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Background: Thrombotic microangiopathy (TMA) is a rare complication after lung transplantation (LT) that has seldom been characterized in detail. Recent evidence has linked TMA other than primary atypical hemolytic uremic syndrome (aHUS) with hyperactivation of the complement alternative pathway. The focus of this investigation was to analyze the treatment response with eculizumab in TMA after LT. Methods: Case series where we have studied 11 patients with TMA after LT from 2 Spanish tertiary healthcare centers. Clinical data and response rates to eculizumab are provided. Results: The main indication for lung transplant was chronic obstructive pulmonary disease (COPD) (36%) and most cases (82%) received bilateral LT. The median time to TMA diagnosis was 11.6 months (4.7–28.9) and the TMA trigger in the majority of cases (73%) was immunosuppressive drugs. Platelet and hemoglobin nadir were 58 × 103/µL (24–108) and 7.7 g/dL (7.1–7.9), respectively. All cases presented acute kidney injury (AKI) with a median creatinine of 4 mg/dL (3.2–4.8) and 54.5% required acute dialysis. Eculizumab was started after a median time of 8 days (6–14) with a median duration of 3 weeks (2–8). Complete TMA response was observed in 7 (63.6%) cases and hematologic response in 10 (90.9%). The time to hematologic and renal response was 23 days (13–29) and 28 days (14–46), respectively. Conclusions: TMA after LT is infrequent but potentially devastating. Our findings suggest that short cycles of eculizumab may be effective for severe TMA after LT. [ABSTRACT FROM AUTHOR]

Background: Evidence of decline in native renal function after heart transplantation (HTx) in the Asian population is limited. This study determined the incidence and risk factors associated with declining kidney function after HTx and its impact on survival. Methods: A retrospective study of consecutive adult heart transplant patients was conducted in a single center between 2010 and 2020. The decline in kidney function was defined as the presence of one of the following criteria, including a ≥ 40% decline in eGFR, absolute value <15 mL/min/1.73 m2 (calculated by the CKD‐EPI method), doubling of serum creatinine, or dialysis. Results: A total of 79 patients (77% male, mean age 44.5 ± 11.53 years, with a mean eGFR at discharge from the heart transplant admission of 87.9 ± 25.48 mL/min/1.73 m2) were included. During the median follow‐up of 42 months, the rate of decline in eGFR was 3.9 mL/min/1.73 m2 per year, with a cumulative probability of decline in kidney function of 22% at 1 year and 43% at 5 years. The need for dialysis was 2.5% at 1 year and 5% at 5 years. The decline in kidney function within 1 year after discharge (hazard ratio (HR), 22.24; p =.007) and pre‐HTx diabetes mellitus (DM) (HR, 8.99; p =.034) were independently associated with the need for dialysis. Post‐HTx dialysis predicted all‐cause mortality (HR, 4.47; p =.017). Conclusions: Approximately 20% of HTx patients developed a decline in kidney function within 1 year after discharge. These individuals and pre‐HTx DM patients needed preventive measures to prevent progression to chronic dialysis, which impacted survival. (thaiclinicaltrials.org number, TCTR20230620004). [ABSTRACT FROM AUTHOR]

Bariatric surgery has been shown to be safe in the dialysis population. Whether bariatric surgery before kidney transplantation influences posttransplant outcomes has not been examined nationally. We included severely obese (BMI >35) dialysis patients between 18 and 70 years who received a kidney transplant according to the US Renal Data System. We determined the association between history of bariatric surgery and risk of 30-day readmission, graft failure, or death after transplantation using multivariable logistic, Fine-Gray, and Cox models. We included 12 573 patients, of whom 503 (4%) received bariatric surgery before transplantation. Median age at transplant was 53 years; 42% were women. Overall, history of bariatric surgery was not statistically significantly associated with graft failure (HR 1.02; 95% CI 0.77-1.35) or death (HR 1.10; 95% CI 0.84-1.45). However, sleeve gastrectomy (vs. no bariatric surgery) was associated with lower risk of graft failure (HR 0.39; 95% CI 0.16-0.95). In conclusion, history of bariatric surgery prior to kidney transplantation was not associated with allograft or patient survival, but findings varied by surgery type. Sleeve gastrectomy was associated with better graft survival and should be considered in severely obese transplant candidates receiving dialysis.

