develop end-stage renal disease (ESRD) also have higher graft failure, suggesting the 2 donor kidneys share risk factors that could inform recipient outcomes. Given that donor ESRD is rare, an earlier and more common postdonation outcome could serve as a surrogate to individualize counseling and management for recipients. Hypertension is a frequent event before donor ESRD; thus, early postdonation hypertension might indicate higher risk of graft failure. We studied Scientific Registry of Transplant Recipients data to quantify the association between early postdonation hypertension and recipient graft failure using propensity score-weighted Cox proportional hazards regression. We also examined the association between postdonation systolic blood pressure and graft failure. Of 37 901 recipients, 2.4% had a donor who developed hypertension within 2 years postdonation. Controlling for donor and recipient characteristics, recipients whose donors developed hypertension had no higher risk for graft failure (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.85-1.25, P = 0.72). This was consistent among subgroups of recipients at higher risk for adverse outcomes due to hyperfiltration: African American recipients (aHR 1.10, 95% CI 0.70-1.73, P = 0.68) and those with ESRD caused by hypertension (aHR 1.10, 95% CI 0.65-1.85, P = 0.73) or diabetes (aHR 0.80, 95% CI 0.56-1.13, P = 0.20). However, graft failure was associated with postdonation systolic blood pressure (per 10 mm Hg, aHR 1.05, 95% CI 1.03-1.08, P < 0.001). Although postdonation systolic blood pressure is associated with graft failure, the reported diagnosis of hypertension as determined by the requirement for blood pressure treatment early postdonation did not portend a higher risk of recipient graft failure in the same way as eventual postdonation ESRD.

Pretransplant Donor-Specific Anti-HLA Antibodies and the Risk for Rejection-Related Graft Failure of Kidney Allografts.

Background The presence of donor-specific antibodies (DSAs) against HLA before kidney transplantation has been variably associated with decreased long-term graft survival. Data on the relation of pretransplant DSA with rejection and cause of graft failure in recipients of donor kidneys are scarce. Methods Patients transplanted between 1995 and 2005 were included and followed until 2016. Donor-specific antibodies before transplantation were determined retrospectively. For cause, renal transplant biopsies were reviewed. Results Pretransplant DSAs were found in 160 cases on a total of 734 transplantations (21.8%). In 80.5% of graft failures, a diagnostic renal biopsy was performed. The presence of pretransplant DSA (DSApos) increased the risk of graft failure within the first 3 months after transplantation (5.2% vs. 9.4%) because of rejection with intragraft thrombosis (p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, Conclusions Pretransplant DSAs are a risk factor for early graft loss and increase the incidence for humoral rejection and graft loss but do not affect the risk for T cell-mediated rejection.

The Effect of the Opioid Epidemic on Donation After Circulatory Death Transplantation Outcomes.

The opioid epidemic and the deaths of otherwise healthy individuals due to drug overdose in the United States has major implications for transplantation. The current extent and safety of utilization of liver and kidney grafts from donation after circulatory death (DCD) donors who died from opioid overdose is unknown. Using national data from 2006 to 2016, we estimated the cumulative incidence of graft failure for recipients of DCD grafts, comparing the risk among recipients of organs from donors who died of anoxic drug overdose and recipients of organs from donors who died of other causes. One hundred seventy-nine (6.2%) of 2908 liver graft recipients and 944 (6.1%) of 15520 kidney graft recipients received grafts from donors who died of anoxic drug overdose. Grafts from anoxic drug overdose donors were less frequently used compared with other DCD grafts (liver, 25.9% versus 29.6%; 95% confidence interval [CI] for difference, -6.7% to -0.7%; kidney, 81.0% versus 84.7%; 95% CI for difference, -7.3% to -0.1%). However, the risk of graft failure at 5 years was similar for recipients of anoxic drug overdose donor grafts and recipients of other grafts (liver risk difference, 1.8%; 95% CI, -7.8% to 11.8%; kidney risk difference, -1.5%; 95% CI, -5.4% to 3.1%). In the context of the current opioid epidemic, utilization of anoxic drug overdose DCD donor grafts does not increase the risk of graft failure and may help to address waitlist demands.

