Graft Biopsy Research Articles

P16.37: Outcomes of COVID-19 Vaccination Among Kidney Transplant Recipients Admitted for COVID-19 at the National Kidney And Transplant Institute: A Retrospective Study

Background: Kidney transplant recipients are immunocompromised hosts of COVID-19 with a higher risk of infection and severe disease due to underlying CKD and long-term immunosuppression, thus vaccination against COVID is strongly recommended. However, studies indicate that transplant recipients mount lower antibody responses following vaccination compared with healthy individuals. Due to limited information on the outcomes of COVID-19 vaccination on transplant recipients, this study will examine the efficacy of vaccination in preventing severe to critical COVID in this immunocompromised population. Objective: To determine the outcomes of kidney transplant recipients admitted for COVID-19 at the National Kidney and Transplant Institute and the impact of COVID-19 vaccination status on their survival. Methods and Materials: A retrospective study of 131 kidney transplant recipients admitted for COVID-19 from March 2020 to December 2021. Descriptive statistics were used to summarize the clinical characteristics and outcomes of the participants. Results: The median age was 51 years old with a male gender distribution of 54.5%. Chronic glomerulonephritis was the most common primary renal disease. Diabetes, hypertension, and cardiovascular disease were the most common co-morbidities. Patients belonging to the critical COVID group were observed to have older kidney allografts with a median age of 120 months. Among 131 kidney transplant recipients, 24.8% were fully vaccinated and 74.2% were either unvaccinated or partially vaccinated. Of the 32 patients in the vaccinated group, 3 were vaccinated with Astra Zeneca, 5 received Janssen, 7 from Moderna, 10 from Pfizer, 1 received Sputnik and 12 received Coronavac (Sinovac). Among the vaccinated group, those who received Moderna and Pfizer vaccines were observed to have moderate COVID-19 disease progression only with 57.1% from the Moderna group and 40% from the Pfizer group. Among patients who progressed to critical COVID-19, it was observed that a significant number of them came from the Coronavac group. The need for oxygenation was observed in 64% of patients, of which 65.5% were unvaccinated. Acute kidney injury was reported in 43.5% of the overall population, 63.2% of which were observed in the unvaccinated group. Of the 16% who had graft loss during COVID-19 admission, 57.1% were unvaccinated. The incidence of death was lower among fully vaccinated than those in the partial and unvaccinated groups. Likewise, the probability of survival is highest among fully vaccinated than those partially vaccinated and unvaccinated. Renal graft biopsy on patients with COVID-19 has not been practiced at NKTI thus rendering rates of biopsy-proven acute rejection a limitation of the study. Conclusion: Our experience shows that lack of COVID-19 vaccination among kidney transplant recipients demonstrates a higher rate of mortality associated with COVID-19. Key words: COVID-19, renal transplantation, survival, Philippines.

Regression of Graft Steatosis After Liver Transplantation.

Introduction: Liver grafts with limited steatosis are currently used for liver transplantation, but the natural history of graft steatosis is not well known. Project Aims or Questions: This program evaluation aimed at assessing changes of steatosis after liver transplantation. Design: A retrospective chart review was performed assessing presence and severity of steatosis in the liver explant and in time zero donor graft biopsies carried out at the time-point of liver transplantation on histopathology and on imaging one year thereafter in 30 well characterized patients. Results: Ten patients (33%) showed steatosis on explant. Time zero biopsy revealed steatosis in 18 grafts (60%) and no steatosis in 12 (40%). One year after transplantation, 8 patients (27%) had steatosis and 22 patients (63%) had none. Fourteen patients (47%) showed changes in steatosis: 12 showed resolution and 2 showed de novo steatosis. Explant macrovesicular steatosis was associated with presence of steatosis 1 year after transplantation (binary logistic regression model, p = 0.014), but not macrovesicular steatosis in the donor graft at time-point of transplantation. Conclusion: Resolution of graft steatosis was frequent. Presence of steatosis in the recipient's liver, but not graft steatosis, was a risk factor for steatosis 1 year after transplantation. Factors related to the recipient seem to prevail over donor-related factors in determining the persistence or de novo appearance of steatosis after liver transplantation.

Immune tolerance induced by hematopoietic stem cell infusion after HLA identical sibling kidney transplantation.