Background Thymoglobulin is used effectively as an induction agent in kidney transplantation, but there is no consensus on the optimal dose. In order to delineate the safest effective dose, an open-labeled randomized clinical trial was designed. Methods In this study, 90 adult kidney transplant recipients ( KTR) were randomized before transplantation in three groups to receive thymoglobulin: Arm A (4.5 mg/kg in 3 days), Arm B (4.5 mg/kg single bolus dose), and Arm C (6 mg/kg in 3 days). Renal function, infections, and rate of readmissions were evaluated during the first post transplantation year. Results Ninety adult kidney recipients were enrolled (51% deceased donor). No significant statistical difference was found in acute rejection episodes or type of rejection between these groups, although patients in Arm A showed more severe histopathologic changes according to Banff 2013 criteria, in renal biopsies ( P=.03). At the first month after transplantation serum Cr was lower ( P=.001) and GFR was higher ( P=.04) in Arm A, but there was no significant difference among the three groups at 3, 6, and 12 months post-transplant. Conclusion Although all regimens showed the same efficacy regarding the rate of rejection episodes, 3-day 4.5 mg/kg Thymoglobulin had significantly fewer complications. [ABSTRACT FROM AUTHOR]

Thrombospondin-1 (TSP-1) is a key mediator of renal ischemia-reperfusion injury (IRI), a major cause of kidney dysfunction under various disease conditions and a risk factor of renal allograft rejection. In this study, we developed a nanotechnology-based therapy targeting TSP-1 to prevent renal IRI. A biocompatible nanoparticle (NP) capable of specific binding to TSP-1 was prepared by conjugating NPs with TSP-1-binding (LSKL) peptides. LSKL/NPs not only effectively adsorbed recombinant TSP-1 proteins in vitro, but also efficiently neutralized TSP-1 in mice undergoing renal IRI. IRI-induced elevation of TSP-1 in the kidney was significantly inhibited by post-IR treatment with LSKL/NPs, but not free LSKL or NPs. Furthermore, TSP-1 proteins adsorbed on LSKL/NPs were functionally inactive and unable to induce apoptosis in renal tubular epithelial cells. Importantly, LSKL/NPs induced strong protection against renal IRI, as shown by markedly diminished serum creatinine levels and improved histological lesions of the kidney. Thus, LSKL/NPs provide a useful means of depleting and inactivating TSP-1 and a potential therapy for renal IRI., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, α-actinin-4 and talin-1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin-1 is a specific proteolytic target of calpain-1, we investigated a potential trigger of calpain activation and talin-1 degradation using human ex vivo precision-cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain-1 by transforming growth factor-β generated proteolytic fragments of talin-1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain-1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidney allocation trends from deceased donors with acute kidney injury (AKI) have not been characterized since initial Kidney Donor Profile Index reporting in 2012 and its use under the revised Kidney Allocation System (KAS) in 2014. We conducted a retrospective analysis of US registry data to characterize kidney procurement and discard trends in deceased donors with AKI, defined by ≥50% or ≥0.3 mg/dl (≥4.0 mg/dl or ≥200% for stage 3) increase in terminal serum creatinine from admission. From 2010 to 2020, 172 410 kidneys were procured from 93 341 deceased donors 16 years or older; 34 984 kidneys were discarded (17 559 from AKI donors). The proportion of stage 3 AKI donors doubled from 6% (412/6841) in 2010 to 12% (1365/11493) in 2020. Procurement of stage 3 AKI kidneys increased from 51% (423/824) to 80% (2183/2730). While discard of stage 3 AKI kidneys increased from 41% (175/423) in 2010 to 44% (960/2183) in 2020, this increase was not statistically significant in interrupted time-series analysis following KAS implementation (slope difference -0.41 [-3.22, 2.4], and level change 3.09 [-6.4, 12.6]). In conclusion, the absolute number of stage 3 AKI kidneys transplanted has increased. Ongoing high discard rates of these kidneys suggest opportunities for improved utilization., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Large-scale evidence comparing the risk of Mycobacterium tuberculosis (TB) between kidney transplant (KT) recipients and dialysis patients is warranted. This is a nationwide retrospective cohort study based on the claims database of South Korea where a moderate prevalence of TB is reported. We included incident KT recipients from 2011 to 2015 and compared their active TB risks with 1:1 matched dialysis and general population control groups, respectively. The risk of incident active TB was assessed by multivariable Cox regression. Associations between active TB and posttransplant death or death-censored graft failure were investigated. The number of matched subjects included in each of the study groups was 7462. The KT group showed a significantly higher risk of active TB than the general population group (hazard ratio [HR] 3.39 [1.88-6.10]), whereas it showed a similar risk to that of the dialysis group (HR 0.98 [0.73-1.31]). In KT patients, active TB was a significant risk factor for both death (HR 2.33 [1.24-4.39]) and death-censored graft failure (HR 2.26 [1.39-3.67]). Although KT recipients may not have to burden the additional risk of active TB when compared with dialysis patients in recent medicine, active TB should not be overlooked as it is associated with a worse prognosis in posttransplant patients., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Sex-specific influences have been shown for a variety of diseases. Whether donor or recipient sex and sex hormone levels impact alloimmune responses remains unclear. In unifactorial and multifactorial analyses of more than 400 000 SRTR listed kidney transplant patients, we found that younger female recipients had an inferior death-censored graft survival that was independent of donor sex. In contrast, graft survival was superior in older female recipients, suggesting the impact of recipient sex hormones over chromosomal sex mismatches. Those clinical changes were delineated in experimental skin and heart transplant models showing a prolongation of graft survival in ovariectomized young female recipients. In contrast, graft survival was comparable in ovariectomized and naïve old female recipients. Young ovariectomized mice showed reduced amounts and a compromised T cell proliferation. Deprivation of female hormones dampened the production of interferon (IFN)-γ and interleukin (IL)-17 + by CD4 + T cells while augmenting systemic counts of Tregs. Increasing estradiol concentrations in vitro promoted the switch of naïve CD4 + T cells into Th1 cells; high physiological estradiol concentrations dampening Th1 responses, promoted Tregs, and prolonged graft survival. Thus, clinical observations demonstrate age-specific graft survival patterns in female recipients. Estrogen levels, in turn, impact the fate of T cell subsets, providing relevant and novel information on age- and sex-specific alloimmunity., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidney allograft failure and return to dialysis carry a high risk of morbidity. A practice survey was developed by the AST Kidney Pancreas Community of Practice workgroup and distributed electronically to the AST members. There were 104 respondents who represented 92 kidney transplant centers. Most survey respondents were transplant nephrologists at academic centers. The most common approach to immunosuppression management was to withdraw the antimetabolite first (73%), while only 12% responded they would withdraw calcineurin inhibitor (CNI) first. More than 60% reported that the availability of a living donor is the most important factor in their decision to taper immunosuppression, followed by risk of infection, risk of sensitization, frailty, and side effects of medications. More than half of respondents reported that embolization was either not available or offered to less than 10% as an option for surgical intervention. Majority reported that ≤50% of failed allograft patients were re-listed before dialysis, and less than a quarter of transplant nephrologists performed frequent visits with their patients with failed kidney allograft after they return to dialysis. This survey demonstrates heterogeneity in the care of patients with a failing allograft and the need for more evidence to guide improvements in clinical practice related to transition of care., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This study aimed to evaluate how 5 preservation solutions for static cold storage affected kidney transplant outcomes. It included all first single kidney transplants during 2010-2014 from donations after brain death in the French national transplant registry, excluding preemptive transplants and transplants of kidneys preserved with a hypothermic perfusion machine. The effects of each preservation solution on delayed graft function (DGF) and 1-year transplant failure were evaluated with hierarchical multivariable logistic regression models. The study finally included 7640 transplanted kidneys: 3473 (45.5%) preserved with Institut Georges Lopez-1 solution (IGL-1), 773 (10.1%) with University of Wisconsin solution, 731 (9.6%) with Solution de Conservation des Organes et Tissus (SCOT, organ and tissue preservation solution), 2215 (29.0%) with Celsior, and 448 (5.9%) with histidine-tryptophan-ketoglutarate. Primary nonfunction rates did not differ by solution. After adjustment for donor, recipient, and transplant characteristics, the DGF risk was significantly lower with IGL-1 than with all other solutions (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.48-0.64). Conversely, SCOT was associated with a DGF risk significantly higher than the other solutions (OR 2.69, 95% CI 2.21-3.27) and triple that of IGL-1 (OR 3.37, 95% CI 2.72-4.16). One year after transplantation, the transplant failure rate did not differ significantly by preservation solution. The difference between the groups for 1-year mean creatinine clearance was not clinically relevant., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The clinical importance of subclinical, early T cell-mediated rejection (Banff TCMR 1A and borderline lesions) remains unclear, due, in part to the fact that histologic lesions used to characterize early