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Supplementary Table 1. Tumorigenic potential of cells sorted from normoxic and hypoxic spheres of the six xenograft models (take rate in percentage)

Figure S1. In the 6 models xenografted with human RCC, we identified 2 models responders to sunitinib and 4 non-responders. When treated with sunitinib, necrosis occurs earlier in the responder models

supplementary figure legends

supplementary methods

Purpose: Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis–associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC.Experimental Design: We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4–coexpressing cells derived from the two responder xenograft models were used for in vitro studies.Results: In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4–coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4–coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased.Conclusions: In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers. Clin Cancer Res; 21(4); 916–24. ©2014 AACR.

HLA-G:ILT2 has recently been positioned as a major immune checkpoint in urologic cancers. In clear cell renal cell carcinoma (ccRCC), tumor-infiltrating CD8+ T cells expressing ILT2 are a highly cytotoxic cell population, distinct from PD1+ T cells, and whose function is inhibited by HLA-G+ targets. Here we report that ILT2 receptor can also be expressed by CD4+ T cells in urologic cancer patients. In the course of deciphering the role of these ILT2+CD4+ T cells, we found a statistical association between the tumor context and these T cells, and a positive correlation between the levels of peripheral and intra-tumoral CD4+ILT2+ T cells. Phenotypic analyses revealed that CD4+ILT2+ T cells express memory T cell (CD27−CD28−CD57+) and cytotoxicity (Tbet+Perforin+KLRG1+NKp80+GPR56+) markers, consistent with a CD4+CTL phenotype. Functional assays showed that ccRCC-infiltrating CD4+ILT2+ T cells indeed have high cytolytic properties and therefore function as proper CD4+CTLs, but are selectively inhibited by HLA-G+ targets. Clinical relevance was provided by immunohistochemical analyses on ccRCC tumor lesions with HLA-G+ HLA class II+ tumor cells next to CD4+ T cell infiltrates. Our findings provide evidence supporting that ILT2+ T cells constitute a reservoir of intratumor cytotoxic T cells that is not targeted by the current checkpoint inhibitors, but could be by anti-HLA-G/anti-ILT2 antibodies as novel immunotherapy in HLA-G+ tumors.

Only some cancer patients respond to the immune-checkpoint inhibitors being used in the clinic, and other therapeutic targets are sought. Here, we investigated the HLA-G/ILT2 checkpoint in clear-cell renal-cell carcinoma (ccRCC) patients and focused on tumor-infiltrating CD8+ T lymphocytes (TIL) expressing the HLA-G receptor ILT2. Using transcriptomics and flow cytometry, we characterized both peripheral blood and tumor-infiltrating CD8+ILT2+ T cells from cancer patients as late-differentiated CD27–CD28–CD57+ cytotoxic effectors. We observed a clear dichotomy between CD8+ILT2+ and CD8+PD-1+ TIL subsets. These subsets, which were sometimes present at comparable frequencies in TIL populations, barely overlapped phenotypically and were distinguished by expression of exclusive sets of surface molecules that included checkpoint molecules and activating and inhibitory receptors. CD8+ILT2+ TILs displayed a more mature phenotype and higher expression of cytotoxic molecules. In ex vivo functional experiments with both peripheral blood T cells and TILs, CD8+ILT2+ T cells displayed significantly higher cytotoxicity and IFNγ production than their ILT2– (peripheral blood mononuclear cells, PBMC) and PD-1+ (TILs) counterparts. HLA-G expression by target cells specifically inhibited CD8+ILT2+ T-cell cytotoxicity, but not that of their CD8+ILT2– (PBMC) or CD8+PD-1+ (TIL) counterparts, an effect counteracted by blocking the HLA-G/ILT2 interaction. CD8+ILT2+ TILs may therefore constitute an untapped reservoir of fully differentiated cytotoxic T cells within the tumor microenvironment, independent of the PD1+ TILs targeted by immune therapies, and specifically inhibited by HLA-G. These results emphasize the potential of therapeutically targeting the HLA-G/ILT2 checkpoint in HLA-G+ tumors, either concomitantly with anti–PD-1/PD-L1 or in cases of nonresponsiveness to anti–PD-1/PD-L1.

