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Optimization of individual immunosuppression, which reduces the risks of both graft loss and patients' death, is considered the best approach to improve long-term outcomes of renal transplantation. Torque Teno Virus (TTV) DNAemia has emerged as a potential biomarker reflecting the depth of therapeutic immunosuppression during the initial year post-transplantation. However, its efficacy in long-term monitoring remains uncertain. In a cohort study involving 34 stable kidney transplant recipients and 124 healthy volunteers, we established lower and upper TTV DNAemia thresholds (3.75-5.1 log10 cp/mL) correlating with T-cell activatability, antibody response against flu vaccine, and risk for subsequent serious infections or cancer over 50 months. Validation in an independent cohort of 92 recipients confirmed that maintaining TTV DNAemia within this range in >50% of follow-up time points was associated with reduced risks of complications due to inadequate immunosuppression, including de novo DSA, biopsy-proven antibody-mediated rejection, graft loss, infections, or cancer. Multivariate analysis highlighted "in-target" TTV DNAemia as the sole independent variable significantly linked to decreased risk for long-term complications due to inadequate immunosuppression (odds ratio [OR]: 0.27 [0.09-0.77]; p = 0.019). Our data suggest that the longitudinal monitoring of TTV DNAemia in kidney transplant recipients could help preventing the long-term complications due to inadequate immunosuppression.
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Infecções por Vírus de DNA , DNA Viral , Terapia de Imunossupressão , Transplante de Rim , Torque teno virus , Transplantados , Humanos , Torque teno virus/genética , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , DNA Viral/sangue , Adulto , Infecções por Vírus de DNA/virologia , Infecções por Vírus de DNA/sangue , Infecções por Vírus de DNA/imunologia , Terapia de Imunossupressão/efeitos adversos , Estudos Longitudinais , Idoso , Rejeição de Enxerto , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Estudos de Coortes , ViremiaRESUMO
Background: About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis. Methods: We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers. Results: Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers. Conclusion: Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.
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Angiotensina II , Hipertensão , Transplante de Pâncreas , Trombose , Doadores de Tecidos , Humanos , Transplante de Pâncreas/efeitos adversos , Masculino , Feminino , Hipertensão/etiologia , Pessoa de Meia-Idade , Adulto , Trombose/etiologia , Fatores de Risco , Sobrevivência de Enxerto , Aloenxertos , Estudos Retrospectivos , Rejeição de Enxerto/imunologiaRESUMO
Endoscopic dissection is the first-choice treatment for superficial pT1 colorectal adenocarcinoma (sCRC). Complementary surgery decision is influenced by histopronostic factors. Prognostic significance and reproducibility of each factor are not well established. The role of immunohistochemistry (IHC) and digital pathology in this context is unknown. Our aims were (1) to evaluate each histopronostic factor reproducibility comparing HES and IHC ± digital pathology and (2) to evaluate how the different techniques would affect indications for additional surgery. We performed a single-centre retrospective study of 98 patients treated between 2010 and 2019 in Hospices Civils de Lyon, France. We analyzed physical or digital slides of HES and keratin/desmin immunostaining of 98 sCRC dissection specimens. Three pathologists evaluate the histopronostic factors including submucosal invasion depth (SMI) measured using different recommended methods. Assessment of SMI with Ueno or JSCCR methods showed good to excellent interobserver reproducibility (IOR) (ICCs of 0.858 to 0.925) using HES staining and IHC. Assessment of budding on HES sections was poorly reproducible compared to IHC which exhibit moderate IOR (κ = 0.714). IHC increased high-grade budding detection. For lymphovascular invasion and poor differentiation, the IOR was poor (κ = 0.141, 0.196 and 0.313 respectively). IHC gave a better reproducibility for further treatment indication according to JSCCR criteria (κ = 0.763) or forthcoming European guidelines (κ = 0.659). Digital pathology was equivalent to the microscope for all analyses. Histopronostic factor reproducibility in sCRC is moderate. Immunohistochemistry may facilitate the evaluation of certain criteria and improve the reproducibility of treatment decisions.