TCMR can be nonspecific. Donor-derived cell-free DNA (dd-cfDNA) is an important molecular marker of active graft injury. Over a study period from June 2017 to May 2019, we assessed clinical outcomes in 79 patients diagnosed with TCMR 1A/borderline rejection across 11 US centers with a simultaneous measurement of dd-cfDNA. Forty-two patients had elevated dd-cfDNA (≥0.5%) and 37 patients had low levels (<0.5%). Elevated levels of dd-cfDNA predicted adverse clinical outcomes: among patients with elevated cfDNA, estimated glomerular filtration rate declined by 8.5% (interquartile rate [IQR] -16.22% to -1.39%) (-3.50 mL/min/1.73 m 2 IQR -8.00 to -1.00) vs 0% (-4.92%, 4.76%) in low dd-cfDNA patients (P = .004), de novo donor-specific antibody formation was seen in 40% (17/42) vs 2.7% (P < .0001), and future or persistent rejection occurred in 9 of 42 patients (21.4%) vs 0% (P = .003). The use of dd-cfDNA may complement the Banff classification and to risk stratify patients with borderline/TCMR 1A identified on biopsy., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Understanding the correlation between transplant symptoms, health-related quality of life (HRQoL), and graft outcomes is needed to support patient-focused drug development and posttransplant management. A post-hoc analysis of patient-reported outcomes from the Phase III belatacept trials was conducted in order to investigate the interrelationship between trajectories of HRQoL, symptom experience, and allograft outcomes. HRQoL and symptom experience were evaluated using Short-Form 36 Survey (SF-36) and Modified Transplant Symptom Occurrence and Distress Scale (MTSOSD-59R), respectively. HRQoL was captured in 831 eligible renal transplant patients at baseline, 12, 24, and 36 months posttransplant. Following transplantation, patients reported improvements in all SF-36 subscales compared to baseline. Latent class analysis revealed four trajectories in perceived general health, which were associated with graft failure after adjustment. Compared to patients with good perceived health, patients with fair and poor perceived health had 4.7 (95% confidence interval [CI] 1.5-14.8, P < .01) and 19.8 (95% CI 5.9-66.0, P < .01) times the risk of graft failure, respectively. Using multinomial logistic regression, different sets of symptoms were associated with perceived general health at baseline and 12 months posttransplant. The study supports monitoring HRQoL and symptom experience to capture each patient's health perspective, improve drug development, and optimize posttransplant management., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Success of transplantation is not limited to initial receipt of a donor organ. Many kidney transplant recipients experience graft loss following initial transplantation and the benefits of expedited placement on the waiting list and retransplantation extend to this population. Factors associated with access to repeat transplantation may be unique given experience with the transplant process and prior viability as a candidate. We examined the incidence, risk factors, secular changes, and center-level variation of preemptive relisting or transplantation (PRLT) for kidney transplant recipients in the United States with graft failure (not due to death) using Scientific Registry of Transplant Recipients data from 2007 to 2018 (n = 39 557). Overall incidence of PRLT was 15% and rates of relisting declined over time. Significantly lower PRLT was evident among patients who were African American and Hispanic, males, older, obese, publicly insured, had lower educational attainment, were diabetic, had longer dialysis time prior to initial transplant, shorter graft survival, longer distance to transplant center, and resided in distressed communities. There was significant variation in PRLT by center, median = 13%, 10th percentile = 6%, 90th percentile = 24%. Cumulatively, results indicate that despite prior access to transplantation, incidence of PRLT is modest with pronounced clinical, social, and center-level sources of variation suggesting opportunities to improve preemptive care among patients with failing grafts., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Donation after cardiac death (DCD) and acute kidney injury (AKI) donors have historically been considered independent risk factors for delayed graft function (DGF), allograft failure, and inferior outcomes. With growing experience, updated analyses have shown good outcomes. There continues to be limited data, however, on outcomes specific to DCD donors who have AKI. Primary outcomes for this study were post-kidney transplant patient and allograft survival comparing two donor groups: DCD AKIN stage 2-3 and DBD AKIN stage 2-3. In comparing these groups, there were no short- or long-term differences in patient (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.54-1.93, P = .83) or allograft survival (HR 1.47, 95% CI 0.64-2.97, P = .32). In multivariate models, the DCD/DBD status had no significant impact on the estimated GFR (eGFR) at 1 (P = .38), 2 (P = .60), and 3 years (P = .52). DGF (57.9% vs 67.9%, P = .09), rejection (12.1% vs 13.9%, P = .12), and progression of interstitial fibrosis/tubular atrophy (IFTA) on protocol biopsy (P = .16) were similar