Background: Local recurrence after radiation therapy for prostate cancer is a major clinical issue. Various local treatments are available with mitigated functional and oncological outcomes. The aim of the present study was to evaluate perioperative and oncological results of salvage cryotherapy (CT) as treatment of local recurrence of prostate cancer. Methods: We retrospectively reviewed all patients treated with hemi-prostatic salvage CT for local recurrence of prostate cancer in 1 academic hospital between November 2011 and April 2019. Local recurrence was defined according to the Phoenix criteria (prostate-specific antigen [PSA] nadir + 2 ng/mL), associated with a prostatic MRI target lesion and confirmed by biopsy. Perioperative and functional complications were collected. Cox regression was conducted to assess factors associated with time to initiation of androgen deprivation therapy (ADT). Statistical analyses were conducted using R Studio. Results: A total of 29 patients were treated with an average follow-up of 37.6 months. Median age at CT was 77 years. Median PSA before CT was 5.1 ng/mL (min-max: 2.74–18). 17.2% of patients displayed a high D’Amico risk group. Median hospital stay was 1.4 days. Four patients (13.8%) experienced postoperative acute urinary retention. Nineteen patients (65.5%) experienced late functional complications (3 erectile dysfunctions, 3 stress incontinence, and 13 urinary frequency). Fourteen patients displayed recurrence after salvage treatment (48.2%). Median time to introduction of ADT was 15.1 months. ADT-free survival at 1 and 2 years was, respectively, 74% and 61%. In multivariate analysis, ISUP score 4 and PSA nadir Conclusions: Salvage focal CT may delay the use of ADT in locally recurrent prostate cancer after RT and offers an alternative for eligible patients. The technique was feasible with acceptable perioperative morbidity and acceptable midterm oncological outcome.

AIM Overtreatment is an actual problem in low risk localized prostate cancer (PC) management. Active surveillance (AS) is a solution to limit this problem, but eligibility criteria remained discussed. The aim was to assess possibilities of widening selection criteria for patient in AS, studying curative treatment free survival (CTFS) according to restricted or expanded eligibility criteria. METHODS We retrospectively studied patients beginning AS between 2008 and 2014, for Gleason 6 localized PC, PSA

Background Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4. Methods Tumor specimens were obtained from patients from two separate cohorts: One from “Evita Pueblo” Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR. Results Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased. Conclusions In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.

International audience; Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in-depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.

We developed and validated an architecture-based grading for clear cell renal cell carcinoma (ccRCC) in an observational retrospective cohort study including 506 tumors (principal cohort, n=254; validation cohort, n=252). Study endpoints were disease-free survival (DFS) and cancer-specific survival (CSS). Relationships with outcome were analyzed using Harrell concordance index, time-dependent receiver operating characteristic curve, area under curve, and Cox regression model. An architecture-based grading was devised on positive likelihood ratio (LR+) for DFS at 50 months as follows: grade 1 (LR+

Inflammation in fibrosis areas (i-IF/TA) of kidney allografts is associated with allograft loss; however, its diagnostic significance remains to be determined. We investigated the clinicohistologic phenotype and determinants of i-IF/TA in a prospective cohort of 1539 kidney recipients undergoing evaluation of i-IF/TA and tubulitis in atrophic tubules (t-IF/TA) on protocol allograft biopsies performed at 1 year posttransplantation. We considered donor, recipient, and transplant characteristics, immunosuppression, and histological diagnoses in 2260 indication biopsies performed within the first year posttransplantation. Nine hundred forty-six (61.5%) patients presented interstitial fibrosis/tubular atrophy (IF/TA Banff grade > 0) at 1 year posttransplant, among whom 394 (41.6%) showed i-IF/TA. i-IF/TA correlated with concurrent t-IF/TA (P

We report the case of a 40-year-old woman who recovered from a diffuse metastatic renal cell carcinoma that developed from a kidney allograft. She was successfully treated by the induction of tumor rejection. Immunosuppression was discontinued, and transplant nephrectomy was deliberately delayed based on the expectation that the tumor mass would trigger the alloimmune response, which was stimulated with pegylated interferon-α-2a. Three years later, the patient remained in complete remission. Despite this severe context, the present case shows that the poor prognosis of allograft metastatic renal cell carcinoma could be dramatically reversed by taking advantage of the donor tumor origin to actively induce a specific alloimmune rejection of the tumor.

The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review. Biopsy tissues were also investigated by CD3, CD20, CD68, CD163, FOXP3 and RORγt immunohistochemical staining. Competing risks models were calculated. Of the 113 patients, 26 (23.0%) died during follow-up and 29 (25.6%) developed ESRD. Among the 94 patients who achieved remission by the end of induction therapy without developing ESRD, 26 (27.6%) experienced RR. The two independent prognostic factors for ESRD were the estimated glomerular filtration rate at presentation (HR 0.35; 95% CI 0.23-0.51; P 0.0001) and IF/TA 25% (HR 2.27; 95% CI 1.18-4.37; P = 0.014). When the distribution of interstitial immune cell phenotypes was included in a second multivariable model, the organization of lymphocytic infiltrates was also an independent predictor of ESRD (HR 2.86; 95% CI 1.35-6.1, P = 0.006). The independent risk factors for RR were a higher CD3/CD20 ratio (HR 1.39; 95% CI 1.05-1.85; P = 0.02) and the presence of RORγt positive cells (HR 2.70; 95% CI 1.11-6.54; P = 0.02). Our results highlight the prognostic value of initial histological evaluations in AAV. Measurements of tubulointerstitial damage and interstitial immune cell phenotype distributions should be considered to improve risk assessments for ESRD and RR.

Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody-mediated rejection (ABMR). We performed a prospective, single-arm pilot study to investigate the potential effects and safety of C1 inhibitor (C1-INH) Berinert added to high-dose intravenous immunoglobulin (IVIG) for the treatment of acute ABMR that is nonresponsive to conventional therapy. Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1-INH and IVIG for 6 months (six patients). The primary end point was the change in eGFR at 6 months after inclusion (M+6). Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6. All patients showed an improvement in eGFR between inclusion and M+6: from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m(2) (p = 0.0277). There was no change in histological features, except a decrease in the C4d deposition rate from 5/6 to 1/6 (p = 0.0455). There was a change in DSA C1q status from 6/6 to 1/6 positive (p = 0.0253). One deep venous thrombosis was observed. In a secondary analysis, C1-INH patients were compared with a similar historical control group (21 patients). C1-INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR.

Objectifs La strategie de prise en charge des oncocytomes reste heterogene de par la crainte d’une croissance tumorale alterant le parenchyme renal restant et de la meconnaissance d’une tumeur mixte. L’objectif de ce travail etait d’evaluer les strategies de prise en charge et l’evolution clinique et radiologique d’une cohorte d’oncocytomes biopsies. Methodes Nous avons revu retrospectivement tous les dossiers de biopsies renales realisees dans deux centres universitaires francais entre 2009 et 2019. Tous les cas d’oncocytomes identifies sur la biopsie renale ont ete extraits. Les donnees suivantes ont ete analysees : âge de la population, terrain genetique, taille de la tumeur sur imagerie et modalites de prise en charge de l’oncocytome. Resultats Cinquante-deux patients ont ete identifies, âge moyen au diagnostic 63 ans, dont un syndrome de Birt–Hogg–Dube. Au total, 18 patients ont ete traites d’emblee (12 par chirurgie partielle et 6 par traitement ablatif percutanee) et 34 n’ont pas eu de traitement actif immediat (25 surveilles et 9 abstentions therapeutiques). La croissance tumorale de l’oncocytome a pu etre evaluee en moyenne a 2 mm par an. La correspondance histologique des biopsies des oncocytomes par rapport a la piece definitive etait de 79 % (1 cellule claire grade 2 et 2 tumeurs hybrides retrouvees). Chez les 25 patients ayant eu une surveillance initiale 5 ont finalement subi un traitement actif (3 cryotherapies, 1 nephrectomie partielle et 1 nephrectomie elargie) motive a chaque fois par croissance tumorale (moyenne 5,2 mm/an). Conclusion Dans notre cohorte, la croissance tumorale etait faible et la surveillance le traitement de choix, cette attitude therapeutique etant adaptee en fonction de la croissance tumorale (plus de 5 mm par an dans notre cohorte) et du terrain particulier (âge jeune, forme familiale connue) faisant craindre une tumeur mixte.

Background Proper usage of renal tumor biopsy (RTB) remains to be determined in the setting of renal tumors diagnosis, particularly in the elderly population. The aim of the study was to evaluate the perioperative and pathological results of RTB in a population of patients over 75 and to compare the performance of the procedure to their younger counterparts. Material and methods Systematic RTB were prospectively performed in a single center between 2009 and 2012. Patients’ and tumor characteristics, operative and pathological results were collected. Data were compared between patients under and over 75 years old. Particular attention was paid to influence of RTB on treatment decision-making. Results A total of 180 patients were included (137 patients 75 years). Size of tumor, clinical stage, radiological aspect and RENAL score were not statistically different between patients under or over 75 years. No difference was observed between the 2 groups regarding complication rate (2.9% vs. 0%, respectively, P = 0.625). One hundred fifty-seven patients (87.2%) had a positive diagnosis at first RTB, with no difference between the 2 groups regarding histology (P = 0.942). After biopsy, only 73.1% of patients 75 years had concordance between radiological and histological findings (P = 0.919). Treatment decision was challenged after RTB in 21.8% of patients 75 years. Conclusions RTB was as safe and accurate in the eldest population, as it is in the general population, and should be performed routinely considering its influence on patient management strategy.