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INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a major public health issue with an incidence/mortality ratio reaching 98 %. Only 15-20 % of patients with PDAC can undergo surgery. Following PDAC surgical resection, 80 % of patients will experience local or metastatic recurrence of this disease. pTNM staging is the gold standard for risk stratification but is not sufficient to recapitulate the prognosis. Several prognostic factors are known to impact survival after surgery when uncovered during pathological examination. However, necrosis has been poorly studied in pancreatic adenocarcinoma. MATERIALS & METHODS: We retrieved clinical data and reviewed all tumor slides from patients who had a pancreatic surgery between January 2004 and December 2017, in the Hospices Civils de Lyon, to assess the presence of histopathological prognosis factors associated with poor prognosis. RESULTS: 514 patients with complete clinico-pathological description were included. Necrosis was found in 231 PDAC (44.9 %) and had an important impact on overall survival with a double risk of death when present in tumor samples (HR: 1.871, 95 % CI [1.523; 2.299], p < 0.001). When integrated in the multivariate model, necrosis is the only morphological aggressive feature to retain high statistical significance associated with the TNM staging but independently of it. This effect is independent of the preoperative treatment. CONCLUSIONS: Despites improvement in treatment of PDAC, mortality rates remain relatively stable amongst the last years. There is a desperate need to better stratify patients. Here, we report the strong and prognostic impact of necrosis in surgical PDAC samples and encourage pathologists to report its presence in the future.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Prognóstico , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Necrose , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
BACKGROUND: No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity. METHODS: The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k-means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval. RESULTS: We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P<0.001), independent of the total activity scores (HR, 5.01; 95% CI, 2.83 to 7.00; P<0.001). These results were validated on an external cohort of 4031 biopsies from 2054 kidney transplant recipients. CONCLUSIONS: The evaluation of total chronicity provides information on kidney transplant pathology that complements the estimation of disease activity from acute lesion scores. Use of the data-driven algorithm used in this study, called RejectClass, may provide a holistic and quantitative assessment of kidney transplant injury phenotypes and severity.
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Nefropatias , Transplante de Rim , Humanos , Transplante de Rim/métodos , Sobrevivência de Enxerto , Rejeição de Enxerto/patologia , Rim/patologia , Biópsia , Nefropatias/patologia , Proteínas do Sistema Complemento , Aloenxertos/patologia , FenótipoRESUMO
The generation of antibodies against donor-specific major histocompatibility complex (MHC) antigens, a type of donor-specific antibodies (DSAs), after transplantation requires that recipient's allospecific B cells receive help from T cells. The current dogma holds that this help is exclusively provided by the recipient's CD4+ T cells that recognize complexes of recipient's MHC II molecules and peptides derived from donor-specific MHC alloantigens, a process called indirect allorecognition. Here, we demonstrated that, after allogeneic heart transplantation, CD3ε knockout recipient mice lacking T cells generate a rapid, transient wave of switched alloantibodies, predominantly directed against MHC I molecules. This is due to the presence of donor CD4+ T cells within the graft that recognize intact recipient's MHC II molecules expressed by B cell receptor-activated allospecific B cells. Indirect evidence suggests that this inverted direct pathway is also operant in patients after transplantation. Resident memory donor CD4+ T cells were observed in perfusion liquids of human renal and lung grafts and acquired B cell helper functions upon in vitro stimulation. Furthermore, T follicular helper cells, specialized in helping B cells, were abundant in mucosa-associated lymphoid tissue of lung and intestinal grafts. In the latter, more graft-derived passenger T cells correlated with the detection of donor T cells in recipient's circulation; this, in turn, was associated with an early transient anti-MHC I DSA response and worse transplantation outcomes. We conclude that this inverted direct allorecognition is a possible explanation for the early transient anti-MHC DSA responses frequently observed after lung or intestinal transplantations.
