Abstract Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Defined by the Banff classification, its gold standard diagnosis remains a challenge, with limited inter-observer reproducibility of the histological scores and efficient immunomarker availability. We performed an immunohistochemical analysis of 3 interferon-related proteins, WARS1, TYMP and GBP1 in a cohort of kidney allograft biopsies including 17 ABMR cases and 37 other common graft injuries. Slides were interpreted, for an ABMR diagnosis, by four blinded nephropathologists and by a deep learning framework using convolutional neural networks. Pathologists identified a distinctive microcirculation staining pattern in ABMR with all three antibodies, displaying promising diagnostic performances and a substantial reproducibility. The deep learning analysis supported the microcirculation staining pattern and achieved similar diagnostic performance from internal validation, with a mean area under the receiver operating characteristic curve of 0.89 (± 0.02) for WARS1, 0.80 (± 0.04) for TYMP and 0.89 (± 0.04) for GBP1. The glomerulitis and peritubular capillaritis scores, the hallmarks of histological ABMR, were the most highly correlated Banff scores with the deep learning output, whatever the C4d status. These novel immunomarkers combined with a CNN framework could help mitigate current challenges in ABMR diagnosis and should be assessed in larger cohorts.
ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens.All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival.The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms.A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10 days plus an intraoperative corticosteroid bolus versus those receiving an intraoperative bolus only.
Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.
ABSTRACT Background While opportunistic infections are a frequent and challenging problem in kidney transplant recipients, their long-term epidemiology remains hardly known. Methods Opportunistic infections were recorded in 1144 recipients transplanted in our center between 2004 and 2015. Incidence rates and baseline risk factors were determined using joint frailty models. Results After a median follow-up of 5.6 years, 544 opportunistic infections occurred in 373/1144 (33%) patients, dominated by viral infections (396/544, 72%), especially cytomegalovirus (CMV) syndromes and diseases (213/544, 39%). One-third of the infected patients experienced at least two opportunistic infections. The incidence of opportunistic infections was 10 times higher during the first year post-transplantation than after that (34.7 infections for 100 patient-years vs 3.64). Opportunistic infections associated with the age of the donor (P = .032), the age of the recipient (P = .049), the CMV serostatus (P < 10−6), a higher class II HLA mismatch (P = .032) and an induction treatment including rabbit anti-thymocyte globulins (P = .026). Repeated opportunistic infections associated with each other (P < 10−6) and with renal death (P < 10−6). Conclusion Opportunistic infections occur with a two-period incidence pattern and many susceptible patients suffer from repeated episodes. This knowledge may help tailor new prevention and follow-up strategies to reduce the burden of opportunistic infections and their impact on transplantation outcome.
Coronavirus disease−2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a significant threat for patients with pre-existing renal disease, including kidney transplant recipients (KTRs).1Caillard S. Anglicheau D. Matignon M. et al.for the French SOT COVID RegistryAn initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants.Kidney Int. 2020; 98: 1549-1558Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 2Caillard S. Chavarot N. Francois H. et al.for the French SOT COVID RegistryIs COVID-19 infection more severe in kidney transplant recipients?.Am J Transplant. 