Pretransplant Biopsy Research Articles

Assessing the reliability of rapid frozen tissue sections from pre-transplant kidney biopsies in DCD donors and correlations with clinico-pathological data: a pilot study.

Compared to donations after brain death, donations after circulatory death present a series of difficulties: the acquisition of the family's consent, the need for qualified personnel and specific resources, death assessment, assessment of the organ, and graft care (pre- and post-transplant). These are all time-related factors that negatively impact the organ, resulting in increased tubular, glomerular, and vascular damage. The evaluation of the organ, as per today's standards, requires three hours for the preparation and processing of formalin-fixed paraffin-embedded (FFPE) samples. An alternative to this is the use of the extemporaneous frozen biopsy. However, frozen samples are considered a second choice in the decision-making process. This retrospective study investigates the reliability of the frozen samples in identifying a series of morphological alterations compared to the more accepted results from FFPE samples. Additionally, two important clinical data, terminal serum creatinine levels and warm ischemia time, were correlated to the presence of some morphological alterations in an attempt to find effective and fast strategies to predict the kidney transplant outcome.

Galileo-an Artificial Intelligence tool for evaluating pre-implantation kidney biopsies.

Pre-transplant procurement biopsy interpretation is challenging, also because of the low number of renal pathology experts. Artificial intelligence (AI) can assist by aiding pathologists with kidney donor biopsyassessment. Herein we present the "Galileo" AI tool, designed specifically to assist the on-call pathologist with interpreting pre-implantation kidney biopsies. A multicenter cohort of whole slide images acquired from core-needle and wedge biopsies of the kidney was collected. A deep learning algorithm was trained to detect the main findings evaluated in the pre-implantation setting (normal glomeruli, globally sclerosed glomeruli, ischemic glomeruli, arterioles and arteries). The model obtained on the Aiforia Create platform was validated on an external dataset by three independent pathologists to evaluate the performance of the algorithm. Galileo demonstrated a precision, sensitivity, F1 score and total area error of 81.96%, 94.39%, 87.74%, 2.81% and 74.05%, 71.03%, 72.5%, 2% in the training and validation sets, respectively. Galileo was significantly faster than pathologists, requiring 2min overall in the validation phase (vs 25, 22 and 31min by 3 separate human readers, p < 0.001). Galileo-assisted detection of renal structures and quantitative information was directly integrated in the final report. The Galileo AI-assisted tool shows promise inspeeding up pre-implantation kidney biopsy interpretation, as well as inreducing inter-observer variability. This toolmay represent a starting point for further improvements based on hardendpoints such as graft survival.

Assessment of biological organ age using molecular pathology in pre-transplant kidney biopsies

Organ shortage is a major challenge in kidney transplantation but the use of older donors, often with co-morbidities, is hampered by inconsistent outcomes. Methods of accurately stratifying marginal donor organs by clinical and histological assessment are lacking. To better understand organ variability, we profiled the transcriptomes of 271 kidneys from deceased donors at retrieval. Following correction for biopsy composition, we assessed molecular pathways that associated with delayed, and sub-optimal one-year graft function. Analysis of cortical biopsies identified an adaptive immune gene-rich module that significantly associated with increasing age and worse outcomes. Cellular deconvolution using human kidney reference single cell transcriptomes confirmed an increase in kidney-specific B and T cell signatures, as well as kidney macrophage, myofibroblast and fibroblast gene sets in this module. Surprisingly, innate immune pathway and neutrophil gene signature enrichment was associated with better outcomes. Thus, our work uncovers cellular molecular features of pathological organ ageing, identifiable at kidney retrieval, with translational potential.