Rationale: Crystal sorting histiocytosis (CSH) is a rare disorder that is morphologically characterized by the accumulation of monoclonal immunoglobulin crystals, predominantly of a kappa light chain type, within lysosomes of macrophages. CSH may result in a variety of clinical manifestations depending on the involved organs. In this case report, we aim to describe a patient with ophthalmic manifestations which lead to the diagnosis of multiple myeloma with crystal-storing histiocytosis, crystalline podocytopathy, and light chain proximal tubulopathy. Patient concerns: A 60-year-old male patient presented with progressive bilateral decreased vision for 2 years. Diagnosis: Ophthalmic explorations showed bilateral macular and papillary edema, and multiple crystalline deposits in the anterior stromal cornea and in the retina. Laboratory tests showed nephrotic syndrome and renal dysfunction. Further work-up revealed IgG kappa multiple myeloma, with biopsy-proven combined crystalline podocytopathy and tubulopathy. Interventions: The patient received chemotherapy (bortezomib, cyclophosphamide, and dexamethasone for 3 cycles, then bortezomib, lenalidomide, and dexamethasone). Outcomes: Despite partial hematologic response and improvement of the papilledema and macular edema, the patient developed dialysis-dependent end-stage renal failure. Lessons: This report, highlighting the protean presentation of paraprotein-mediated injuries, provides additional information on the ocular anomalies not previously described that may be associated with crystal-storing histiocytosis.

Objectifs Le traitement du cancer de vessie (CV) engendre des couts tres eleves et est source de multiples hospitalisations alterant la qualite de vie des patients. Dans ce contexte, la RTUVA permet de reduire les couts en limitant le temps d’hospitalisation. Notre travail avait deux objectifs : rechercher des facteurs associes a la survenue de complications postoperatoires et etudier l’influence d’une RTUVA sur les Resultats oncologiques. Methodes Notre etude retrospective monocentrique a porte sur tous les patients traites pour un cancer de la vessie par RTUVA entre fevrier 2016 et decembre 2018. Les criteres suivant ont ete analyses : – complications postoperatoires selon Clavien–Dindo, taux de conversion en hospitalisation conventionnelle, taux de consultation aux urgences et de rehospitalisation secondaire ; – resultats anatomopathologiques (stade, grade, presence de CIS), qualite oncologique de la RTUVA jugee par la presence de muscle sur les copeaux de resection, survie sans recidive a 12 et 24 mois. Une regression logistique a ete realisee afin d’identifier les facteurs associes a la survenue de complication. Analyses conduite avec R version 3.3.2. Resultats Cent quatre-vingt-sept patients consecutifs ont ete inclus d’âge moyen 64 ans. Pour 119 patients (64 %) il s’agissait de la resection d’une recidive (en moyenne 1,6 resections anterieures). Parmi les lesions, 53,5 % etaient multifocales, avec un nombre et une taille moyens respectivement de 2,3 et 1,3 cm. Le muscle etait present dans 79 % des cas. Dans 3 % des cas la tumeur etait infiltrante. Une complication postoperatoire est survenue chez 33 patients (17,6 %) dont une majorite de Clavien 2. Vingt patients (10,7 %) ont necessite une conversion en hospitalisation, 8 (4,3 %) une rehospitalisation et 16 (8,6 %) une consultation aux urgences. Le nombre de tumeurs resequees etait le seul zfacteur associe a la survenue d’une complication (OR = 1,20, p = 0,04). Les survies sans recidive a 12 et 24 mois etaient de 80 et 62 %. Conclusion La RTUVA apparait etre une technique sure, avec un taux de complications de 17 %, qui n’altere ni la qualite de la resection ni les resultats carcinologiques. Le seul facteur associe a la survenue d’une complication est le nombre de tumeurs resequees.

We report here the case of a young patient with metastatic clear-cell sarcoma of the kidney resistant to standard chemotherapy, and with complete response under sorafenib treatment. The remarkable response of her tumor to sorafenib led us to study sorafenib molecular targets in the metastatic tissue. Background: Biomarkers predicting response to anti-angiogenic tyrosine kinase inhibitors remain to be identified. Methods and Findings: In this paper, we studied the molecular targets of sorafenib in the lung metastasis of a kidney clear-cell sarcoma. In a patient with complete response under sorafenib treatment, we showed high VEGFR2 expression by tumor endothelial cells from the lung metastasis. Conclusion: The original mechanistic results that we obtained using immunostainings and quantitative RT-PCR on laser-microdissected tumor endothelial cells have a direct application in daily clinical practice: metastatic tumors with a large angiogenic component should be tested for VEGFRs expression to consider anti-angiogenic tyrosine kinase inhibitor treatments.