2021; 21: 1295-1303Crossref PubMed Scopus (182) Google Scholar, 3Thaunat O. Legeai C. Anglicheau D. et al.for the French Nationwide Registry of Solid Organ Transplant Recipients with COVID-19IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT).Kidney Int. 2020; 98: 1568-1577Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,S1,S2 Although there is ample literature to suggest a role for kidney impairment in the severity of COVID-19, its clinical course in KTRs can vary widely, from minimal symptoms to life-threatening illness. Much of the recent focus in COVID-19 research has revolved around predictors of death and severe disease. Several studies in the adult general population have found an association between elevation of cardiac injury, coagulation, and inflammatory biomarkers and COVID-19−related mortality.4Shi S. Qin M. Shen B. et al.Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.JAMA Cardiol. 2020; 5: 802-810Crossref PubMed Scopus (3057) Google Scholar, 5Helms J. Tacquard C. Severac F. et al.High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.Intensive Care Med. 2020; 46: 1089-1098Crossref PubMed Scopus (2000) Google Scholar, 6Moore J.B. June C.H. Cytokine release syndrome in severe COVID-19.Science. 2020; 368: 473-474Crossref PubMed Scopus (1398) Google Scholar,S3 Nevertheless, only a limited number of single-center studies7Benotmane I. Perrin P. Vargas G.G. et al.Biomarkers of cytokine release syndrome predict disease severity and mortality from COVID-19 in kidney transplant recipients.Transplantation. 2021; 105: 158-169Crossref PubMed Scopus (33) Google Scholar,S4 have specifically explored the clinical utility of circulating biomarkers for the prediction of COVID-19−related mortality in solid organ transplant recipients (see Azzi et al.8Azzi Y. Bartash R. Scalea J. et al.COVID-19 and solid organ transplantation: a review article.Transplantation. 2021; 105: 37-55Crossref PubMed Scopus (227) Google Scholar for a recent review). By taking advantage of data from a French nationwide registry of KTRs with COVID-19, we sought to investigate the prognostic significance of increased biomarkers of cardiac injury, coagulation, and inflammation in this population. The study sample consisted of 494 KTRs who were included in the French SOT COVID registry during the first wave of the pandemic. A total of 411 patients were admitted to hospital, whereas the remaining 83 were managed at home. The baseline characteristics of the study patients are shown in Supplementary Table S1. The median age was 61 years (interquartile range [IQR] = 52−69 years), and two-thirds were men. SARS-CoV-2 infection was diagnosed after a median of 6 years from kidney transplantation. The median interval between symptom onset and hospital admission was 5 days (IQR = 3−8 days). The most common symptom was fever (73%), followed by cough (63%), dyspnea (45%), diarrhea (33%), and anosmia (16%). Supplementary Table S2 summarizes the clinical management and the evolution of disease over time. The 60-day overall survival rate in the entire study cohort was 80% (Supplementary Figure S1). The median levels of CRP and procalcitonin were 63 mg/l and 0.29 ng/ml, respectively. The median lymphocyte count was 0.62 ×109/l, whereas thrombocytopenia was identified in 94 (29%) patients. The median concentrations of hs-troponin I, lactate dehydrogenase (LDH), and D-dimer were 22 ng/l, 288 UI/l, and 927 μg/l, respectively (Supplementary Table S2). After setting the maximum point of the Youden index on the receiver operating characteristic (ROC) curve as the optimal cut-off value for each biomarker, we found that patients with serum creatinine >150 μmol/l, CRP >50 mg/l, procalcitonin >0.3 mg/l, hs-troponin I >20 ng/l, LDH >280 UI/l, and D-dimer >1500 UI/l were at an increased risk for COVID-19−related mortality (Supplementary Figure S2). Cumulative patient survival was significantly lower in KTRs who showed increased concentrations of these biomarkers at the time of hospital admission or diagnosis (Figure 1). Survival curves according to different cut-off points for each biomarker of interest are shown in Supplementary Figure S3. The hazard ratios for mortality according to each clinical and laboratory