Development and validation of a novel nomogram model for predicting delayed graft function in deceased donor kidney transplantation based on pre-transplant biopsies

BackgroundDelayed graft function (DGF) is an important complication after kidney transplantation surgery. The present study aimed to develop and validate a nomogram for preoperative prediction of DGF on the basis of clinical and histological risk factors.MethodsThe prediction model was constructed in a development cohort comprising 492 kidney transplant recipients from May 2018 to December 2019. Data regarding donor and recipient characteristics, pre-transplantation biopsy results, and machine perfusion parameters were collected, and univariate analysis was performed. The least absolute shrinkage and selection operator regression model was used for variable selection. The prediction model was developed by multivariate logistic regression analysis and presented as a nomogram. An external validation cohort comprising 105 transplantation cases from January 2020 to April 2020 was included in the analysis.Results266 donors were included in the development cohort, 458 kidneys (93.1%) were preserved by hypothermic machine perfusion (HMP), 96 (19.51%) of 492 recipients developed DGF. Twenty-eight variables measured before transplantation surgery were included in the LASSO regression model. The nomogram consisted of 12 variables from donor characteristics, pre-transplantation biopsy results and machine perfusion parameters. Internal and external validation showed good discrimination and calibration of the nomogram, with Area Under Curve (AUC) 0.83 (95%CI, 0.78–0.88) and 0.87 (95%CI, 0.80–0.94). Decision curve analysis demonstrated that the nomogram was clinically useful.ConclusionA DGF predicting nomogram was developed that incorporated donor characteristics, pre-transplantation biopsy results, and machine perfusion parameters. This nomogram can be conveniently used for preoperative individualized prediction of DGF in kidney transplant recipients.

Bone marrow findings post allogeneic transplant for myeloproliferative neoplasms and chronic myelomonocytic leukemia with increased fibrosis.

Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease.

Apolipoprotein E is enriched in dense deposits and is a marker for dense deposit disease in C3 glomerulopathy

C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative pathway of complement. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both of which are characterized by bright glomerular C3 staining on immunofluorescence studies. However, on electron microscopy (EM), DDD is characterized by dense osmiophilic mesangial and intramembranous deposits along the glomerular basement membranes (GBM), while the deposits of C3GN are not dense. Why the deposits appear dense in DDD and not in C3GN is not known. We performed laser microdissection (LCM) of glomeruli followed by mass spectrometry (MS) in 12 cases each of DDD, C3GN, and pretransplant kidney control biopsies. LCM/MS showed marked accumulation of complement proteins C3, C5, C6, C7, C8, C9 and complement regulating proteins CFHR5, CFHR1, and CFH in C3GN and DDD compared to controls. C3, CFH and CFHR proteins were comparable in C3GN and DDD. Yet, there were significant differences. First, there was a six-to-nine-fold increase of C5-9 in DDD compared to C3GN. Secondly, an unexpected finding was a nine-fold increase in apolipoprotein E (ApoE) in DDD compared to C3GN. Most importantly, immunohistochemical and confocal staining for ApoE mirrored the dense deposit staining in the GBM in DDD but not in C3GN or control cases. Validation studies using 31 C3G cases confirmed the diagnosis of C3GN and DDD in 80.6 % based on ApoE staining. Overall, there is a higher burden of terminal complement pathway proteins in DDD compared to C3GN. Thus, our study shows that dense deposits in DDD are enriched with ApoE compared to C3GN and control cases. Hence, ApoE staining may be used as an adjunct to EM for the diagnosis of DDD and might be valuable when EM is not available.

Ex Vivo Drug Sensitivity Evaluation of a ZMYM2::FGFR1 Fusion-Positive 8p11 Myeloproliferative Syndrome (EMS) Leukemia