After the first attempt to induce operational tolerance, it has taken decades to implement it in clinical practice. Recipients with Human leukocyte antigen (HLA) identical sibling donors were enrolled. Hematopoietic stem cells (HSCs) infusion was done after HLA identical sibling kidney transplantation (KTx). Three cases included were followed up for over 8 years. The perioperative conditioning protocol included anti-CD20, rabbit anti-thymocyte globulin (ATG), total lymphoid irradiation (TLI), and cyclophosphamide. Infusion of CD3+ cells and CD34+ cells was conducted. The withdrawal of immunosuppression was determined by mixed lymphocyte reaction (MLR) and graft biopsy. Case 1 and Case 2 showed persistent chimerism, while chimerism was not detected in Case 3. All three recipients showed a low-level response to donor-specific stimulation. Case 1 and Case 3 met the withdrawal rules at 16 and 32 months after transplantation, respectively. Graft function was stable, and no rejection signs were observed in routine biopsies until 94 and 61 months after transplantation. Case 2 was diagnosed with graft-versus-host disease (GVHD) 9 months after transplantation and recovered after an enhanced immunosuppression therapy. Steroids were withdrawn after 1 year, and 0.5 mg tacrolimus twice a day is currently the only immunosuppression at 8 years and 8 months. In conclusion, our clinical experience indicated the efficacy of non-myeloablative conditioning protocol for tolerance induction in HLA identical patients. Complete chimerism might be a risk factor for GVHD.

Antibody-mediated allograft rejection is associated with an increase in peripheral differentiated CD28-CD8+ T cells - Analyses of a cohort of 1032 kidney transplant recipients.

SummaryBackgroundCD28-CD8+ T cells represent a differentiated CD8+ T cell subset that is found to be increased in various conditions associated with chronic antigenic stimulation such as aging, chronic viral infections, autoimmune diseases, cancers, and allotransplantation.MethodsUsing multivariate models, we analyzed a large cohort of 1032 kidney transplant patients in whom 1495 kidney graft biopsies were performed concomitant with a peripheral blood leukocyte phenotyping by flow cytometry. We investigated the association between the level of CD28-CD8+ T cells in the blood and the diagnosis of graft rejection according to the recent Banff classification of renal allograft pathology.FindingsWe found that antibody-mediated rejection (ABMR) was associated with a significant increase in the percentage as well as the absolute number of CD28-CD8+ T cells in the peripheral blood of kidney transplant patients at the time of biopsy. The confounder-adjusted mean difference of log percentage and log absolute value between the ABMR group and the normal/subnormal histology group were 0.29 (p=0.0004) and 0.38 (p=0.0004), respectively. Moreover, we showed that CD28-CD8+ T cells from the patients diagnosed with ABMR responded more rigorously to TCR and FcγRIIIA (CD16) engagement compared to their CD28+ counterparts as evidenced by an increase in the expression of IFNγ, TNFα, and CD107a.InterpretationCollectively, our data suggest that differentiated CD28-CD8+ T cells, with increased frequency, number, and function, may participate in the pathobiology of ABMR. Further studies are warranted to clarify the immunological role of this T cell subset in kidney graft rejection.FundingAgence nationale de la recherche (France).

Liver Graft MicroRNAs Expression in Different Etiology of Acute Jaundice after Living Donor Liver Transplantation.

Simple SummaryAcute jaundice, a critical problem after living donor liver transplantation, often required efforts to discriminate its etiologies. MicroRNAs are small non-coding RNAs, which express differently during disease development. To differentiate the etiology of acute jaundice after living donor liver transplantation, we examined hepatic microRNA expression patterns in several liver graft pathologies. Eighty liver transplant recipients undergoing post-transplant liver graft biopsy for the evaluation of acute jaundice were enrolled in this one-year prospective study. Using real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified intra-graft microRNA (microRNA-122, microRNA-301, microRNA-133a, and microRNA-21) signatures in various allograft pathologies (37 recipients with acute cholangitis, 20 recipients with acute rejection, 12 recipients with recurrent hepatitis, 6 recipients with non-specific pathological change and 5 recipients with fatty change). In acute cholangitis, intra-graft microRNA-122, microRNA-301, and microRNA-21 significantly down-regulated; in acute rejection, intra-graft microRNA-122 significantly up-regulated and intra-graft microRNA-133a significantly down-regulated; in recurrent hepatitis, intra-graft microRNA-122, microRNA-301, and microRNA-21 remarkably up-regulated; and in fatty change, only intra-graft microRNA-133a up-regulated in significance. Our study suggests that specific intra-graft microRNA expression patterns as a checklist may be helpful for differential diagnosis of acute jaundice etiologies following living donor liver transplantation.Background: Acute jaundice remains a critical problem following liver transplantation. MicroRNAs (miRNAs) are involved in regulating gene expression related to various disease phenotypes and statuses. Aims: To differentiate acute jaundice etiology after living donor liver transplantation (LDLT), we examined the hepatic miRNA expression patterns in several liver graft pathologies. Methods: Eighty liver transplant recipients undergoing post-LDLT graft biopsy for the evaluation of acute jaundice were enrolled in this 1-year prospective study. Using a real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified hepatic miRNA (miRNA-122, miRNA-301, miRNA-133a, and miRNA-21) signatures in various allografts pathologies. Results: Pathologic findings of the 80 recipients were as follows: acute cholangitis (AC), 37 (46%); acute rejection (AR), 20 (25%); recurrent hepatitis (RH), 12 (15%); non-specific pathological change, 6 (8%); and fatty change (FC), 5 (6%). None of these identified hepatic miRNAs expression pattern was significantly correlated with serum parameters, including neutrophil-lymphocyte ratio. In AC, hepatic miRNA-122, miRNA-301, miRNA-133a, and miRNA-21 expression was significantly downregulated (p < 0.05). MicroRNA-122 expression was elevated in cases of AR and RH (p < 0.05); miRNA-301 and miRNA-21 expression was higher in RH than in AC (p < 0.05); and miRNA-133a expression was higher in FC than in AR (p < 0.05). Conclusions: Our study suggests that specific hepatic miRNA expression patterns as a checklist may be useful for differential diagnosis of acute jaundice following liver transplantation.