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Formação de Anticorpos , Isoanticorpos , Animais , Rejeição de Enxerto , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Classe II , Humanos , Isoantígenos , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos , Receptores de Antígenos de Linfócitos BRESUMO
Renal ischemia-reperfusion (IR) injury can lead to acute kidney injury, increasing the risk of developing chronic kidney disease. We hypothesized that mild therapeutic hypothermia (mTH), 34 °C, applied during ischemia could protect the function and structure of kidneys against IR injuries in mice. In vivo bilateral renal IR led to an increase in plasma urea and acute tubular necrosis at 24 h prevented by mTH. One month after unilateral IR, kidney atrophy and fibrosis were reduced by mTH. Evaluation of mitochondrial function showed that mTH protected against IR-mediated mitochondrial dysfunction at 24 h, by preserving CRC and OX-PHOS. mTH completely abrogated the IR increase of plasmatic IL-6 and IL-10 at 24 h. Acute tissue inflammation was decreased by mTH (IL-6 and IL1-ß) in as little as 2 h. Concomitantly, mTH increased TNF-α expression at 24 h. One month after IR, mTH increased TNF-α mRNA expression, and it decreased TGF-ß mRNA expression. We showed that mTH alleviates renal dysfunction and damage through a preservation of mitochondrial function and a modulated systemic and local inflammatory response at the acute phase (2-24 h). The protective effect of mTH is maintained in the long term (1 month), as it diminished renal atrophy and fibrosis, and mitigated chronic renal inflammation.
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Injúria Renal Aguda , Hipotermia Induzida , Traumatismo por Reperfusão , Injúria Renal Aguda/genética , Animais , Atrofia/patologia , Fibrose , Inflamação/metabolismo , Interleucina-6/metabolismo , Isquemia/metabolismo , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , RNA Mensageiro/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The standard-of-care protocol, based on plasma exchanges, high-dose intravenous immunoglobulin and optimization of maintenance immunosuppression, can slow down the evolution of antibody-mediated rejection (AMR), but with high interindividual variability. Identification of a reliable predictive tool of the response to AMR treatment is a mandatory step for personalization of the follow-up strategy and to guide second-line therapies. METHODS: Interrogation of the electronic databases of 2 French university hospitals (Lyon and Strasbourg) retrospectively identified 81 renal transplant recipients diagnosed with AMR without chronic lesions (cg score ≤1) at diagnosis and for whom a follow-up biopsy had been performed 3-6 months after initiation of therapy. RESULTS: The evolution of humoral lesions on follow-up biopsy (disappearance versus persistence versus progression) correlated with the risk for allograft loss (logrank test, P = .001). Patients with disappearance of humoral lesions had â¼80% graft survival at 10 years. The hazard ratio for graft loss in multivariate analysis was 3.91 (P = .04) and 5.15 (P = .02) for patients with persistence and progression of lesions, respectively. The non-invasive parameters classically used to follow the intensity of humoral alloimmune response (evolution of immunodominant DSA mean fluorescence intensity) and the decline of renal graft function (estimated glomerular filtration rate decrease and persistent proteinuria) showed little clinical value to predict the histological response to AMR therapy. CONCLUSION: We conclude that invasive monitoring of the evolution of humoral lesions by the mean of follow-up biopsy performed 3-6 months after the initiation of therapy is an interesting tool to predict long-term outcome after AMR treatment.
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Rejeição de Enxerto , Transplante de Rim , Humanos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Estudos Retrospectivos , Seguimentos , Transplante de Rim/efeitos adversos , Sobrevivência de Enxerto , Biópsia , Anticorpos , IsoanticorposRESUMO
BACKGROUND: Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure. METHODS: The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance. RESULTS: Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters. CONCLUSIONS: A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.
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Rejeição de Enxerto/patologia , Nefropatias/patologia , Nefropatias/cirurgia , Transplante de Rim/estatística & dados numéricos , Doença Aguda , Adulto , Idoso , Análise por Conglomerados , Estudos de Coortes , Feminino , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Humanos , Nefropatias/mortalidade , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Fenótipo , Reprodutibilidade dos TestesRESUMO
Acute kidney injury (AKI) caused by hantavirus infections is rare but should be suspected in any patient presenting with flu-like symptoms, signs of haemolytic-uraemic syndrome or presence of anti-glomerular basement membrane (anti-GBM) antibodies. We report the first case of Dobrava-Belgrade virus in France imported from southeastern Europe. The characteristic macroscopic appearance of the fresh renal biopsy specimen, displaying a haemorrhagic appearance of the medulla, suggested hantavirus infection. AKI caused by hantavirus infections remains a diagnostic challenge, especially outside endemic areas.
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The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation.