variable of interest are shown in Table 1. On multivariate analysis, procalcitonin and troponin I retained their independent association with mortality. The results of correlation analyses between different biomarkers are summarized in Supplementary Table S3. In the subgroup of patients (n = 276) who had at least 1 available biomarker, the combination of a marker of inflammation (procalcitonin), thrombosis (D-dimer), and cell lysis (hs-troponin I) was highly predictive of COVID-19−related mortality. Specifically, the 60-day survival rate was as high as 92% in patients (n = 110) without elevation of any of the 3 markers, whereas it declined to 77% in those (n = 120) who had at least 1 elevated biomarker. Less favorable outcomes were observed in patients (n = 36) with 2 (60-day survival rate, 58%) and 3 (n = 10) elevated biomarkers (60-day survival rate, 40%) (Figure 2a). On analyzing the subgroup of patients for which all 3 biomarkers were available on admission (n = 80), similar results were observed (Figure 2b).Table 1Univariate and multivariate analyses showing hazard ratios for COVID-19–related death in kidney transplant recipients (n = 491) according to age, cardiovascular history, and different biomarkers measured at the time of diagnosis or on patient admissionVariableUnivariate analysisMultivariate analysisHR95% CIPPaP value after bootstrap resampling for internal validation.HR95% CIPPaP value after bootstrap resampling for internal validation.Age >60 yr3.642.23-5.94<0.0010.0017.331.91-28.10.0040.004CV history1.251.03-1.520.0270.036SCr >150 μmol/l1.391.07-1.780.0140.009PCT >0.3 mg/l2.281.51-3.64<0.0010.0013.731.53-9.130.0040.001DD >1500 UI/l1.891.31-2.720.0010.001hs-Troponin I >20 ng/l2.111.39-3.19<0.0010.0012.911.02-8.340.0470.022CI, confidence interval; CV, cardiovascular; DD, D-dimer; HR, hazard ratio; hs, high-sensitivity; PCT, procalcitonin; SCr, serum creatinine;a P value after bootstrap resampling for internal validation. Open table in a new tab Figure 2Kaplan−Meier survival plots for kidney transplant recipients with COVID-19, stratified according to the number of biomarkers above the optimal cut-off value at the time of diagnosis or hospital admission. (a) Patients with at least 1 available biomarker (n = 276, P < 0.001); (b) patients for whom all 3 biomarkers were available (n = 80, P < 0.001).View Large Image Figure ViewerDownload Hi-res image Download (PPT) CI, confidence interval; CV, cardiovascular; DD, D-dimer; HR, hazard ratio; hs, high-sensitivity; PCT, procalcitonin; SCr, serum creatinine; In this study comprising 494 KTRs, we found that elevations of markers of inflammation, cardiac injury, and thrombosis were significantly associated with an increased risk of COVID-19−related mortality. Growing evidence indicates that inflammatory mediators are paramount in determining the severity of COVID-19, with poor outcomes frequently resulting from a massive release of proinflammatory cytokines, also known as "cytokine storm."6Moore J.B. June C.H. Cytokine release syndrome in severe COVID-19.Science. 2020; 368: 473-474Crossref PubMed Scopus (1398) Google Scholar,S5 Notably, the optimal cut-off values for serum CRP (50 mg/l) and procalcitonin (0.3 mg/l) levels identified in our study are consistent with those reported in previous investigations.7Benotmane I. Perrin P. Vargas G.G. et al.Biomarkers of cytokine release syndrome predict disease severity and mortality from COVID-19 in kidney transplant recipients.Transplantation. 2021; 105: 158-169Crossref PubMed Scopus (33) Google Scholar,S6-S9 On analyzing the survival figures of our KTRs, we found that individuals with elevated levels of circulating hs-troponin I, a well-known biomarker of myocardial injury, were at an increased risk for COVID-19-related mortality. Li et al.9Li C. Jiang J. Wang F. et al.Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients.J Mol Cell Cardiol. 