Publications by authors named "Pierre Merville"

114 Publications

Evolution of body composition following successful kidney transplantation is strongly influenced by physical activity: results of the CORPOS study.

BMC Nephrol 2021 Jan 18;22(1):31. Epub 2021 Jan 18.

AURAD Aquitaine, Gradignan, France.

Background: Weight gain (mainly gain of fat mass) occurs quickly after successful kidney transplantation and is associated with metabolic complications (alterations of glycaemic control, hyperlipidaemia). Determinants of weight gain are multifactorial and are mainly related to the transplant procedure itself (glucocorticoid use, increased appetite). In the modern era of transplantation, one challenge is to limit these metabolic alterations by promoting gain of muscle mass rather than fat mass. This prospective study was performed to assess determinants of fat mass, fat-free mass and body cell mass changes after kidney transplantation with a focus on physical activity and nutritional behaviour before and after transplantation.

Methods: Patients were included at the time of listing for deceased donor kidney transplantation. Body composition was determined using dual X-ray absorptiometry and bioimpedance spectroscopy to assess fat mass, fat-free mass and body cell mass (= fat-free mass - extracellular water) at the time of inclusion, 12 months later, and 1, 6, 12 and 24 months after transplantation. Recall dietary data and physical activity level were also collected.

Results: Eighty patients were included between 2007 and 2010. Sixty-five had a complete 24-month follow-up after kidney transplantation. Fat mass, fat-free mass and body cell mass decreased during the waiting period and early after kidney transplantation. The nadirs of body cell mass and fat-free mass occurred at 1 month and the nadir for fat mass occurred at 6 months. Maximum levels of all parameters of body composition were seen at 12 months, after which body cell mass and fat-free mass decreased, while fat mass remained stable. In multivariate analysis, male recipients, higher physical activity level and lower corticosteroid dose were significantly associated with better body cell mass recovery after kidney transplantation.

Conclusions: Lifestyle factors, such as physical activity level, together with low dose of corticosteroids seem to influence body composition evolution following kidney transplantation with recovery of body cell mass. Specific strategies to promote physical activity in kidney transplant recipients should be provided before and after kidney transplantation.
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http://dx.doi.org/10.1186/s12882-020-02214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814641PMC
January 2021

Reply to Coussement et al.

Clin Infect Dis 2021 Jan 15. Epub 2021 Jan 15.

Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.

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http://dx.doi.org/10.1093/cid/ciab022DOI Listing
January 2021

Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study.

Clin Transplant 2020 Dec 28:e14207. Epub 2020 Dec 28.

CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèse, Hôpital Pellegrin, Bordeaux, France.

After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p = .37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p = .09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.
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http://dx.doi.org/10.1111/ctr.14207DOI Listing
December 2020

Efficacy of plasmapheresis and semi-selective immunoadsorption for removal of anti-HLA antibodies.

J Clin Apher 2020 Nov 30. Epub 2020 Nov 30.

CNRS UMR 5164, ImmunoConcEpT, Univ. Bordeaux, Bordeaux, France.

Background: In organ transplantation, apheresis is frequently used for removal of anti-HLA antibodies. However, it is unclear whether plasmapheresis (PP) or semi-selective immunoadsorption (IA) should be employed, and the optimal number of apheresis sessions required to reach post-treatment objectives is also unknown.

Methods: We enrolled 43 patients from Bordeaux University Hospital who were treated with PP (n = 29) or IA (n = 14) for antibody-mediated rejection or pre-transplant desensitization. Using Luminex single-antigen flow beads, we assessed the initial mean fluorescence intensity (MFI) of 1416 positive beads with MFIs obtained after 7 to 8 apheresis sessions (extended protocol) and, if a serum was available, after the first four sessions (short protocol).