The Role of Early Sequential Biopsies in Delayed Renal Graft Function of Transplanted Kidney Is Reduced in Modern Immunosuppression Era

Background: Delayed graft function (DGF) immediately after kidney transplantation is considered a risk factor for acute rejection. According to clinical guidelines, a weekly allograft biopsy should be performed until DGF resolves. Based on clinical evidence, the first biopsy is considered appropriate. However, the recommendation for further biopsies is based on sparse evidence from era of earlier immunosuppression protocols, and the benefit of the second and further biopsies remains uncertain. The aim of this study was to reevaluate this policy. Methods: The database of a transplant medical center was retrospectively reviewed for all patients who underwent kidney transplantation in 2011–2020. Those with DGF who performed two or more graft biopsies within the first 60 days after transplantation were identified. Clinical data were collected from the medical files. The rates of diagnosis of acute rejection at the second and subsequent biopsies were analyzed relative to the previous ones. Results: Kidney transplantation was performed in 1,722 patients during the study period, of whom 225 (13.07%) underwent a total of 351 graft biopsies within 60 days after transplantation, mostly due to DGF. A second biopsy was performed in 32 patients (14.2%), and a third biopsy in 8, at weekly intervals. In 2 patients (6.25%), the diagnosis changed from the first biopsy (acute tubular necrosis or toxic damage) to acute rejection in the second biopsy. In both, the rejection was borderline. Third and fourth biopsies did not add information to the previous diagnosis. Conclusions: The common practice of performing sequential biopsies during a postoperative course of DGF seems to be of low benefit and should be considered on a case-by-case basis.

Two-Dimensional Shear Wave Elastography Evaluation of Post-transplantation Complications in Pediatric Receipt: A Retrospective Cohort.

BackgroundThe 20-year survival rate in pediatric patients after liver transplantation (LT) was no more than 70%. Hepatic fibrosis is one of the principal factors affecting the long-term prognosis. Imaging evaluation was the first-line examination for pediatric liver graft assessment. However, the sensitivity and specificity were insufficient. Thus, two-dimensional shear wave elastography (2D-SWE) was performed to evaluate liver graft stiffness and complication in post-transplant pediatric receipt.Materials and MethodsIn this retrospective cohort, 343 pediatric recipients who underwent liver graft biopsy in our tertiary LT center were recruited between June 2018 and December 2020. The 2D-SWE evaluation, laboratory examination, routine post-transplant biopsy, and hepatic pathological assessment were performed.ResultsNinety-eight of the 343 pediatric patients were included according to the protocol. The Liver Stiffness Measurements (LSM) value of 2D-SWE was significantly elevated in post-transplant fibrosis (p < 0.0001). The LSM value of patients with post-transplant biliary complications (p < 0.0001) and biopsy-proven rejection (BPR, p = 0.0016) also rose compared to regular recovery patients. Concerning the sensitivity and specificity of 2D-SWE in diagnosing liver graft fibrosis, the area under the ROC curve (AUC) was 88%, and the optimal cutoff value was 10.3 kPa.ConclusionPediatric LSM by 2D-SWE was efficient. Routine 2D-SWE evaluation could be optimal to predict significant liver graft fibrosis.

International Survey of Clinical Monitoring Practices in Pancreas and Islet Transplantation.