2020; 147: 74-87Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar published a population-based study of 2068 patients with laboratory-confirmed COVID-19, of whom 8.8% had elevated hs-troponin I; the prevalence rate increased to 30% in critically ill patients, who experienced a mortality rate of 38%. An increase in the mortality rates among patients with COVID-19 and elevated hs-troponin I supports the utility of this biomarker for prognostic stratification. The mechanisms of cardiac involvement in COVID-19 include, but are not limited to, the following: cytokine-mediated cardiac tissue damage, an imbalance between oxygen supply and demand, ischemic injury due to micro- and/or macrovascular thrombosis, endothelial dysfunction, and myocardial injury caused by direct SARS-CoV-2 invasion into cardiomyocytes.S10,S11 The complex interplay between the disproportionate hyperinflammatory reaction occurring in severe COVID-19 and the severity of cardiac injury deserves further scrutiny.9Li C. Jiang J. Wang F. et al.Longitudinal correlation of biomarkers of cardiac injury, inflammation, and coagulation to outcome in hospitalized COVID-19 patients.J Mol Cell Cardiol. 2020; 147: 74-87Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Finally, our results add to the growing literature indicating that D-dimer concentrations may be a useful laboratory parameter that should be taken into account for prognostic stratification of patients with COVID-19.5Helms J. Tacquard C. Severac F. et al.High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.Intensive Care Med. 2020; 46: 1089-1098Crossref PubMed Scopus (2000) Google Scholar,S3 However, published studies did not provide specific data for KTRs. Elevated D-dimer levels reflect a hypercoagulability state that may increase the risk of venous thromboembolic disease. A large multicenter study involving 400 hospitalized patients with COVID-19 who received prophylactic anticoagulation reported an incidence rate of thrombotic complications of 9.5%.S6 The final multivariable analysis showed an increased risk of thrombotic complications during hospitalization (adjusted odds ratio, 6.8) for patients with D-dimer levels >2500 ng/ml on admission.S6 In a French study, patients with D-dimer levels >2590 ng/ml were found to have a 17-fold increase in the adjusted risk of pulmonary embolism.S12 Although the rate of thrombotic events observed in our KTRs was relatively low (7.5%), screening of venous thromboembolic disease was not systematically performed. Several caveats of our investigation need to be considered. First, the retrospective nature of the study could be associated with information bias, and some biomarker values were missing. Second, although we analyzed serum levels of hs-troponin I as a biomarker of cardiac injury, the use of transthoracic echocardiography and electrocardiography might have improved the power of the study in terms of identifying myocardial dysfunction.S13 Finally, we had no systematic screening of vascular thrombosis or pulmonary embolism. Despite these limitations, our data represent a promising step in understanding the value of several biochemical markers for predicting COVID-19−related mortality in KTRs. In addition, the current study is one of the largest to date specifically focusing on this clinical issue in a frail population under immunosuppressive therapy. In conclusion, our study findings indicated that, in KTRs with COVID-19, elevations in biochemical markers of inflammation, cardiac injury, and coagulation are associated with less favorable survival figures. If independently validated, the use of biomarkers may help to guide therapeutic decision making in transplant patients. All the authors declared no competing interests. Download .pdf (1.89 MB) Help with pdf files Supplementary File (PDF) Table S1. Baseline characteristics of kidney transplant recipients with COVID-19 Table S2. Laboratory data, management of immunosuppression, treatment modalities, and outcomes of kidney transplant recipients with COVID-19 Table S3. Spearman correlation coefficients between baseline patient characteristics and biomarker levels measured at the time of diagnosis or on admission Figure S1. Kaplan−Meier survival plot of kidney