Introduction : Fibroblast growth factor receptors (FGFRs) are conserved single transmembrane receptor tyrosine kinases (RTKs) with an extracellular ligand-binding domain and a cytoplasmic tyrosine kinase domain. They play vital roles in cellular proliferation, survival, development, fetal organogenesis, metabolism, and tissue repair. 8p11 myeloproliferative syndrome (EMS) is a hematologic malignancy caused by a translocation of the fibroblast growth factor receptor 1 (FGFR1) gene on chromosome 8p11-12. The most common fusion partner of FGFR1 is the zinc-finger domain ZNF198 (also known as ZMYM2) on chromosome 13q12. Pemigatinib is approved for FGFR fusion positive myeloid/lymphoid neoplasms (MLNs), and other FGFR inhibitors are being tested in clinical trials. However, EMS patients still face a poor prognosis and drug resistance, necessitating further research to overcome these challenges. This study evaluated ex vivo drug screening assay data generated from ZMYM2::FGFR1 positive primary leukemia samples throughout the course of an EMS patient's clinical response and validated these findings on a ZMYM2::FGFR1 positive cell line. Methods : Ex vivo and drug screening experiments were performed on freshly isolated primary patient samples and a ZMYM2::FGFR1-expressing cell line. The fusion was confirmed using FISH, and additional clinical specimens were collected with informed patient consent. Ex vivo drug sensitivity assays were conducted on patient mononuclear cells isolated from blood and bone marrow. IL-3 dependent BaF3 cells were infected with retrovirus containing a ZMYM2::FGFR1-V5 construct. ZMYM2::FGFR1 transformed BaF3 cells were evaluated with single agent and drug combination panels. Sanger sequencing of the FGFR portion of the fusion was performed on patient samples to confirm the breakpoint and identify potential mutations affecting sensitivity to Ponatinib throughout the course of treatment. Results : Sample were obtained with informed consent from a 36-year-old man diagnosed with 8p11 myeloproliferative syndrome and a ZMYM2::FGFR1 fusion along with a RUNX1 R201Q mutation. Ex vivo drug screens performed on isolated mononuclear cells demonstrated sensitivity to Ponatinib and Pemigatinib. He underwent treatment with HyperCVAD plus Ponatinib and subsequently HyperCVAD with Ponatinib and Velcade (Bortezomib) to CR1, FISH for FGFR1 rearrangement was undetected. He was scheduled to proceed with hematopoietic stem cell transplant (HSCT), however his pre-transplant bone marrow biopsy showed return of his FGFR1 translocation by FISH. Ex vivo drug screening assays confirmed resistance to Ponatinib, but continued sensitivity to Pemigatinib. He was transitioned to treatment with single agent Pemigatinib and was able to re-clear his FGFR1 fusion by FISH, and has since undergone hematopoietic stem cell transplantation. He remains in remission on post-transplant Pemigatinib maintenance therapy. Sanger sequencing performed at the time of progression on Ponatinib identified a nucleotide alteration resulting in an amino acid substitution (FGFR1 F686L; ZMYM2::FGFR1 F1171L) within the kinase domain that could contribute to decreased Ponatinib sensitivity. Bortezomib and Axitinib exhibited high efficacy on the patient's sample. Ex vivo drug assays performed on ZMYM2::FGFR1 transformed BaF3 cells confirmed the efficacy of Pemigatinib and Ponatinib. Other FGFR inhibitors, including Olverematinib, AZD4547, Axitinib, Cediranib, Dovitinib, and Lenvatinib, also demonstrated exquisite sensitivity. Despite extensive screening, no other single agents or drug combinations exhibited increased effectiveness in the ZMYM2::FGFR1 transformed BaF3 cells except for Trametinib, a MEK inhibitor, and the combination of Belvarafenib (RAF inhibitor) and Gilteritinib (FLT3 inhibitor). Conclusions : Ex vivo drug sensitivity assays demonstrated the highly selective efficacy of FGFR inhibitors in ZMYM2::FGFR1 fusion-positive leukemia cells and a fusion-expressing BaF3 cell line. Mutations in the FGFR1 kinase domain (ZMYM2::FGFR1 F1171L) could contribute to Ponatinib insensitivity. These ex vivo drug screening results provide further support for ongoing clinical trials which are investigating the use of single agent Pemigatinib and other FGFR1 inhibitors for the treatment of patients with FGFR1-fusion positive leukemias.

Contrast-enhanced ultrasonography for identifying acute kidney injury in brain-dead donors.