The long-term outcomes of both pancreas and islet allotransplantation have been compromised by difficulties in the detection of early graft dysfunction at a time when a clinical intervention can prevent further deterioration and preserve allograft function. The lack of standardized strategies for monitoring pancreas and islet allograft function prompted an international survey established by an International Pancreas and Islet Transplant Association/European Pancreas and Islet Transplant Association working group. A global survey was administered to 24 pancreas and 18 islet programs using Redcap. The survey addressed protocolized and for-cause immunologic and metabolic monitoring strategies following pancreas and islet allotransplantation. All invited programs completed the survey. The survey identified that in both pancreas and islet allograft programs, protocolized clinical monitoring practices included assessing body weight, fasting glucose/C-peptide, hemoglobin A1c, and donor-specific antibody. Protocolized monitoring in islet transplant programs relied on the addition of mixed meal tolerance test, continuous glucose monitoring, and autoantibody titers. In the setting of either suspicion for rejection or serially increasing hemoglobin A1c/fasting glucose levels postpancreas transplant, Doppler ultrasound, computed tomography, autoantibody titers, and pancreas graft biopsy were identified as adjunctive strategies to protocolized monitoring studies. No additional assays were identified in the setting of serially increasing hemoglobin A1c levels postislet transplantation. This international survey identifies common immunologic and metabolic monitoring strategies utilized for protocol and for cause following pancreas and islet transplantation. In the absence of any formal studies to assess the efficacy of immunologic and metabolic testing to detect early allograft dysfunction, it can serve as a guidance document for developing monitoring algorithms following beta-cell replacement.

POS-044 ECULIZUMAB INTERRUPTION IN KIDNEY TRANSPLANT RECIPIENTS WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME: ANALYSIS OF A BRAZILIAN SHORTAGE

IntroductionAfter a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted.MethodsWe screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy.ResultsWe analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%.ConclusionsThis study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.No conflict of interest IntroductionAfter a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted. After a period of eculizumab shortage in Brazil, an interruption of therapy in Atypical Hemolytic Uremic Syndrome (aHUS) patients brought about high relapse rate. This study aimed to analyze the aHUS relapse rate in kidney transplant recipients who had eculizumab therapy interrupted. MethodsWe screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy. We screened 800 Brazilian centers of dialysis, transplantation and nephrology throughout Brazil, through electronic mail and formal invitation by the Brazilian Society of Nephrology. We included kidney transplant recipients with aHUS who underwent interruption of eculizumab therapy for at least 30 days between January 1st, 2016 and December 31st, 2019 during the maintenance phase of treatment. Relapse was defined by the development of thrombocytopenia, hemolytic anemia, acute kidney injury or thrombotic microangiopathy in a renal graft biopsy. ResultsWe analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%. We analyzed 9 patients and 9 episodes of exposure to risk of relapse. Median age was 34 (27 - 36) years, 5 (55%) patients were female, 8 (88%) had genetic study performed and 5 (55%) had any complement variant identified, among them, one (11%) had CFH variant found. Four patients (44%) had relapse after eculizumab withdrawal. Genetic characteristics related to relapses were: one patient did not have genetic study performed, one did not have pathogenic variants in complement genes identified, one had pathogenic variants found in CFI and CFB and one, in C3, CFI and CFHR1-CFHR3. The cumulative incidence of aHUS relapse at one year was 60%. ConclusionsThis study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.No conflict of interest This study showed a high cumulative incidence of relapse (60%) at one year when eculizumab therapy in kidney transplant recipients was interrupted after a shortage in Brazil.

Notch3 expression in capillary pericytes predicts worse graft outcome in human renal grafts with antibody-mediated rejection.

Microvasculature consisting of endothelial cells and pericytes is the main site of injury during antibody‐mediated rejection (ABMR) of renal grafts. Little is known about the mechanisms of activation of pericytes in this pathology. We have found recently that activation of Notch3, a mediator of vascular smooth muscle cell proliferation and dedifferentiation, promotes renal inflammation and fibrosis and aggravates progression of renal disease. Therefore, we studied the pericyte expression of Notch3 in 49 non‐selected renal graft biopsies (32 for clinical cause, 17 for graft surveillance). We analysed its relationship with patients’ clinical and morphological data, and compared with the expression of partial endothelial mesenchymal transition (pEndMT) markers, known to reflect endothelial activation during ABMR. Notch3 was de novo expressed in pericytes of grafts with ABMR, and was significantly correlated with the microcirculation inflammation scores of peritubular capillaritis and glomerulitis and with the expression of pEndMT markers. Notch3 expression was also associated with graft dysfunction and proteinuria at the time of biopsy and in the long term. Multivariate analysis confirmed pericyte expression of Notch3 as an independent risk factor predicting graft loss. These data suggest that Notch3 is activated in the pericytes of renal grafts with ABMR and is associated with poor graft outcome.

The Use of Machine Learning Algorithms and the Mass Spectrometry Lipidomic Profile of Serum for the Evaluation of Tacrolimus Exposure and Toxicity in Kidney Transplant Recipients.