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Transplante de Rim , Biomarcadores , Biópsia , Estudos de Coortes , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Rim , Transplante de Rim/efeitos adversos , RNA Mensageiro , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. METHODS AND RESULTS: Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. CONCLUSIONS: The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.
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Aloenxertos/patologia , Ativação do Complemento/fisiologia , Rejeição de Enxerto/etiologia , Antígenos de Histocompatibilidade Classe I/sangue , Transplante de Rim/efeitos adversos , Células Matadoras Naturais/fisiologia , Adulto , Aloenxertos/imunologia , Técnicas de Cultura de Células , Complemento C3d/metabolismo , Células Endoteliais/fisiologia , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Deep infiltrating endometriosis frequently affects the rectosigmoid region. It clinically presents as a chronic painful condition affecting women in their reproductive time. Here, we present a case of a 28-yr-old female patient who had a history of dysmenorrhea, dyspareunia, chronic abdominal and pelvic pain, and constipation secondary to rectal wall endometriosis. Microscopic examination of the resected rectal segment showed endometriosis with vascular and lymph node involvement. Vascular involvement is an uncommon histologic finding that may raise concern for potential malignancy. The aim of this report is to alert pathologists and physicians about this infrequent pitfall that can be mistaken for a neoplastic process and to discuss the underlying pathophysiology of vascular involvement by endometrial tissue in otherwise benign conditions.
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Constipação Intestinal/diagnóstico , Dismenorreia/diagnóstico , Dispareunia/diagnóstico , Endometriose/diagnóstico , Dor Pélvica/diagnóstico , Doenças Retais/diagnóstico , Adulto , Constipação Intestinal/patologia , Dismenorreia/patologia , Dispareunia/patologia , Endometriose/patologia , Feminino , Humanos , Dor Pélvica/patologia , Doenças Retais/patologiaRESUMO
The Banff classification for antibody-mediated rejection (ABMR) has undergone important changes, mainly by inclusion of C4d-negative ABMR in Banff'13 and elimination of suspicious ABMR (sABMR) with the use of C4d as surrogate for HLA-DSA in Banff'17. We aimed to evaluate the numerical and prognostic repercussions of these changes in a single-center cohort study of 949 single kidney transplantations, comprising 3662 biopsies that were classified according to the different versions of the Banff classification. Overall, the number of ABMR and sABMR cases increased from Banff'01 to Banff'13. In Banff'17, 248 of 292 sABMR biopsies were reclassified to No ABMR, and 44 of 292 to ABMR. However, reclassified sABMR biopsies had worse and better outcome than No ABMR and ABMR, which was mainly driven by the presence of microvascular inflammation and absence of HLA-DSA, respectively. Consequently, the discriminative performance for allograft failure was lowest in Banff'17, and highest in Banff'13. Our data suggest that the clinical and histological heterogeneity of ABMR is inadequately represented in a binary classification system. This study provides a framework to evaluate the updates of the Banff classification and assess the impact of proposed changes on the number of cases and risk stratification. Two alternative classifications introducing an intermediate category are explored.
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Transplante de Rim , Biópsia , Estudos de Coortes , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Isoanticorpos , Rim , Transplante de Rim/efeitos adversosRESUMO
Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of ß2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.
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Rejeição de Enxerto/imunologia , Transplante de Coração/métodos , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Animais , Células Cultivadas , Células Endoteliais/imunologia , Células Endoteliais/patologia , Humanos , Células K562 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/patologia , Doadores de Tecidos , Transplante Homólogo , Microglobulina beta-2/genética , Microglobulina beta-2/imunologia , Microglobulina beta-2/metabolismoRESUMO
Clinical outcome in antibody-mediated rejection (AMR) shows high inter-individual heterogeneity. Sialylation status of the Fc fragment of IgGs is variable, which could modulate their ability to bind to C1q and/or Fc receptors. In this translational study, we evaluated whether DSA sialylation influence AMR outcomes. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of DSA by Luminex. The sialylation status of total IgG and DSA was quantified using Sambucus nigra agglutinin-based chromatography. All patients had similar levels of sialylation of serum IgGs (~2%). In contrast, the proportion of sialylated DSA were highly variable (median = 9%; range = 0-100%), allowing to distribute the patients in two groups: high DSA sialylation (n = 44; 64%) and low DSA sialylation (n = 25; 36%). The two groups differed neither on the intensity of rejection lesions (C4d, ptc, and g; p > 0.05) nor on graft survival rates (Log rank test, p = 0.99). in vitro models confirmed the lack of impact of Fc sialylation on the ability of a monoclonal antibody to trigger classical complement cascade and activate NK cells. We conclude that DSA sialylation status is highly variable but has not impact on DSA pathogenicity and AMR outcome.