Management of donation after brain death (DBD) in the ICU: the potential donor is identified, what's next?

The success of any donation process requires that potential brain-dead donors (PBDD) are detected and referred early to professionals responsible for their evaluation and conversion to actual donors. The intensivist plays a crucial role in organ donation. However, identification and referral of PBDDs may be suboptimal in the critical care environment. Factors influencing lower rates of detection and referral include the lack of specific training and the need to provide concomitant urgent care to other critically ill patients. Excellent communication between the ICU staff and the procurement organization is necessary to ensure the optimization of both the number and quality of organs transplanted. The organ donation process has been improved over the last two decades with the involvement and commitment of many healthcare professionals. Clinical protocols have been developed and implemented to better organize the multidisciplinary approach to organ donation. In this manuscript, we aim to highlight the main steps of organ donation, taking into account the following: early identification and evaluation of the PBDD with the use of checklists; donor management, including clinical maintenance of the PBDD with high-quality intensive care to prevent graft failure in recipients and strategies for optimizing donated organs by simplified care standards, clinical guidelines and alert tools; the key role of the intensivist in the donation process with the interaction between ICU professionals and transplant coordinators, nurse protocol managers, and communication skills training; and a final remark on the importance of the development of research with further insight into brain death pathophysiology and reversible organ damage.

KIR Ligand Incompatibility in the Host Versus Graft Direction Predicts Graft Failure and Dominant Graft in Cord Blood Transplantation but Not in Haploidentical Transplantation

Donor-derived natural killer (NK) cell alloreactivity has been shown to improve clinical outcomes following allogeneic stem cell transplant (HSCT). Host versus graft (HvG) directed NK cell alloreactivity can also occur. Several epitopes of HLA-B and HLA-C are ligands for inhibitory killer immunoglobulin-like receptors (KIRs) that regulate NK cell cytotoxicity. These KIR ligands (KIR-L) may be surrogates of NK cell alloreactivity in the HLA-mismatched setting. To determine the impact of donor/recipient KIR-L mismatch (KIR-L-MM) direction on engraftment, we examined cord blood (CBT) and haploidentical (Haplo) HSCT performed at our institution between 2011 and 2018. We computed KIR-L and direction of KIR-L-MM for recipient/ donor pairs using the KIR ligand calculator (https://www.ebi.ac.uk/ipd/kir/ligand.html). Summary data and the relative risk of graft failure were analyzed. In the CBT cohort (N=70), there were KIR-L mismatches (KIR-L-MM) in the HvG and GvH direction in 32 and 31 recipient-cord blood unit pairs respectively. There were no KIR-L-MM in 26 transplants while seven had KIR-L-MM in both GvH and HvG directions. Overall, 16 CBT failed to engraft (23%). There was an increased risk of graft failure in recipients of HvG KIR-L-MM transplants (R.R 2.15; p=0.063) with this trend most significant when the mismatch was in HLA-C ligand (R.R 2.46; p=0.027); Figure 1. Out of 8 double CBTs where one cord unit had HvG KIR-L-MM, the non-mismatched unit fully engrafted in 7 cases (87.5%). In 6 double CBTs where there was KIR-L-MM from one cord unit in the GvH and the GvG (graft versus other graft) direction, 4 (67%) of such units became the dominant graft. Of 8 double CBTs in which both cord units had KIR-L-MM in the HvG direction there was graft failure in 3 (37.5%). Time to neutrophil engraftment and lymphocyte recovery when engraftment occurred was not significantly impacted by KIR-L-MM. In the Haplo cohort (N=26), all of the 5 graft failures (19%) were KIR-L mismatched only in the GvH direction (R.R 9.53; p=0.114). There were 9 HvG KIR-L-MM transplants and they all engrafted. Fourteen transplant pairs in this cohort had KIR-L-MM in the GvH direction; 2 pairs had both HvG and GvH KIR-L-MM while 3 pairs did not have any KIR-L-MM. Time to neutrophil engraftment was not impacted by GvH or HvG KIR-L-MM. This study suggests an increased likelihood of graft failure in CBT when HvG KIR-L-MM exists. There is also a trend in favor of engrafting the GvH/GvG KIR-L-MM unit in double CBT. These factors should be considered when selecting cord units for CBT. A similar graft failure effect of HvG KIR-L-MM is not seen in this small Haplo cohort; on the contrary the data suggests GvH directed KIR-L-MM associates with graft failure. This association merits exploration in a larger database.