Tacrolimus has a narrow therapeutic window; a whole-blood trough target concentration of between 5 and 8 ng/mL is considered a safe level for stable kidney transplant recipients. Tacrolimus serum levels must be closely monitored to obtain a balance between maximizing efficacy and minimizing dose-related toxic effects. Currently, there is no specific tacrolimus toxicity biomarker except a graft biopsy. Our study aimed to identify specific serum metabolites correlated with tacrolinemia levels using serum high-precision liquid chromatography–mass spectrometry and standard laboratory evaluation. Three machine learning algorithms were used (Naïve Bayes, logistic regression, and Random Forest) in 19 patients with high tacrolinemia (8 ng/mL) and 23 patients with low tacrolinemia (5 ng/mL). Using a selected panel of five lipid metabolites (phosphatidylserine, phosphatidylglycerol, phosphatidylethanolamine, arachidyl palmitoleate, and ceramide), Mg2+, and uric acid, all three machine learning algorithms yielded excellent classification accuracies between the two groups. The highest classification accuracy was obtained by Naïve Bayes, with an area under the curve of 0.799 and a classification accuracy of 0.756. Our results show that using our identified five lipid metabolites combined with Mg2+ and uric acid serum levels may provide a novel tool for diagnosing tacrolimus toxicity in kidney transplant recipients. Further validation with targeted MS and biopsy-proven TAC toxicity is needed.

FC 106: Validation of the Optimal Torque Teno Virus Range for Risk Stratification of Graft Rejection and Infection in Kidney Transplant Recipients by TTV R-GENE®

Abstract BACKGROUND AND AIMS The nonpathogenic and ubiquitous Torque Teno virus (TTV) plasma load is associated with immunosuppression in solid organ transplant recipients. An optimal TTV range has been defined for risk stratification of graft rejection and infection in the first year post kidney transplant applying an in-house PCR. Recently, a commercial PCR—the TTV R-GENE® kit—has been CE certified for clinical use. The present study was designed to validate and refine the optimal TTV range applying the TTV R-GENE® kit. METHOD Patients and events were selected from the prospective TTV-POET trial, including all 628 consecutive adult recipients of a kidney allograft transplanted at the Medical University of Vienna, between January 2016 and July 2020. Patients were followed for 12 months post-transplant or until drop-out. TTV was quantified longitudinally by the TTV R-GENE® kit. The primary outcome was biopsy proven graft rejection and the secondary end-point was infection. RESULTS A total of 78 patients with 85 graft biopsies (rejection, n = 18) and 274 patients with 80 infectious events following TTV quantification after reaching steady state in month 3 post-transplantation were selected. TTV was quantified at a median of 17 days before rejection was diagnosed and 63 days before onset of infection. The risk for rejection decreased by 25% with every log level increase in TTV load [RR 0.75, 95% confidence interval (95% CI) 0.67–0.85; &amp;lt; 0.001]. For TTV loads &amp;lt; 5log10 c/mL a high specificity of 90% for rejection was calculated. The risk for an infection increased by 6% with every log level increase of TTV load (RR 1.06, IQR 1.00–0.12; = 0.047). For TTV loads &amp;gt; 7log10 c/mL a high specificity of 91% for infection was calculated. Multivariate modelling revealed an independent associated between TTV and rejection and infection, respectively. CONCLUSION These data support the value of TTV quantified by TTV R-GENE® for risk stratification of graft rejection and infection in the first year post kidney transplantation. The optimal TTV range defined within this study will be applied in an interventional randomized controlled trial to assess the safety of TTV-guided immunosuppression: the TTVguideIT trial.

MP36-13 ANALYSIS OF PRIMARY NON-FUNCTION, DELAYED GRAFT FUNCTION AND OVERALL GRAFT SURVIVAL FOR EXPANDED CRITERIA DONORS' KIDNEYS