Acute kidney injury (AKI) is frequently found in deceased donors; however, few studies have reported the use of imaging to detect and identify this phenomenon. The purpose of this study was to detect renal microcirculatory perfusion in brain-dead donors using contrast-enhanced ultrasonography (CEUS), investigate the value of CEUS in identifying AKI, and analyze the correlation between CEUS and preimplantation biopsy results and early post-transplant renal function of grafts. This prospective study recruited 94 kidneys from brain-dead donors (AKI =44, non-AKI =50) from August 2020 to November 2022. The inclusion criteria were age ≥18 years and brain death. The exclusion criteria encompassed donors maintained with extracorporeal membrane oxygenation (ECMO) and the presence of irregular kidney anatomy. The mean age of the donors was 45.1±10.4 [standard deviation (SD)] years, and the majority were male (86.2%). CEUS was performed prior to organ procurement, and time-intensity curves (TICs) were constructed. The time to peak (TTP) and peak intensity (PI) of kidney segmental artery (KA), kidney cortex (KC), and kidney medulla (KM) were calculated using TIC analysis. Arrival time (AT) of KA (P<0.001) and TTP of kidney cortex (TTPKC) (P<0.001) of the non-AKI group were significantly shorter than those of the AKI group. The PI of the KA (P=0.003), KM (P=0.005), and kidney cortex (PIKC; P<0.001) of the non-AKI group were significantly higher than those of the AKI group. Multivariable logistic regression analysis showed that serum creatinine [odds ratio (OR) =1.06; 95% CI: 1.03-1.1; P<0.001], TTPKC (OR =1.38; 95% CI: 1.03-1.84; P=0.03), and PIKC (OR =0.95; 95% CI: 0.91-1; P=0.046) were the independent factors of AKI. The area under the receiver operating characteristic curve (AUC) for identifying AKI for TTPKC and PIKC was 0.73 and 0.71, respectively. TTPKC showed a weak correlation with interstitial fibrosis (r=0.23; P=0.03), PIKC showed a weak correlation with arterial intimal fibrosis ((r=-0.29; P=0.004) and arteriolar hyalinosis (r=-0.27; P=0.008), and PIKC showed the strongest correlation with eGFR on postoperative day 7 (r=-0.46; P=0.046) in the donor kidneys with AKI. CEUS can be used to identify AKI in brain-dead donors. Furthermore, there is a correlation between CEUS-derived parameters and pretransplant biopsy results and early preimplantation renal function of grafts.

SP5.10 Is there a difference in Survival Outcomes of Dual Kidney Transplants (DKTs) of Allografts Procured from DCD versus DBD Donors in absence of a Dedicated National Pathology Service? A Propensity Score Analysis of UK Transplant Registry. An Epidemiology in Transplant Study Group (ETrSG) Initiative

Abstract Background Dual kidney transplants (DKTs) are generally from supra-marginal or small-for-size kidneys that are implanted to provide optimum total nephron-mass. Glomerulosclerosis Pathology Scoring is used globally to guide whether single or DKT are indicated for transplant. Additionally, there are reported concerns regarding donation after cardiac death (DCD) transplant outcomes’ inferiority to donation after brain death (DBD) transplants but there are no reported survival outcomes of DKT procured from DCD v/s DBD donors. Aim This study aims to research if there is a difference in survival outcomes of DKTs of allografts procured from DCD versus DBD Donors in the UK. Methods In this exploratory analysis, adults who underwent DKT in the UK between Jan 1, 2000, and December 31, 2019, were identified in the NHSBT-Transplant registry data. Post-transplantation graft survival at 1&amp; 3 years was assessed with cox-regression analysis, with propensity scores being used to control for selection bias. Results 51,961 renal transplants were reported to NHSBT during the study period, of whom 525 were DKT. After confounders were controlled for with propensity scores, no significant differences in survival outcomes were found between DCD and DBD transplants. Region of Transplant (OR 1.6, 1.0-2.5; p=0.02), transplant post-Year-2011 (OR 3.0, 1.7-5.2; p&amp;lt;0.00), and non-diabetic donors (OR 2.1, 1.1-3.9, p=0.009) were associated with better graft survival, while DBD transplants were associated with low delayed graft function rates (OR 0.4, 0.27 - 0.59; p&amp;lt;.001). Conclusions Survival outcomes of DKT procured from DCD versus DBD donors are equivalent. These results are admirable as the UK does not have a dedicated National-Pathology-Service to report pre-transplant renal biopsies.