The Direction of KIR Ligand Incompatibility Is Associated with Graft Failure and May Predict the Dominant Donor Following Double Umbilical Cord Blood Transplantation

While there is plausible evidence suggesting the benefit of natural killer (NK) cell alloreactivity in post-transplantation outcomes, there is no consensus on how such alloreactivity can be best predicted when selecting unrelated graft donors. Epitopes of HLA Class I molecules HLA-B and HLA-C are the ligands for inhibitory killer immunoglobulin-like receptors (KIRs) that regulate NK cell cytotoxicity. Based on the hypothesis that NK cell licensing in the bone marrow selects for circulating NK cells with corresponding inhibitory KIRs for self KIR ligands (KIR-L), these ligands, as determined by HLA-B/C antigens have been used as surrogates to predict NK cell alloreactivity in mismatched transplants. There is also the potential for alloreactivity by NK cells in the host versus graft (HvG) direction particularly in cord blood transplantation where reduced intensity conditioning is common. We examined cord blood transplantations at our institution to determine the impact of donor/recipient KIR ligand mismatch, and its direction, on graft failure.Methods: We analyzed the Stem Cell Transplant database of all cord blood transplants (CBT) performed at University Hospitals Seidman Cancer Center between December 2010 and April 2018. Data extracted from electronic medical record review included demographics, indication for transplant, disease status at time of transplant, conditioning regimen, graft versus host disease (GVHD) prophylaxis including the use of antithymocyte globulin (ATG) and post transplantation outcomes. For the cohort we computed KIR ligands for transplant recipients and cord blood unit(s), then predicted direction of alloreactivity using the KIR ligand calculator available online (https://www.ebi.ac.uk/ipd/kir/ligand.html). We determined the relative risk of developing graft failure as well as summary statistics of time to neutrophil engraftment and achieving a stable lymphocyte count of 500/ul or more in those that engrafted.Results: We identified 67 patients that received cord blood transplants for which donor and recipient KIR-L could be adequately computed. Three of these patients required a second cord blood transplant for graft failure, resulting in a total of 70 CBTs. Demographics, disease characteristics and treatment regimens are outlined in Table 1. There were KIR-L mismatches (MM) in the HvG and GvH direction in 32 and 31 recipient-cord blood unit pairs respectively. While there were no KIR-L MM in 26 transplants, 7 transplants had KIR-L mismatches in both GvH and HvG directions. There was an increased risk of graft failure in recipients of HvG-directed KIR-L MM transplants (R.R 2.15; p=0.063) with this trend most significant when the mismatch was in HLA-C ligand (R.R 2.46; p=0.027); Table 2. Out of 8 double CBTs where 1 cord unit had HvG-directed KIR-L MM, the non-mismatched unit fully engrafted in 7 (75%) cases. In 1 case the non-mismatched unit shared donor chimerism with the KIR-L MM unit at 85% and 15% respectively till 10 months post-transplant. In 6 double CBTs where there was KIR-L MM from only 1 cord unit in the GvH-direction, 4 (67%) of such units became the dominant graft. Of 8 double CBTs in which both cord units had KIR-L MM in the HvG direction there was graft failure in 3 (37.5%). The time to neutrophil engraftment and lymphocyte recovery in the patients that engrafted was not significantly impacted by KIR-L incompatibility (Table 3).Conclusions: From this study we see an increased likelihood of graft failure when KIR-ligand incompatibility exists in the host versus graft direction for CBT. There is also a trend in favor of engrafting the cord unit that is KIR-L mismatched in the graft versus host direction against the second cord in double CBT. These factors should be considered when selecting cord units for double CBT as well as in making single cord decisions where multiple options are available. [Display omitted] DisclosuresLittle:Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding; PCORI: Research Funding; NHLBI: Research Funding. Malek:Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

Improved Hematopoietic Gene Therapy in a Mouse Model of Fanconi Anemia Mediated by Mesenchymal Stromal Cells.