You have accessJournal of UrologyCME1 May 2022MP36-13 ANALYSIS OF PRIMARY NON-FUNCTION, DELAYED GRAFT FUNCTION AND OVERALL GRAFT SURVIVAL FOR EXPANDED CRITERIA DONORS' KIDNEYS Monica Peradejordi Font, Antoni Vilaseca Cabo, Lluis Peri Cusi, Mireia Musquera Felip, Tarek Ajami Fardoun, Claudia Mercader Barrull, Angel Ruiz Arranz, David Paredes Zapata, Fritz Diekmann, and Antonio Alcaraz Asensio Monica Peradejordi FontMonica Peradejordi Font More articles by this author , Antoni Vilaseca CaboAntoni Vilaseca Cabo More articles by this author , Lluis Peri CusiLluis Peri Cusi More articles by this author , Mireia Musquera FelipMireia Musquera Felip More articles by this author , Tarek Ajami FardounTarek Ajami Fardoun More articles by this author , Claudia Mercader BarrullClaudia Mercader Barrull More articles by this author , Angel Ruiz ArranzAngel Ruiz Arranz More articles by this author , David Paredes ZapataDavid Paredes Zapata More articles by this author , Fritz DiekmannFritz Diekmann More articles by this author , and Antonio Alcaraz AsensioAntonio Alcaraz Asensio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002590.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The use of kidneys from expanded criteria donors (ECD) is increasing due to donor shortage. Predicting the outcome of these grafts is still a challenge. The aim of this study is to determine which factors are related to primary non-function (PNF), delayed graft function (DGF) and overall graft survival for kidneys retrieved from expanded criteria donors (ECD). METHODS: From January 2017 to December 2019 we retrospectively evaluated the pre-transplantation renal biopsy results and the pulsatile machine renal vascular resistance (RVR) of 97 kidneys from ECD that were implanted in our hospital. Those kidneys came from 40 donors after brain death and 57 from donors after cardiac death (6 Maastricht II, 50 Maastricht III and 1 Maastricht IV). The recipients’ evolution was analyzed. The association of the studied factors with PNF and DGF of the graft were studied with a logistic univariate regression. A Kaplan-Meier model was used to study its relationship with overall graft survival. RESULTS: The renal biopsy score was the only analyzed variable that presented with a statistically significant relation with PNF (OR 1.86, p<0.05), specifically the % of glomerulosclerosis (OR 1.11, p<0.05) and the grade of interstitial fibrosis (OR 5.36, p<0.05). Regarding DGF, the age of the donor (OR 0.90, p<0.05), serum creatinine >1.5 mg/dl (OR 11.57, p<0.05) and donation after cardiac death (OR 3.1 p<0.05) showed statistical difference. The recipient’s age and having diabetes were also related to developing DGF (OR 0.95, p<0.05 and OR 2.83, p<0.05). None of the biopsy results or the perfusion machine parameters resulted in statistically significant differences. Overall graft survival was inferior for grafts with RVR≥0.5 and/or renal biopsy score≥4 (p<0.05) (Figure 1). Presenting with DGF was not related to a worse graft survival (p=0.114). CONCLUSIONS: In this unicenter study, factors associated with PNF were related to graft biopsy results, whereas DGF was influenced by clinical donor and recipient characteristics. Overall survival of the graft is inferior for those grafts with RVR≥0.5 or renal biopsy score≥4. Source of Funding: There is no source of funding to disclose © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e602 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Monica Peradejordi Font More articles by this author Antoni Vilaseca Cabo More articles by this author Lluis Peri Cusi More articles by this author Mireia Musquera Felip More articles by this author Tarek Ajami Fardoun More articles by this author Claudia Mercader Barrull More articles by this author Angel Ruiz Arranz More articles by this author David Paredes Zapata More articles by this author Fritz Diekmann More articles by this author Antonio Alcaraz Asensio More articles by this author Expand All Advertisement PDF DownloadLoading ...

The Kidney Donor Profile Index (KDPI) Correlates With Histopathologic Findings in Post-reperfusion Baseline Biopsies and Predicts Kidney Transplant Outcome.

BackgroundThe increasing organ shortage in kidney transplantation leads to the necessity to use kidneys previously considered unsuitable for transplantation. Numerous studies illustrate the need for a better decision guidance rather than only the classification into kidneys from standard or expanded criteria donors referred to as SCD/ECD-classification. The kidney donor profile index (KDPI) exhibits a score utilizing a much higher number of donor characteristics. Moreover, graft biopsies provide an opportunity to assess organ quality.MethodsIn a single center analysis 383 kidney transplantations (277 after deceased and 106 after living donation) performed between January 1st, 2006, and December 31st, 2016, retrospectively underwent SCD/ECD and KDPI scoring. Thereby, the quality of deceased donor kidneys was assessed by using the KDPI and the living donor kidneys by using the living KDPI, in the further analysis merged as (L)KDPI. Baseline biopsies taken 10 min after the onset of reperfusion were reviewed for chronic and acute lesions. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards analysis within a 5-year follow-up.ResultsThe (L)KDPI correlated with glomerulosclerosis (r = 0.30, p < 0.001), arteriosclerosis (r = 0.33, p < 0.001), interstitial fibrosis, and tubular atrophy (r = 0.28, p < 0.001) as well as the extent of acute tubular injury (r = 0.20, p < 0.001). The C-statistic of the (L)KDPI concerning 5-year death censored graft survival was 0.692. Around 48% of ECD-kidneys were classified as (L)KDPI<85%. In a multivariate Cox proportional hazard analysis including (preformed) panel reactive antibodies, cold ischemia time, (L)KDPI, and SCD/ECD-classification, the (L)KDPI was significantly associated with risk of graft loss (hazard ratio per 10% increase in (L)KDPI: 1.185, 95% confidence interval: 1.033–1.360, p = 0.025). Survival analysis revealed decreased death censored (p < 0.001) and non-death censored (p < 0.001) graft survival in kidneys with an increasing (L)KDPI divided into groups of <35, 35–85, and >85%, respectively.ConclusionWith a higher granularity compared to the SCD/ECD-classification the (L)KDPI is a promising tool to judge graft quality. The correlation with chronic and acute histological lesions in post-reperfusion kidney biopsies underlines the descriptive value of the (L)KDPI. However, its prognostic value is limited and underlines the urgent need for a more precise prognostic tool adopted to European kidney transplant conditions.