Hantavirus nephropathy (HVN) is an uncommon etiology of acute renal failure due to hantavirus infection. Pathological features suggestive of HVN historically reported are medullary interstitial hemorrhages in a background of acute interstitial nephritis (AIN). However, interstitial hemorrhages may be lacking because of medullary sampling error. This emphasizes that other pathological criteria may be of interest. We performed a retrospective clinicopathological study of 17 serologically proven HVN cases with renal biopsy from 2 nephrology centers in northern France. Histologic analysis was completed by immunohistochemistry with anti-CD3, anti-CD68, and anti-CD34 antibodies. Three control groups were not related to hantavirus infection: acute tubular necrosis (ATN) of ischemic or toxic etiology and AIN were used for comparison. Renal biopsy analysis showed that almost all HVN cases with medullary sampling (9/10) displayed interstitial hemorrhages, whereas focal hemorrhages were detected in 2 of the 7 "cortex-only" specimens. ATN was common, as it was present in 15 (88.2%) of 17 HVN cases. By contrast, interstitial inflammation was scarce with no inflammation or only slight inflammation, representing 15 (88.2%) of 17 cases. Moreover, HVN showed inflammation of renal microvessels with cortical peritubular capillaritis and medullary vasa recta inflammation; peritubular capillaritis was significantly higher in HVN after comparison with ischemic and toxic ATN controls (P = .0001 and P = .003, respectively), but not with AIN controls. Immunohistochemical studies highlighted the involvement of T cells and macrophages in renal microvascular inflammation related to HVN. Our study showed that microvascular inflammation, especially cortical peritubular capillaritis, and ATN are important histologic features of HVN.

// Francois Desgrandchamps 1, 2, * , Joel LeMaoult 1, 3, * , Annabelle Goujon 1, 2 , Adrien Riviere 1, 2 , Antonio Rivero-Juarez 1, 4 , Malika Djouadou 1, 2 , Amory de Gouvello 1, 2 , Clement Dumont 1, 5 , Ching-Lien Wu 1, 3 , Stephane Culine 1, 5 , Jerome Verine 1, 6 , Nathalie Rouas-Freiss 1, 3 , Christophe Hennequin 1, 7 , Alexandra Masson-Lecomte 1, 2 and Edgardo D. Carosella 1, 3 1 CEA, DRF-Francois Jacob Institute, Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France 2 AP-HP, Saint-Louis Hospital, Department of Urology, Paris, France 3 University Paris Diderot, Sorbonne Paris Cite, UMR E_5 Institut Universitaire d’Hematologie, Saint-Louis Hospital, Paris, France 4 Infectious Diseases Unit, Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Hospital Universitario Reina Sofia, Universidad de Cordoba, Cordoba, Spain 5 AP-HP, Saint-Louis Hospital, Department of Medical Oncology, Paris, France 6 AP-HP, Saint-Louis Hospital, Department of Pathology, Paris, France 7 AP-HP, Saint-Louis Hospital, Department of Radiotherapy, Paris, France * These authors contributed equally to this work Correspondence to: Joel LeMaoult, email: Joel.LeMaoult@cea.fr Keywords: ILT2; HLA-G; immune checkpoint; bladder; cancer Received: January 20, 2018 Accepted: August 03, 2018 Published: September 04, 2018 ABSTRACT Background and Objective: Recurrence of non-muscle invasive bladder cancer (NMIBC) after initial management occurs in 60–70% of patients. Predictive criteria for recurrence remain only clinical and pathological. The aim of this study was to investigate the prognostic significance of the proportion of checkpoint HLA-G’s receptor ILT2-expressing peripheral CD8 + T cells. Results: The proportion of CD4 + ILT2 + and CD8 + ILT2 + T cells was not increased in NMIBC compared to controls. However, a strong association was found between recurrence and CD8 + ILT2 + T cell population levels ( p = 0.0006). Two-year recurrence-free survival was 83% in patients with less than 18% CD8 + ILT2 + T cells, 39% in the intermediary group, and 12% in patients with more than 46% CD8 + ILT2 + T cells. Multivariate analyses demonstrated that the proportion of CD8 + ILT2 + T cells was an independent predictive factor for recurrence. Adding CD8 + ILT2 + T cells population level to clinical variables increased the predictive accuracy of the model by 4.5%. Materials and Methods: All patients treated for NMIBC between 2012 and 2014 were included prospectively. Blood samples, tumor and clinico-pathological characteristics were collected. HLA-G expression was measured using IHC, and CD8 + ILT2 + T cell levels using flow cytometry. Association between HLA-G and CD8 + ILT2 + T cell population levels with NMIBC risk of recurrence was investigated using Cox regression analyses. Prediction was measured using the concordance index statistic. Conclusions: We demonstrated a strong association between the proportion of circulating CD8 + ILT2 + T cells and NMIBC risk of recurrence. Gain in prediction was substantial. If externally validated, such immunological marker could be integrated to predict NMIBC recurrence.