between the two groups. With careful selection, good outcomes can be achieved utilizing severe AKI DCD kidneys. Historic concerns regarding primary nonfunction, DGF resulting in interstitial fibrosis and rejection, and inferior outcomes were not observed. Given the ongoing organ shortage, increased effort should be undertaken to further utilize these donors., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd-cfDNA quantification of copies/mL plasma (dd-cfDNA[cp/mL]) was compared to dd-cfDNA fraction (dd-cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy-proven rejection (BPR), median dd-cfDNA(cp/mL) was 3.3-fold and median dd-cfDNA(%) 2.0-fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy-proven rejection (BPR). dd-cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd-cfDNA(cp/mL) (AUC = 0.83) compared to dd-cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd-cfDNA(cp/mL), and 6.02 for dd-cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd-cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd-cfDNA(cp/mL) with lower tacrolimus levels (<8 μg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd-cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd-cfDNA(cp/mL) allowed for better discrimination than dd-cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies., (© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

The current Banff scoring system was not developed to predict graft loss and may not be ideal for use in clinical trials aimed at improving allograft survival. We hypothesized that scoring histologic features of digitized renal allograft biopsies using a continuous, more objective, computer-assisted morphometric (CAM) system might be more predictive of graft loss. We performed a nested case-control study in kidney transplant recipients with a surveillance biopsy obtained 5 years after transplantation. Patients that developed death-censored graft loss (n = 67) were 2:1 matched on age, gender, and follow-up time to controls with surviving grafts (n = 134). The risk of graft loss was compared between CAM-based models vs a model based on Banff scores. Both Banff and CAM identified chronic lesions associated with graft loss (chronic glomerulopathy, arteriolar hyalinosis, and mesangial expansion). However, the CAM-based models predicted graft loss better than the Banff-based model, both overall (c-statistic 0.754 vs 0.705, P < .001), and in biopsies without chronic glomerulopathy (c-statistic 0.738 vs 0.661, P < .001) where it identified more features predictive of graft loss (% luminal stenosis and % mesangial expansion). Using 5-year renal allograft surveillance biopsies, CAM-based models predict graft loss better than Banff models and might be developed into biomarkers for future clinical trials., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We previously reported a system for assessing rejection in kidney transplant biopsies using microarray-based gene expression data, the Molecular Microscope ® Diagnostic System (MMDx). The present study was designed to optimize the accuracy and stability of MMDx diagnoses by replacing single machine learning classifiers with ensembles of diverse classifier methods. We also examined the use of automated report sign-outs and the agreement between multiple human interpreters of the molecular results. Ensembles generated diagnoses that were both more accurate than the best individual classifiers, and nearly as stable as the best, consistent with expectations from the machine learning literature. Human experts had ≈93% agreement (balanced accuracy) signing out the reports, and random forest-based automated sign-outs showed similar levels of agreement with the human experts (92% and 94% for predicting the expert MMDx sign-outs for T cell-mediated (TCMR) and antibody-mediated rejection (ABMR), respectively). In most cases disagreements, whether between experts or between experts and automated sign-outs, were in biopsies near diagnostic thresholds. Considerable disagreement with histology persisted. The balanced accuracies of MMDx sign-outs for histology diagnoses of TCMR and ABMR were 73% and 78%, respectively. Disagreement with histology is largely due to the known noise in histology assessments (ClinicalTrials.gov NCT01299168)., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Acute kidney injury (AKI) is common after lung transplantation, but molecular markers remain poorly studied. The endothelial activation markers soluble thrombomodulin (sTM), protein C, and plasminogen activator inhibitor-1 (PAI-1) are implicated in kidney microcirculatory injury in animal models of AKI. We tested the association of 6-hour postreperfusion plasma levels of these markers with posttransplant AKI severity in patients enrolled in the Lung Transplant Outcomes Group prospective cohort study at the University of Pennsylvania during two eras: 2004-06 (n = 61) and 2013-15 (n = 67). We defined AKI stage through postoperative day 5 using Kidney Disease Improving Global Outcomes creatinine criteria. We used multivariable ordinal logistic regression to determine the association of each biomarker with AKI, adjusted for primary graft dysfunction and extracorporeal life support. AKI occurred in 57 (45%) patients across both eras: 28 (22%) stage 1, 29 (23%) stage 2-3. Higher sTM and lower protein C plasma levels were associated with AKI stage in each era and remained so in multivariable models utilizing both eras (sTM: OR 1.76 [95% CI 1.19-2.60] per standard deviation, P = .005; protein C: OR 0.54 [1.19-2.60], P = .003). We conclude that 6-hour postreperfusion plasma sTM and protein C levels are associated with early postlung transplant AKI severity., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The development of de novo donor-specific HLA antibody (dnDSA) is a critical feature contributing to late allograft failure. The complexity of the issue is further complicated by organ-specific differences, detection techniques, reliance of tissue histopathology and changing diagnostic criteria, ineffective therapies, and lack of consensus. To tackle these issues, the Sensitization in Transplantation Assessment of Risk (STAR) 2017 was initiated as a collaboration of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics consisting of 8 working groups with the goal to provide guidelines on how to assess risk and risk stratify patients based on their potential alloimmune and DSA status. Herein is a summary of discussions by the Naïve Abdominal Working Group, highlighting currently available data and identifying gaps in our knowledge on the development and impact of dnDSA following kidney transplantation., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence., (© 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Insufficient hemodynamics during agonal phase-ie, the period between withdrawal of life-sustaining treatment and circulatory arrest-in Maastricht category III circulatory-death donors (DCD) potentially exacerbate ischemia/reperfusion injury. We included 409 Dutch adult recipients of DCD donor kidneys transplanted between 2006 and 2014. Peripheral oxygen saturation (SpO2-with pulse oximetry at the fingertip) and systolic blood pressure (SBP-with arterial catheter) were measured during agonal phase, and were dichotomized into minutes of SpO2 > 60% or SpO2 < 60%, and minutes of SBP > 80 mmHg or SBP < 80 mmHg. Outcome measures were and primary non-function (PNF), delayed graft function (DGF), and three-year graft survival. Primary non-function (PNF) rate was 6.6%, delayed graft function (DGF) rate was 67%, and graft survival at three years was 76%. Longer periods of agonal phase (median 16 min [IQR 11-23]) contributed significantly to an increased risk of DGF (P = .012), but not to PNF (P = .071) and graft failure (P = .528). Multiple logistic regression analysis showed that an increase from 7 to 20 minutes in period of SBP < 80 mmHg was associated with 2.19 times the odds (95% CI 1.08-4.46, P = .030) for DGF. In conclusion, duration of agonal phase is associated with early transplant outcome. SBP < 80 mmHg during agonal phase shows a better discrimination for transplant outcome than SpO2 < 60% does., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKI and CKD and examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKI was assessed in the first year posttransplant. Among 303 children, perioperative AKI (within the first week) occurred in 67% of children, and AKI after the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty-three children (8%) developed CKD after a median follow-up of 3.4 years. Less than 5 children developed end-stage renal disease, all within 65 days posttransplant. Those with 1 AKI episode by 3 months posttransplant had significantly greater risk for developing CKD after adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13-6.80, P trend = .008). AKI is common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney-sparing strategies to decrease risk for progression to CKD., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Calcineurin inhibitors induce nephrotoxicity through poorly understood mechanisms thereby limiting their use in transplantation and other diseases. Here we define a microRNA (miRNA)-messenger RNA (mRNA) interaction map that facilitates exploration into the role of miRNAs in cyclosporine-induced nephrotoxicity (CIN) and the gene pathways they regulate. Using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we isolated RNAs associated with Argonaute 2 in the RNA-induced silencing complex (RISC) of cyclosporine A (CsA) treated and control human proximal tubule cells and identified mRNAs undergoing active targeting by miRNAs. CsA causes specific changes in miRNAs and mRNAs associated with RISC, thereby altering post-transcriptional regulation of gene expression. Pathway enrichment analysis identified canonical pathways regulated by miRNAs specifically following CsA treatment. RNA-seq performed on total RNA indicated that only a fraction of total miRNAs and mRNAs are actively targeted in the RISC, indicating that PAR-CLIP more accurately defines meaningful targeting interactions. Our data also revealed a role for miRNAs in calcineurin-independent regulation of JNK and p38 MAPKs caused by targeting of MAP3K1. Together, our data provide a novel resource and unique insights into molecular pathways regulated by miRNAs in CIN. The gene pathways and miRNAs defined may represent novel targets to reduce calcineurin induced nephrotoxicity., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)