Different Patterns of Foxp3 Gene Expression in Pre-and Post-Transplantation Kidney Biopsies and the Effect of Use Mammalian Target of Rapamycin Inhibitors

Trafficking of regulatory T cells (Tregs) modulates the inflammatory response after kidney transplantation (KTx). There is scarce information on whether circulating and intragraft Tregs are similarly affected by immunosuppressive drugs and the type of deceased kidney donor. FOXP3 gene expression was measured in the pretransplant kidney biopsies (PIBx) from donors who met extended (ECD) and standard (SCD) criteria donors. In the third month after KTx, the patients were divided according to tacrolimus (Tac) or everolimus (Eve) and the type of kidney they had received. FOXP3 gene expression in the peripheral blood (PB) and kidney biopsies (Bx) was analyzed using real-time polymerase chain reaction. FOXP3 gene expression in the PIBx was higher in ECD kidneys. FOXP3 gene expression in the PB and Bx was greater in Eve- than in Tac-treated patients. However, SCD recipients treated with Eve (SCD/Eve) had higher FOXP3 expression than ECD/Eve. Pretransplant kidney biopsies from ECD kidneys had higher FOXP3 gene expression than SCD, and the use of Eve may affect the expression of the FOXP3 gene only in SCD kidneys.

Τhe Impact of Pre-Transplant Kidney Biopsy on the Evaluation of Prospective Living Kidney Donors

Living kidney donation contributes to increasing the donor pool. Since safety and excellent outcomes of living kidney donors (LKD) are essential, renal biopsy must be part of the pre-transplant evaluation in donors with isolated urine abnormalities or other risk factors. We retrospectively collected data on potential living donors evaluated in the pre-transplant outpatient clinic of Laiko General Hospital of Athens between 2007 and 2022, who underwent a pre-transplant biopsy. Biopsy indications included microscopic hematuria, borderline proteinuria and comorbidities suggestive of chronicity. Those with glomerular diseases or chronic lesions were excluded from donation. We identified 59 potential living donors who underwent renal biopsy. Of these, 10 (16.9%) were male. Median age was 58 (IQR 51-63) years, while 23 (39%) were older than 60 years. 49 out of 59 (83%) had glomerular hematuria, 10 (16.7%) had proteinuria (150-300 mg/d). Out of the 59 donors, 21 (35.6%) were hypertensive, three (5.1%) had impaired glucose tolerance and seven (11.9%) had a BMI > 30 kg/m2. A total of 32 (54.2%) potential donors were accepted for donation. Eight (13.6%) had IgA nephropathy, 10 (16.9%) TBMD and nine (15.3%) had increased chronicity including secondary FSGS. When compared with a control group of donors who did not need a pre-transplant biopsy, those 32 who donated were more frequently hypertensive (p = 0.003), but had similar eGFR [61.3 (±10.4) vs. 61.9 (±13.8), p = 0.866] after a follow-up of 79 (36-114) months. Renal biopsy is a useful tool in the evaluation of prospective LKD. Thorough assessment of donors with isolated urine abnormalities and marginal donors is critical to ensure good post-donation outcomes.

Pre-Implantation Kidney Biopsies in Extended Criteria Donors: From On Call to Expert Pathologist, from Conventional Microscope to Digital Pathology

The number of patients awaiting a kidney transplant is constantly rising but lack of organs leads kidneys from extended criteria donors (ECD) to be used to increase the donor pool. Pre-transplant biopsies are routinely evaluated through the Karpinski-Remuzzi score but consensus on its correlation with graft survival is controversial. This study aims to test a new diagnostic model relying on digital pathology to evaluate pre-transplant biopsies and to correlate it with graft outcomes. Pre-transplant biopsies from 78 ECD utilized as single kidney transplantation were scanned, converted to whole-slide images (WSIs), and reassessed by two expert nephropathologists using the Remuzzi-Karpinski score. The correlation between graft survival at 36 months median follow-up and parameters assigned by either WSI or glass slide score (GSL) by on-call pathologists was evaluated, as well as the agreement between the GSL and the WSIs score. No relation was found between the GSL assessed by on-call pathologists and graft survival (&lt;i&gt;P&lt;/i&gt; &amp;#61; 0.413). Conversely, the WSI score assigned by the two nephropathologists strongly correlated with graft loss probability, as confirmed by the ROC curves analysis (DeLong test &lt;i&gt;P&lt;/i&gt; &amp;#61; 0.046). Digital pathology allows to share expertise in the transplant urgent setting, ensuring higher accuracy and favoring standardization of the process. Its employment may significantly increase the predictive capability of the pre-transplant biopsy evaluation for ECD, improving the quality of allocation and patient safety.