BACKGROUND: Existing data suggest that increased interstitial fibrosis may occur abnormally in renal transplants from donations after uncontrolled circulatory death (uDCD). METHODS: To evaluate the factors that are associated with the progression of fibrosis and its functional impact on renal grafts, we compared 76 uDCD recipients with 86 recipients of kidney donations after brain death at 1-year after transplantation. Groups were matched for donor age, rank of transplantation, and absence of human leukocyte antigen sensitization. Histology was performed on sequential biopsies in uDCD recipients. Associations between variables were analyzed using linear mixed models and univariate analyses. RESULTS: In the uDCD group, increased fibrosis was detected 3 months after transplantation compared to before implantation. After 1 year, interstitial fibrosis and tubular atrophy score was significantly greater (1.5±0.7 vs. 1.0±0.9; P=0.003) and estimated glomerular filtration rate (49.5±17.4 vs. 60.6±19.1 mL/min/1.73 m2; P=0.0003) was significantly lower in the uDCD group than in the donations after brain death group. No flow duration and donor age were significantly associated with accelerated fibrosis. Interstitial fibrosis and tubular atrophy score, interstitial inflammation score, and estimated glomerular filtration rate were significantly worse in uDCD patients with no flow longer than 10 min. CONCLUSION: Donations after uncontrolled circulatory death grafts show more fibrosis after transplantation. No flow duration is associated with accelerated fibrosis and should be considered during uDCD graft allocation.

Background Henoch-Schonlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P

Background Kidney graft survival in simultaneous pancreas–kidney (SPK) recipients is known to decrease after pancreas graft failure. Methods Sixty-three consecutive SPK recipients were retrospectively reviewed. Kidney graft function and proteinuria were evaluated at three months after the transplantation and at last follow-up. Histopathologic findings of protocol biopsies performed three months and one yr after transplantation were analyzed. Results Twelve patients lost the pancreas graft. Donors' characteristics were similar in patients with or without pancreas failure. After a median follow-up of 36 months, mean eGFR with a functional pancreas was 69.5 mL/min/1.73 m² vs. 56.3 mL/min/1.73 m² (p = 0.01) after pancreas loss. Patients who lost pancreas had a median proteinuria of 0.28 g vs. 0.13 g per 24 h (p = 0.02). Analysis of three-month protocol biopsies revealed more frequent isolated glomerulitis after pancreas failure (p = 0.0001), without peritubular capillaritis or C4d deposition. No donor-specific anti-HLA antibodies were detectable in these patients. Chronic tubulointerstitial changes were more frequent in patients with pancreas loss. There was no evidence of diabetic nephropathy recurrence. Conclusion SPK recipients develop an early kidney graft dysfunction after pancreas failure. Histopathologic findings revealed frequent glomerulitis without antibody-mediated rejection and early chronic changes.

Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16–2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11–2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell–mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus–associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA–associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of premature and accelerated allograft fibrosis acting independently of traditional risk factors and antibody-mediated rejection.

Resume La nephropathie a immunoglobulines A (IgA) est la glomerulonephrite primitive la plus repandue au monde. Elle est responsable d’une insuffisance renale progressive evoluant vers l’insuffisance renale terminale dans pres d’un tiers des cas. Les mecanismes physiopathologiques de cette pathologie mediee par des complexes immuns restent encore non elucides. La presentation et l’evolution clinique, ainsi que l’aspect en microscopie optique de la biopsie renale peuvent etre extremement variables, rendant toute classification histologique difficile. La plupart des etudes therapeutiques n’incluent donc jusqu’a present les patients que sur des criteres cliniques de gravite. La nouvelle classification d’Oxford devrait changer cette situation. Seule la prise en charge des patients ayant une nephropathie avec lesions glomerulaires minimes et syndrome nephrotique, ou une glomerulonephrite extracapillaire et une insuffisance renale rapidement progressive, est consensuelle, avec traitement par corticoides seuls pour les premiers et associes a des immunosuppresseurs pour les seconds. Une corticotherapie peut etre discutee chez les patients ayant une proteinurie superieure a 1 g/j sans insuffisance renale. Tous les patients atteints de nephropathie a IgA doivent beneficier de la prise en charge globale d’une glomerulopathie chronique, comprenant notamment un traitement par bloqueur du systeme renine-angiotensine en presence d’une hypertension arterielle ou d’une proteinurie.

Primary adenocarcinoma of the seminal vesicle is a rare condition with only about 60 cases described in the literature. The unusual characteristics of this disease makes diagnosis difficult and treatment strategies differ as there are no specific guidelines available. This report presents a case of adenocarcinoma of the seminal vesicle with lung metastases in which surgical and chemotherapeutic treatments have been carried out. The MVAC dose dense regimen following local resection seems effective in this scenario and may be used in the treatment of this disease.