transplant recipients hospitalized with COVID-19. Figure S2. Receiver operating characteristic curve analysis of COVID-19−related mortality. Figure S3. Kaplan−Meier survival plots for kidney transplant recipients with COVID-19. Supplementary References ∗The French SOT COVID Registry Collaborators are as follows: Sophie Caillard, Bruno Moulin, Service de Néphrologie et Transplantation, Hôpitaux Universitaires de Strasbourg, Strasbourg; Samira Fafi-Kremer, Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg; Marc Hazzan, Service de Néphrologie, Hôpital Huriez, Lille; Dany Anglicheau, Service de Néphrologie et Transplantation Adultes, AP-HP, Hôpital Necker, Paris; Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Service de Néphrologie, AP-HP, Hôpital La Pitié Salpétrière, Paris; Emmanuel Morelon, Olivier Thaunat, Service de Néphrologie, Hôpital Edouard Herriot, Lyon; Lionel Couzi, Pierre Merville, Service de Néphrologie–Transplantation–Dialyse, Hôpital Pellegrin, Bordeaux; Valérie Moal, Tristan Legris, Service de Néphrologie et Transplantation, AP-HM, Hôpital de la Conception, Marseille; Pierre-François Westeel, Maïté Jaureguy, Service de Néphrologie, CHU Amiens Picardie, Amiens; Luc Frimat, Service de Néphrologie, CHRU Nancy, Vandoeuvre; Didier Ducloux, Jamal Bamoulid, Service de Néphrologie, Hôpital Jean-Minjoz, Besancon; Dominique Bertrand, Service de Néphrologie, CHU de Rouen, Rouen; Michel Tsimaratos, Florentine Garaix-Gilardo, Service de Pédiatrie Multidisciplinaire, Hôpital La Timone, Marseille; Jérôme Dumortier, Service d'Hépato-Gastroentérologie, Hôpital Edouard Herriot, Lyon; Sacha Mussot, Antoine Roux, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson; Laurent Sebbag, Service d'Insuffisance Cardiaque, Hôpital Louis Pradel, Bron; Yannick Le Meur, Service de Néphrologie, Hôpital de la Cavale Blanche, Brest; Gilles Blancho, Christophe Masset, Service de Néphrologie–Transplantation, Hôtel Dieu, Nantes; Nassim Kamar, Service de Néphrologie et Transplantation, Hôpital Rangueil, Toulouse; Hélène Francois, Eric Rondeau, Service de Néphrologie, Dialyse et Transplantation, AP-HP, Hôpital Tenon, Paris; Nicolas Bouvier, Service de Néphrologie, Dialyse, Transplantation Rénale, CHU, Caen; Christiane Mousson, Service de Néphrologie, Dijon; Matthias Buchler, Philippe Gatault, Service de Néphrologie, Tours; Jean-François Augusto, Agnès Duveau, Service de Néphrologie, Dialyse, Transplantation, CHU Angers, Angers; Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Service de Néphrologie, CHU de Rennes, Rennes; Philippe Grimbert, Marie Matignon, Antoine Durrbach, Service de Néphrologie, Hôpital Henri-Mondor, Creteil; Clarisse Greze, Service de Néphrologie, AP-HP, Hôpital Bichat Claude Bernard, Paris; Renaud Snanoudj, Service de Néphrologie, Hôpital Foch, Service de Néphrologie et Transplantation Hôpital du Kremlin Bicêtre, Le Kremlin Bicetre; Charlotte Colosio, Betoul Schvartz, Service de Néphrologie, Hôpital Maison Blanche, Reims; Paolo Malvezzi, Service de Néphrologie, Hémodialyse, Transplantation Rénale, Hôpital La Tronche, Grenoble; Christophe Mariat, Service de Néphrologie, CHU de Saint Etienne, Saint Etienne; Antoine Thierry, Service de Néphrologie, Hémodialyse et Transplantation Rénale, Hôpital Jean Bernard, Poitiers; Moglie Le Quintrec, Service de Néphrologie−Transplantation−Dialyse, CHU Lapeyronie, Montpellier; Antoine Sicard, Service de Néphrologie, Hôpital Pasteur, Nice; Jean Philippe Rerolle, Service de Néphrologie, CHU Dupuytren, Limoges; Anne-Élisabeth Heng, Cyril Garrouste, Service de Néphrologie, CHU Gabriel Montpied, Clermont-Ferrand; Henri Vacher Coponat, Service de Néphrologie, CHU de La Réunion, Saint Denis; Éric Epailly, Service de Cardiologie, Hôpitaux Universitaires de Strasbourg, Strasbourg; Olivier Brugiere, Service d'Hépatologie, Hôpital Foch, Suresnes; Sébastien Dharancy, Service d'Hépatologie, Hôpital Huriez, Lille; Éphrem Salame, Service de Chirurgie Hépatique, Hôpital Universitaire de Tours, Tours; Faouzi Saliba, Service d'Hépatologie, Centre hépato-biliaire Paul Brousse, Villejuif, France.