Pretransplant kidney transcriptome captures intrinsic donor organ quality and predicts 24-month outcomes

With the development of novel prognostic tools derived from omics technologies, transplant medicine is entering the era of precision medicine. Currently, there are no established predictive biomarkers for posttransplant kidney function. A total of 270 deceased donor pretransplant kidney biopsies were collected and posttransplant function was prospectively monitored. This study first assessed the utility of pretransplant gene expression profiles in predicting 24-month outcomes in a training set (n=174). Nearly 600 differentially expressed genes were associated with 24-month graft function. Grafts that progressed to low function at 24 months exhibited upregulated immune responses and downregulated metabolic processes at pretransplantation. Using penalized logistic regression modeling, a 55 gene model area under the receiver operating curve (AUROC) for 24-month graft function was 0.994. Gene expression for a subset of candidate genes was then measured in an independent set of pretransplant biopsies (n=96) using quantitative polymerase chain reaction. The AUROC when using 13 genes with three donor characteristics (age, race, body mass index) was 0.821. Subsequently, a risk score was calculated using this combination for each patient in the validation cohort, demonstrating the translational feasibility of using gene markers as prognostic tools. These findings support the potential of pretransplant transcriptomic biomarkers as novel instruments for improving posttransplant outcome predictions and associated management.

S2956 Delayed Onset Drug-Induced Acute Liver Failure Caused by Glatiramer Acetate (GA) in Multiple Sclerosis Requiring Liver Transplantation

Introduction: Glatiramer acetate (GA) has been used for multiple sclerosis (MS) since 1996. Regular liver function test monitoring is not required for the medication because there have not been any reported cases of liver toxicity.1Here, we report the first case of delayed onset GA-induced ALF requiring liver transplantation. Case Description/Methods: A 59-year-old woman with well-controlled MS presented to the emergency department with three weeks of jaundice and dark-colored urine. Initial labs showed AST 2527 IU/L (81x ULN), ALT 2512 IU/L (81x ULN), total bilirubin 22.7 mg/dL (19x ULN), ALP 210 IU/L (2x ULN), INR 2.65. Further workup showed normal ceruloplasmin, alpha-1-antitrypsin, and IgG. Hepatitis, HSV, VZV, T-spot, HIV, ANA, anti-mitochondrial antibody, anti-LKM antibody were negative. Anti-smooth muscle antibody was 1:40. Her liver enzymes were normal one year prior to presentation, and she had no family history of autoimmune or liver disease. Computed tomography abdomen/pelvis showed patent vasculature and no evidence of cirrhosis. MRI/MRCP showed no biliary obstruction. Her only medication was GA, which she had been taking since 2008. Physical exam was notable for mild asterixis, and she was started on IV N-acetyl cysteine for 3 days. Liver biopsy demonstrated submassive necrosis (70%) consistent with drug induced liver injury (Fig. 1A). GA was thought to be the most likely etiology of her liver injury and was held. Liver transplant was ultimately deferred because her liver enzymes and her mental status improved. She was discharge on day 6. Four days later she developed severe abdominal pain, lethargy and re-presented to the hospital. She was slow to respond, had scleral icterus and asterixis with AST 909 IU/L, ALT 839 IU/L, total bilirubin 27.2 mg/dL, INR 2.94. The patient underwent expedited liver transplant evaluation and was listed on the same day. She successfully underwent deceased donor liver transplant three days later. Liver explant showed mixed zone 1 and 3 liver necrosis (50%) with associated inflammation, mild lobular inflammation and cholestasis (Fig. 1B-D). Discussion: Our case illustrates the first case of GA-induced ALF requiring liver transplantation. Previous reports showed that patients with GA drug-induced-liver injury recovered completely in 1-5 months after drug withdrawal and time of presentation ranges from 1 to 8 months, as opposed to 14 years in our case. Patients on GA should have long term regular liver monitoring.Figure 1.: Histological analysis of pre-transplant and explant liver. A. Hematoxylin and eosin (H&E) stain of the pre-transplant biopsy showed extensive necrosis including zone 3 (x100). B. Gross picture of explant (weight 500.3 gram). The surface showed wrinkles, which were characteristics of acute liver failure with massive hepatocyte necrosis. C. H&E stain of explant showed no viable hepatocytes in the worst area. (x200). D. Masson trichrome stain showed no fibrosis, which confirms the acute process (x200).