Introduction Le diagnostic de vascularites associees aux anticorps anticytoplasme des polynucleaires neutrophiles (AAV) repose sur la ponction-biopsie renale. Une classification histologique glomerulaire proposee en 2010 par Berden et al. aide a etablir le pronostic renal de ces patients atteints d’AAV [1] . Le but de notre etude etait de reevaluer la valeur pronostique de cette classification et de determiner les facteurs de risque de rechute renale. Patients et methodes Les donnees clinicobiologiques et histologiques de 113 patients atteints d’une AAV renale, diagnostiquee entre 2003 et 2013, ont ete recueillies dans cette etude retrospective et multicentrique. Resultats Notre etude permettait de valider cette classification en analyse de survie renale et globale. La survie renale a 1 an et 5 ans etait respectivement de 94 % et 89,5 % pour le groupe focal, 80 % et 80 % pour le groupe croissant, 82 % et 66,5 % pour la classe mixte, 72 % et 54,5 % pour le groupe sclereux. En analyse multivariee, une fibrose interstitielle (CI > 25 % ; p = 0,01) et un debit de filtration glomerulaire bas au diagnostic (p 25 % partageaient la meme survie renale que le groupe sclereux alors que ceux ayant ≤ 25 % de CI avait un pronostic renal intermediaire avec la classe focale. Enfin, une duree plus longue d’immunosuppression en entretien et un infiltrat interstitiel > 25 % etaient les deux seuls facteurs protecteurs d’une rechute renale en analyse multivariee (p = 0,0004 et p = 0,016 respectivement). Discussion L’evaluation du degre de fibrose interstitielle apparait determinante dans cette etude et s’averait plus discriminante que la classification de Berden et al. pour juger du pronostic renal. Conclusion Nous avons valide la classification de Berden et al. en termes de survie renale et globale. Neanmoins, Berden et al. n’etaient pas un facteur pronostique independant, a la difference de la fibrose interstitielle. Proposer une classification de Berden et al. modifiee par la fibrose interstitielle pourrait etre interessante pour ameliorer l’evaluation des capacites de recuperation des patients atteints d’AAV renale a partir de donnees histologiques initiales.

OBJECTIVE To study the natural history of renal cell carcinoma (RCC) development in renal grafts and their management. PATIENTS AND METHODS We report a single-centre series of de novo RCC in allografts from a cohort of 2396 consecutive renal transplant recipients. RESULTS In all, 17 RCCs were detected in 12 patients, representing 0.5% of kidney recipients. The mean patient age was 55 years and the time to RCC diagnosis since transplantation was 13 years. The mean diameter of the RCC was 23 mm. Biopsies were taken in all cases. Concordance between biopsy and surgical specimens was 100% for nuclear grade and pathological type. Four graft removals were performed and six patients underwent nephron-sparing surgery (NSS). Two cryoablations were performed. Overall, nine papillary RCC, five clear cell carcinomas, and one chromophobe cell carcinoma were removed surgically. The mean follow-up was 43 months. One local recurrence was reported in a patient treated by NSS. CONCLUSIONS Our findings support evidence that radiological screening of kidney recipients allows the detection of small tumours for which a conservative management by NSS or non-surgically destructive techniques can be proposed with mid-term oncological safety. Systematic tumour biopsy may help in the management and treatment decision. Several questions remain unanswered such as the importance of mammalian target of rapamycin inhibitors in the chemoprevention of the recurrence and the genetic cell origin of RCC in renal grafts.

We report a 46-year-old man who has sex with men (MSM) patient, of Scottish descent, who had no history of arterial hypertension, diabetes, or illicit drug use, was hepatitis C virus (HCV) negative but underwent right nephrectomy for urothelial tumor in 2006. Before starting antiretroviral therapy, he had a CD4 cell count of 316/mm(3) and plasma HIV RNA level was 1,020,537 copies per milliliter. He developed acute renal failure only 2 weeks after introduction of tenofovir-based antiretroviral therapy and then required 3 months of hemodialysis. After the end of hemodialysis, antiviral therapy was resumed with abacavir (300 mg×2/day), lamivudine (300 mg every day), and lopinavir/ritonavir (400/100 mg twice daily). Renal biopsy revealed severe and diffuse toxic acute tubular necrosis Two years after tenofovir discontinuation, the patient's renal function remained subnormal. Although severe renal toxicity due to tenofovir is rare, patients receiving tenofovir must be monitored closely for renal dysfunction especially during the first weeks of tenofovir therapy.

BACKGROUND Most recent trials in human leukocyte antigen (HLA)-identical living donor (LD) renal transplantation have used immunosuppressive regimens with no induction therapy, corticosteroid-free long-term treatment, and calcineurin inhibitor minimization. PATIENTS AND METHODS Seven HLA-identical LD recipients were prospectively enrolled. Immunosuppression included induction therapy with antithymocyte globulins for 10 days and long-term monotherapy with mycophenolate mofetil (2 g/day) in six cases and sirolimus (target trough levels: 6-10 ng/mL) in the last case. A single preoperative steroid bolus was administered. RESULTS After a median follow-up time of 26 months (range: 5-50 months), patient and graft survival was 100%. Only one patient experienced borderline lesions at 3 months and received steroids for a 5-month period. All patients had a protocol biopsy at 3 months, and four had a second at 12 months. Acute cellular rejection was not observed. Median serum creatinine at 3 months, 12 months, and last follow-up were 103.1, 107.1, and 106.1 [mu]mol/L, respectively. For four patients, measured glomerular filtration rate was evaluated at 3 months, and the mean value was 71.2 mL/min/1.73 m2. CONCLUSIONS Induction therapy with antithymocyte globulins followed by mycophenolate mofetil or sirolimus monotherapy provides excellent patient and graft survival, excellent renal function, and no acute rejection episodes in HLA-identical LD renal transplant recipients.