In this study we propose a novel approach based on the use of mesenchymal stromal cells (MSCs), aiming at limiting risks of graft failure in gene therapy protocols associated with low conditioning regimens. Because the engraftment of corrected hematopoietic stem cells (HSCs) is particularly challenging in Fanconi anemia (FA), we have investigated the relevance of MSCs in an experimental model of FA gene therapy. Our results showed, first, that risks of graft failure in recipients conditioned with a moderate dose of 5 Gy and infused with limited numbers of wild-type HSCs are significantly higher in Fanca-/- recipients as compared with wild-type recipients. However, when wild-type HSC numbers inducing 30-50% of graft failures in Fanca-/- recipients were coinfused with MSCs, no graft failures were observed. Moreover, graft failures associated with the infusion of low numbers of gene-corrected Fanca-/- HSCs were also significantly overcome by MSC coinfusion. Our study shows for the first time that MSC coinfusion constitutes a simple and nontoxic approach to minimize risks of graft failure in gene therapy applications associated with low conditioning regimens and infusion of limited numbers of corrected HSCs.

The association of donor and recipient age with graft survival in paediatric renal transplant recipients in a European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplantation Association Registry study.

The impact of donor age in paediatric kidney transplantation is unclear. We therefore examined the association of donor-recipient age combinations with graft survival in children. Data for 4686 first kidney transplantations performed in 13 countries in 1990-2013 were extracted from the ESPN/ERA-EDTA Registry. The effect of donor and recipient age combinations on 5-year graft-failure risk, stratified by donor source, was estimated using Kaplan-Meier survival curves and Cox regression, while adjusting for sex, primary renal diseases with a high risk of recurrence, pre-emptive transplantation, year of transplantation and country. The risk of graft failure in older living donors (50-75 years old) was similar to that of younger living donors {adjusted hazard ratio [aHR] 0.74 [95% confidence interval (CI) 0.38-1.47]}. Deceased donor (DD) age was non-linearly associated with graft survival, with the highest risk of graft failure found in the youngest donor age group [0-5 years; compared with donor ages 12-19 years; aHR 1.69 (95% CI 1.26-2.26)], especially among the youngest recipients (0-11 years). DD age had little effect on graft failure in recipients' ages 12-19 years. Our results suggest that donations from older living donors provide excellent graft outcomes in all paediatric recipients. For young recipients, the allocation of DDs over the age of 5 years should be prioritized.

Renal outcome after kidney-transplantation in Korean patients with lupus nephritis.

We investigated renal outcome of kidney-transplantation in 19 Korean recipients with biopsy-proven lupus nephritis and compared it with 18 Korean age- and gender-matched recipients without lupus nephritis who were diagnosed with end-stage renal disease caused by renal diseases other than lupus nephritis in a single centre. We reviewed histological findings of kidneys and calculated cumulative dose of immunosuppressive agents. We assessed renal flare of systemic lupus erythematosus, recurrence of lupus nephritis and graft failure as prognosis. The mean age of recipients with lupus nephritis was 43.5 years and all patients were female. Six patients had class III, 10 had class IV and three had class V. There were no meaningful differences in demographic data, renal replacement modality, cumulative doses of immunosuppressants and prognosis between recipients with and without lupus nephritis. Eight patients experienced renal flare of systemic lupus erythematosus, but there were no cases of recurrence of lupus nephritis or graft failure in recipients with lupus nephritis. Kidney-recipients with class IV lupus nephritis exhibited a lower cumulative renal flare of systemic lupus erythematosus free survival rate than those with class III lupus nephritis. In conclusion, renal outcome of kidney-transplantation in patients with lupus nephritis is similar to that in those without lupus nephritis, and class IV was associated with renal flare of systemic lupus erythematosus.