Presence of CD163+ macrophages in DCD kidneys with high DGF reduces the risk for acute cellular rejection in 6 months after kidney transplantation

Acute cellular rejection (ACR) occurs in 10% of renal allograft recipients and is characterized by leukocyte infiltration as observed in needle biopsies. ACR onset is subject to several risk factors, including delayed graft function (DGF). As the impact of DGF on the etiology of ACR remains unclear, this study analyzed the association between presence of leukocyte subsets and ACR onset, in DCD kidney biopsies with extensive DGF following transplantation. Immunohistochemical analysis of protocol biopsies taken 10 days after kidney transplantation revealed that patients with high levels of renal CD163+ macrophages have a decreased risk (OR = 0.021, P = 0.008) for ACR in the first 6 months after transplantation. In pre-transplant biopsies of a comparable DCD cohort, with >80% DGF, presence of donor CD163+ macrophages showed no effect on ACR risk. Therefore, leukocyte infiltrate present during the inflammatory response at the time of DGF may contain anti-inflammatory macrophages that exert a protective effect against ACR development.

413.6: How Whole Slide Imaging and AI Can Improve Organ Transplants

Introduction: As the advancement and implementation of technology in healthcare diagnostics continue, the full capabilities may not be fully realized. Research and development of artificial intelligence (AI) within the transplantation realm are primary examples. The expansion of whole slide imaging and AI in kidney and liver transplantation presents immense opportunities to address significant logistical concerns. This includes the quality of pathology reports, speed of organ offer acceptance, and minimizing ischemic time. Globally, there is a high demand for organs to compensate for the increasing diagnosis of comorbidities requiring transplantation. Unfortunately, the technical and logistical barriers of evaluating cadaveric donor organs in an emergent but precise manner prohibit efficient allocation. Organ allocation can be further refined and post-transplant outcomes improved by seeking solutions that will produce consistent, high-quality pathology reports, regardless of time or properly trained pathologists. The implementation of AI stands to address these issues by introducing machine learning in accurately reading donation biopsies. Methods: In the case of kidney and liver transplantation, when a cadaveric donor becomes available, biopsies are acquired to assess the viability of organ transplantation. Under ideal circumstances, these biopsies are read by a specialized pathologist. But many times biopsies are read by any available pathologist. This results in sub-par, inconsistent, and frequently delayed pathology reports. The reliance upon these reports subject’s organ recipients to inconsistent results that will impact long-term outcomes. Once the slides are digitized an AI algorithm can be trained to provide a consistent, accurate organ donation-focused pathology report at any time of day. Conclusion: Whole slide imaging and AI can fill the gaps that negatively impact surgical decision-making and long-term patient outcomes. Technology that can improve the quality and accuracy of pre-transplantation biopsy reports, AI can significantly reduce the duration of getting organs to patients and avoid the transplantation of unviable organs. It can identify fibrosis and inflammation of the liver and kidney, sclerotic glomeruli, atrophied tubules in kidney samples, and large and small droplet macrosteatosis fat in liver samples. Increased efforts and resources to bolster the research and development of AI systems in transplantation can significantly benefit all parties involved in delivering high-quality care and positive long-term patient outcomes.

Impact of Donor Liver Macrovesicular Steatosis on Deceased Donor Yield and Posttransplant Outcome.

The Scientific Registry of Transplant Recipients (SRTR) had not traditionally considered biopsy results in risk-adjustment models, yet biopsy results may influence outcomes and thus decisions regarding organ acceptance. Using SRTR data, which includes data on all donors, waitlisted candidates, and transplant recipients in the United States, we assessed (1) the impact of macrovesicular steatosis on deceased donor yield (defined as number of livers transplanted per donor) and 1-y posttransplant graft failure and (2) the effect of incorporating this variable into existing SRTR risk-adjustment models. There were 21 559 donors with any recovered organ and 17 801 liver transplant recipients included for analysis. Increasing levels of macrovesicular steatosis on donor liver biopsy predicted lower organ yield: ≥31% macrovesicular steatosis on liver biopsy was associated with 87% to 95% lower odds of utilization, with 55% of these livers being discarded. The hazard ratio for graft failure with these livers was 1.53, compared with those with no pretransplant liver biopsy and 0% to 10% steatosis. There was minimal change on organ procurement organization-specific deceased donor yield or program-specific posttransplant outcome assessments when macrovesicular steatosis was added to the risk-adjustment models. Donor livers with macrovesicular steatosis are disproportionately not transplanted relative to their risk for graft failure. To avoid undue risk aversion, SRTR now accounts for macrovesicular steatosis in the SRTR risk-adjustment models to help facilitate use of these higher-risk organs. Increased recognition of this variable may also encourage further efforts to standardize the reporting of liver biopsy results.