Introduction Les vascularites granulomateuses renales sans atteinte glomerulaire sont des pathologies rares dont la presentation, les etiologies, la prise en charge et le pronostic sont mal connus. Patients/materiels et methodes Etude retrospective multicentrique regroupant tous les cas histologiquement prouves de vascularites granulomateuses sans atteinte glomerulaire entre 1985 et 2017. Resultats Treize patients etaient inclus, dont 5 hommes (âge median 60 ans, etendue 30–73). Les patients presentaient des signes generaux avec un syndrome grippal (n = 12) et une HTA inconstante (n = 4). Il existait une insuffisance renale aigue (creatininemie mediane 3,4 mg/dL [1,4–9,5]) associee a une faible proteinurie (n = 12) (0,45 g/g [0–2,6]) et un syndrome inflammatoire biologique (CRP mediane 144 mg/L [11–209]). L’hematurie et la leucocyturie etaient inconstantes (respectivement n = 8 et n = 6). Les atteintes extrarenales etaient articulaires (n = 4), pulmonaire (n = 3), neurologique (n = 3), ophtalmologique (n = 3), ORL (n = 3) et hepatique (n = 3). Toutes les biopsies renales retrouvaient une inflammation granulomateuse des arteres (n = 11) et/ou des arterioles (n = 8) et rarement de l’interstitium (n = 3). Les diagnostics finaux retenus etaient les suivants : 3 vascularites pauci-immunes, 2 sarcoidoses, 2 vascularites medicamenteuses (antibiotiques et AINS), une peri-arterite noueuse (PAN), une cryoglobulinemie et 3 d’origine indeterminee. Une corticotherapie etait instauree pour tous les patients excepte un des patients presentant une vascularite medicamenteuse. L’evolution etait marquee par un deces (hemorragie cerebrale en lien avec la PAN), une insuffisance renale terminale chez 3 patients (2 vascularites pauci-immunes et une sarcoidose), et une amelioration de la fonction renale pour les autres patients (DFG estime median 70 mL/min/1,73 m2 [32–104]), l’evolution la plus favorable concernant les vascularites medicamenteuses (DFG estime 74 et 104 mL/min/1,73 m2). Conclusion Le diagnostic etiologique des vascularites granulomateuses est varie et peut etre difficile. Le pronostic est tres variable selon l’etiologie et semble plus favorable dans les cas attribues a une prise medicamenteuse.

Different strategies appear to improve the success in treatment of antibody-mediated rejection (AMR), although no one best method has yet emerged. The objective of this study was to compare the efficacy of the combination of Plasmapheresis/intravenous immunoglobulin (IVIg)/anti-CD20-based regimes versus high-dose IVIg alone in the treatment of AMR. Group A (12 patients) was treated with high-dose IVIg between January 2000 and December 2003; group B (12 patients) was treated by Plasmapheresis/IVIg/anti-CD20 between January 2004 and December 2005. Graft survival at 36 months was 91.7% in group B versus 50% in group A (p = 0.02). Donor-specific human leukocyte antigens (DSA) levels detected by Luminex single antigen (Luminex SA) and ELISA, 3 months postrejection are significantly lower in group B than in group A: DSA ELISA class 2 score 6-8 (p = 0.02), DSA mean intensity of fluorescence (MFI) max (p = 0.009) and DSA mean MFI (p = 0.0004). The persistence of elevated DSA levels posttreatment is more frequent in patients with graft loss as compared to those with preserved renal function: score 6-8 on ELISA (p = 0.04); mean MFI (p = 0.00009) and MFImax (p = 0.018). We conclude that: (1) high dose IVIg alone is inferior to Plasmapheresis/IVIg/anti-CD20 as therapy for AMR and (2)DSA postrejection can be quantified using solid phase assays, showing that 3 months after AMR, DSA levels are higher in patients with graft loss.

This study reports the case of an HIV-infected patient with disseminated tuberculosis who presented an immune reconstitution inflammatory syndrome (IRIS) revealed by an acute kidney disease 45 and 15 days after initiation of antituberculosis therapy and HAART, respectively. Prednisone therapy and the transient withdrawal of HAART improved the renal function and the clinical condition of this patient. All published case reports of IRIS revealed by acute renal failure in HIV-infected patients are also reviewed.