Liver Graft Pathology and Low Serum 25-Hydroxyvitamin D after Living Donor Liver Transplantation.

Background: Most cases of advanced liver diseases are associated with low serum 25-hydroxyvitamin D and vitamin D deficiency. This phenomenon may occur in living donor liver transplantation (LDLT). Aims: We conducted this study to explore the interplay between VDR and CYP2R1 in liver graft and compared our findings with the pathological interpretation of serum 25(OH)D concentration. Methods: In total, 60 patients received liver graft biopsy after LDLT and were separated (1:1) into two groups: graft rejection group and graft non-rejection group. We extracted both of the recipients’ and donors’ serum DNA to investigate the vitamin D receptor (VDR) rs2228530 and CYP2R1 rs10741657 single nucleotide polymorphisms (SNPs) using real-time polymerase chain reaction. We also extracted DNA from liver graft tissues to explore the genetic alleles of VDR rs2228530 and CYP2R1 rs10741657 after LDLT. Serum biochemistry profile and 25(OH)D concentrations were measured before and after LDLT. Results: There were no significant differences in serum VDR rs2228530 and CYP2R1 rs10741657 genetic alleles between recipients and donors. The percentage of genetic modification was 33.4% (10/30) for the rejection and non-rejection groups in VDR rs2228530, and 66.7% (20/30) for both groups in CYP2R1 rs10741657. Serum 25(OH)D concentrations were significantly lower after LDLT D30 than that before LDLT in the rejection (p = 0.0001) and non-rejection graft pathology (p = 0.0017) groups. Conclusions: The presence of low serum 25(OH)D concentrations after LDLT suggested that post-transplant low serum 25(OH)D concentrations may develop with the homogenous phenomenon of VDR rs2228530 and CYP2R1 rs10741657 genetic modifications in recipients regardless of graft pathology.

The Presence of Donor-specific Antibodies Around the Time of Pancreas Graft Biopsy With Rejection Is Associated With an Increased Risk of Graft Failure.

Donor-specific antibodies (DSA) against HLA are an important biomarker predicting graft injury, rejection (Rej), and failure in various solid-organ transplant recipients. However, the impact of DSA with or without histopathological evidence of rejection among pancreas transplant recipients (PTRs) is unknown. In this study, we included all PTRs at our center between 2005 and 2020, with pancreas allograft biopsy before March 31, 2021, and with DSA checked within 15 d of the biopsy. PTRs were divided into 4 groups based on the biopsy findings on the index biopsy and DSA status as Rej-/DSA-, Rej+/DSA-, Rej-/DSA+, and Rej+/DSA+. Two hundred two PTRs had a pancreas allograft biopsy during the study period. Thirty-nine were in Rej-/DSA-, 84 Rej+/DSA-, 24 Rej-/DSA+, and 55 Rej+/DSA+. The mean interval from transplant to index biopsy was not statistically different between the 4 groups. The most common type of rejection was T cell-mediated rejection; however, antibody-mediated rejection was more prevalent in the Rej+/DSA+ group. At 5 y postbiopsy, the rate of death-censored graft failure (DCGF) for Rej-/DSA- was 18%, 24% in Rej+/DSA-; 17% in Rej-/DSA+ and 36% in Rej+/DSA+ (P = 0.14). In univariate analysis, mixed rejection (hazard ratio [HR], 3.0; 95% confidence intervals [CI], 1.22-7.39; P = 0.02) along with solitary pancreas transplantation and Rej+/DSA+ were associated with DCGF. In multivariate analysis, compared with Rej-/DSA-, Rej+/DSA+ was significantly associated with DCGF (HR, 2.32; 95% CI, 1.03-5.20; P = 0.04); however, Rej+/DSA- was not (HR, 1.06; 95% CI, 0.32-3.56; P = 0.92). PTRs with pancreas allograft rejection and concomitant DSA have an increased risk of DCGF.

Acute Kidney Injury and Urinary and Histopathological Disorders in Kidney Transplant Patients with SARS-CoV-2 Infection