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Rejeição de Enxerto/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Isoanticorpos/imunologia , Ácido N-Acetilneuramínico/imunologia , Doadores de Tecidos , Adulto , Ativação do Complemento , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Extra-pulmonary tuberculosis is frequently located in the kidneys and, in such cases, could be associated with a granulomatous interstitial nephritis. Granulomas are not always detected, especially in human immunodeficiency virus (HIV)-positive patients. We report here a case of tubulointerstitial nephritis without granulomas in an HIV-negative patient. Since all laboratory tests failed to isolate Mycobacterium tuberculosis in the kidney, a targeted biopsy guided by positron emission tomography-computed tomography was performed on a mediastinal node, revealing a positive culture. After 6 months of treatment, no recovery of the renal injury has been observed.
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BACKGROUND: Kidney transplantation following uncontrolled donation after circulatory death (uDCD) presents a high risk of delayed graft function due to prolonged warm ischemia time. In order to minimise the effects of ischemia/reperfusion injury during warm ischemia, normothermic recirculation recently replaced in situ perfusion prior to implantation in several institutions. The aim of this study was to compare these preservation methods on kidney graft outcomes. METHODS: The primary endpoint was the one-year measured graft filtration rate (mGFR). We collected retrospective data from 64 consecutive uDCD recipients transplanted over a seven-year period in a single centre. RESULTS: Thirty-two grafts were preserved by in situ perfusion and 32 by normothermic recirculation. The mean ± SD mGFR at 1 year post-transplantation was 43.0 ± 12.8 mL/min/1.73 m2 in the in situ perfusion group and 53.2 ± 12.8 mL/min/1.73 m2 in the normothermic recirculation group (p = 0.01). Estimated GFR levels were significantly higher in the normothermic recirculation group at 12 months (p = 0.01) and 24 months (p = 0.03) of follow-up. We did not find any difference between groups regarding patient and graft survival, delayed graft function, graft rejection, or interstitial fibrosis. CONCLUSIONS: Function of grafts preserved by normothermic recirculation was better at 1 year and the results suggest that this persists at 2 years, although no difference was found in short-term outcomes. Despite the retrospective design, this study provides an additional argument in favour of normothermic recirculation.
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Sobrevivência de Enxerto/fisiologia , Parada Cardíaca/diagnóstico , Parada Cardíaca/fisiopatologia , Transplante de Rim/métodos , Preservação de Órgãos/métodos , Doadores de Tecidos , Adulto , Função Retardada do Enxerto/diagnóstico , Função Retardada do Enxerto/fisiopatologia , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/fisiopatologia , Rejeição de Enxerto/prevenção & controle , Humanos , Transplante de Rim/tendências , Masculino , Pessoa de Meia-Idade , Preservação de Órgãos/normas , Estudos Retrospectivos , Choque/diagnóstico , Choque/fisiopatologia , Resultado do TratamentoRESUMO
We report a case of a patient who had the mitochondrial cytopathy complex of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome diagnosed at age 11 years with a biopsy-proven kidney involvement that progressed to end-stage renal disease at age 21 years. Mutations of mitochondrial DNA (mtDNA) are maternally inherited and lead to mitochondrial cytopathies with predominant neurologic manifestations: psychomotor retardation, epilepsy, ataxia, neuropathy, and myopathy. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. Mutations in the MT-ATP6 gene of mtDNA have been shown to cause NARP syndrome without renal involvement. We report a patient who had NARP syndrome diagnosed at age 11 years in whom glomerular proteinuria was present very early after diagnosis. Although neurologic manifestations were stable over time, he developed worsening proteinuria and kidney function. He started dialysis therapy at age 21 years. Kidney biopsy confirmed the mitochondrial cytopathy histologically, with abnormal mitochondria seen on electron microscopy. The MT-ATP6 gene mutation was detected in the kidney biopsy specimen.