Proteinuria in Deceased Kidney Transplant Donors for Prediction of Chronic Lesions in Pretransplant Biopsies: A Prospective Observational Study.

Pretransplant kidney graft biopsies have been suggested for organ quality assessment. Data on the association between donor proteinuria and organ quality of deceased donors are not available. In this prospective study, we analyzed 147 pretransplant kidney biopsies from 88 deceased adult donors procured and transplanted consecutively at the Medical University Vienna between July 2017 and May 2020. Lesions in each renal compartment were scored from 0 to 5 with each ascending score representing a 20% increase in organ damage. A chronic lesions score was calculated including glomerulosclerosis, intima fibrosis, hyalinosis, interstitial fibrosis, and tubular atrophy. The median chronic lesion score was 2 (interquartile range [IQR] 1-4) and the median donor urinary protein to creatinine ratio (UPCR) was 382 mg/dL (IQR 222-703). There was a positive correlation between UPCR and number of chronic lesions (β 0.15, 95% confidence interval, 0.03-0.28; P = 0.019). Biopsies with 2 or more lesions had a median UPCR of 486 mg/dL (IQR 251-717) compared with 274 mg/dL (IQR 211-556; P = 0.016) in biopsies with <2 lesions. The risk for detection of 2 or more lesions rose by 18% for every log increase in UPCR (risk ratio 1.18, 95% confidence interval, 1.03-1.25; P = 0.017). Multivariable and sensitivity analysis revealed an independent and robust association between chronic lesions and UPCR. Donor UPCR is associated with chronic lesions in pretransplant deceased donor kidney graft biopsies. This finding justifies further investigation of donor proteinuria for the assessment of organ quality and outcome.

A1094 - Are pre-transplant kidney biopsies safe? A cross-sectional study

A1094 - Are pre-transplant kidney biopsies safe? A cross-sectional study

Deep Learning Algorithms for the Prediction of Posttransplant Renal Function in Deceased-Donor Kidney Recipients: A Preliminary Study Based on Pretransplant Biopsy.

BackgroundPosttransplant renal function is critically important for kidney transplant recipients. Accurate prediction of graft function would greatly help in deciding acceptance or discard of allocated kidneys.Methods: Whole-slide images (WSIs) of H&E-stained donor kidney biopsies at × 200 magnification between January 2015 and December 2019 were collected. The clinical characteristics of each donor and corresponding recipient were retrieved. Graft function was indexed with a stable estimated glomerular filtration rate (eGFR) and reduced graft function (RGF). We used convolutional neural network (CNN)-based models, such as EfficientNet-B5, Inception-V3, and VGG19 for the prediction of these two outcomes.ResultsIn total, 219 recipients with H&E-stained slides of the donor kidneys were included for analysis [biopsies from standard criteria donor (SCD)/expanded criteria donor (ECD) was 191/28]. The results showed distinct improvements in the prediction performance of the deep learning algorithm plus the clinical characteristics model. The EfficientNet-B5 plus clinical data model showed the lowest mean absolute error (MAE) and root mean square error (RMSE). Compared with the clinical data model, the area under the receiver operating characteristic (ROC) curve (AUC) of the clinical data plus image model for eGFR classification increased from 0.69 to 0.83. In addition, the predictive performance for RGF increased from 0.66 to 0.80. Gradient-weighted class activation mappings (Grad-CAMs) showed that the models localized the areas of the tubules and interstitium near the glomeruli, which were discriminative features for RGF.ConclusionOur results preliminarily show that deep learning for formalin-fixed paraffin-embedded H&E-stained WSIs improves graft function prediction accuracy for deceased-donor kidney transplant recipients.