BackgroundAcute kidney injury (AKI) is a manifestation of SARS-CoV-2 infection. The evidence in kidney transplant (KT) is limited, as there are scarce data about the histologic features in graft biopsies of these patients.Material and MethodsA retrospective cohort study of KTs with SARS-CoV-2 infection from August 28, 2020, to April 23, 2021. We collected the incidence of AKI and the presence of urinary and histopathological disorders. Both groups were compared (AKI vs no AKI). Immunohistochemical and reverse transcription-polymerase chain reaction studies were performed on the anatomopathological samples.ResultsIn our study, 72 KTs had SARS-CoV-2 infection and, among them, 27 patients (35.1%) developed AKI related to increased severity and a worse evolution of the infection, defined by a greater presence of pneumonia (P < .001), hospitalization (P < .001), admission to the intensive care unit (P < .001), the need for ventilation support (P < .001), and continuous renal replacement therapy (P < .001). In the multivariable analysis, pneumonia behaved as an independent predictor for AKI development (P = .046). No differences were observed between proteinuria a month before and after infection (P = .224). In addition, 5 patients showed microhematuria and 2 patients presented transient glycosuria without hyperglycemia. Of the 5 kidney biopsies performed, 1 biopsy (20%) showed positive reverse transcription polymerase chain reaction for SARS-CoV-2.ConclusionsAKI is a frequent and potentially serious complication in KT patients. Occasionally it could be accompanied by abnormalities in the urinary sediment. Of 5 biopsied patients, 1 patient had positive reverse transcription polymerase chain reaction in renal tissue, which suggests the systemic spread of the virus and the tropism for the renal graft.

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.

Tissue Engineering Scaffolds for Minimally-Invasive Immunosurveillance of Acute Cellular Graft Rejection

<h3>Purpose</h3> As there is no assay to predict the risk of acute cellular allograft rejection (ACAR), clinicians rely on protocol graft biopsy and aggressive, <i>one-size-fits-all</i> immunosuppression. Immunosuppression protects grafts from ACAR but increases systemic toxicities. Endomyocardial biopsy (EMB) histology suffers from variability and lags behind molecular biomarkers. <b>A minimally invasive surveillance method is urgently needed to quantify early risk of rejection for minimizing graft biopsy and personalizing treatment.</b> <h3>Methods</h3> Biomaterial scaffolds accumulate immune cells producing biomarkers of ACAR as an engineered immunological niche. We implanted subcutaneous poly-caprolactone scaffolds in murine heart or skin transplants to determine if they could identify ACAR. Rag2KO mice received full MHC mismatch allografts or syngeneic controls, and ACAR was initiated as a tunable event by C57BL/6 T cell transfer. Scaffolds were explanted and analyzed via histology and differential gene expression by RNA sequencing. <h3>Results</h3> The scaffolds provided a novel measure of graft health. We algorithmically identified <b>11 differentially-expressed genes as biomarkers</b> that distinguish mice with rejecting grafts from those with healthy grafts. <i>Importantly, the scoring system detects oncoming ACAR prior to clinical signs of rejection.</i> Also, histology of these niches identified changes associated with ACAR progression. <h3>Conclusion</h3> Gene expression in the cell-capture scaffold identified a biomarker signature of early ACAR, without invasive biopsy. <b>Scaffold cell capture technology provides a leading indicator of ACAR by monitoring tissue-specific immune responses associated with allograft rejection.</b> This implantable scaffold enables minimally invasive histological evaluation and molecular calculation of the early risk of rejection to reduce the frequency of routine EMB and personalize immune suppression that ultimately could prolong transplant life while minimizing risk.

Sub-classification of borderline changes into diffuse or focal and its impact on long-term renal transplant outcomes

BackgroundBorderline changes (BL) with stable renal function is a controversial category in renal transplantation, given its contradictory outcomes. The aim of this study was to compare the clinical outcomes of BL in patients with stable renal function classified as focal and diffuse according to the extent of tubulitis. MethodsPatients with no history of rejection with a surveillance graft biopsy at 3 or 12 months showing BL (n = 40), acute cellular rejection (n = 20) or normal biopsies (n = 20), were included in this study. Biopsies with BL were divided into diffuse BL (BLD) and focal BL (BLF) according to the extent of tubulitis. Because of the low frequency of subclinical ACR (ACRND) (n = 12), biopsies with ACR and graft dysfunction (ACRD) (n = 8) were also included. A composite outcome that included the presence of rejection in subsequent biopsies, graft loss, patient death, decrease in GFR ≥30% or presence of de novo DSA (dnDSA) during the first year of follow-up was evaluated. ResultsThe primary composite outcome occurred in five patients of each of the Normal, BLF and ACRND, eight patients with BLD and six patients with ACRD (p = 0.105). A trend towards more rejection episodes was observed in the ACRND and ACRD. Also, a shorter time to rejection in the BLD, ACRND and ACRD groups compared to BLF and Normal groups (p = 0.039) was observed. During the first year of follow-up, no patient in the ACRND group developed dnDSA, compared to 15–25% in the other groups. The median time of dnDSA development in the BLF group was 45 months, and in the BLD group was 10 months (p = 0.020). ConclusionClassifying BL biopsies with stable renal function into focal and diffuse categories, is a simple and feasible strategy that helps to differentiate between BLD with a phenotype that shows a trend towards worse outcomes, and BLF that behaves more similar to normal biopsies.