Results: MFI reduction after extended apheresis protocol was stronger with IA [87% (61%-100%)] than with PP [73% (22%-100%)] (P < .001). Indeed, 59% of the beads had a final MFI < 2000 with IA, whereas only 38% with PP (P < .001). The efficacy of removal depended on initial MFI but not on HLA specificity. A short protocol of apheresis showed excellent results without superiority of IA over PP for antibodies with an initial MFI < 3000. For antibodies showing MFI ≥2000 after four sessions, the residual MFI predicted the effectiveness of four additional sessions.

Conclusion: Monitoring the MFI of anti-HLA antibodies before and during apheresis protocol can guide physicians in the selection of apheresis technique and the number of sessions to be performed.
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http://dx.doi.org/10.1002/jca.21858DOI Listing
November 2020

The incidence of post-transplant malignancies in kidney transplant recipients treated with Rituximab.

Clin Transplant 2021 Feb 12;35(2):e14171. Epub 2020 Dec 12.

Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France.

Background: Rituximab has been proposed as induction therapy in kidney transplant recipients (KTRs) with preformed donor-specific antibodies (DSA) or a positive flow cross-match. We here evaluated whether adding rituximab was associated with a higher incidence of post-transplant malignancies (PTM) due to greater immunosuppression.

Patients And Methods: Forty-eight HLA-sensitized KTRs received induction therapy with anti-thymocyte globulin (ATG) and rituximab because of preformed DSA or a positive flow cross-match (RTX group). They were compared with a control group of 154 patients receiving ATG alone.

Results: Thirty-nine of 202 (19.3%) patients developed PTM; the rate was similar in the RTX and no-RTX groups (14.6% vs. 20.8%, respectively, P = .3). The distributions of the types of cancer were similar between the two groups, with the majority being non-melanoma skin cancer (NMSC, n = 24). The risk factors for PTM were male gender, age, history of cancer, and azathioprine.

Conclusion: Our data do not indicate a higher rate of post-transplantation de novo malignancies after kidney transplantation in high-immunological risk patients who received induction therapy based on ATG and rituximab.
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http://dx.doi.org/10.1111/ctr.14171DOI Listing
February 2021

Identification of predictive markers and outcomes of late-onset Pneumocystis jirovecii pneumonia in kidney transplant recipients.

Clin Infect Dis 2020 Oct 23. Epub 2020 Oct 23.

Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.

Background: In the era of prophylaxis, Pneumocystis pneumonia has become a late-onset opportunistic infection requiring indications for prolonged prophylaxis to be defined. The primary objective of our study was therefore to evaluate risk factors associated with late-onset Pneumocystis pneumonia. The secondary objective was to assess the impact of this infection on graft and patient survival.

Methods: We conducted a French case-control study in Bordeaux and Toulouse center by matching 1 case to 1 or 2 controls from the same center based on the transplant date and the type of induction treatment.

Results: Seventy cases and 134 controls were included. Pneumocystis pneumonia occurred at a median of 3 years after transplantation. The total lymphocyte count, CD4+ and CD8+ T lymphocytes values were lower in the cases than in their matched controls on the day of infection and annually up to 4 years earlier. The covariables independently associated with Pneumocystis pneumonia were the total lymphocyte count one year before Pneumocystis, mTOR inhibitors used as maintenance immunosuppressive drugs and the administration of corticosteroid boluses used in acute rejection. A total lymphocyte count threshold <1000/µL offered the best predictive value for infection occurrence. Pneumocystis pneumonia was associated with high incidence of graft loss and patient death (30% and 17% respectively, three years after PCP).

Conclusions: Pneumocystis pneumonia has dramatic consequences in kidney transplant recipients and a targeted prophylaxis based on simple criteria, such as chronic lymphopenia and/or history of corticosteroid boluses could be useful to avoid life-threatening complications.
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http://dx.doi.org/10.1093/cid/ciaa1611DOI Listing
October 2020

Understanding human γδ T cell biology toward a better management of cytomegalovirus infection.

Immunol Rev 2020 Nov 22;298(1):264-288. Epub 2020 Oct 22.

ImmunoConcEpT UMR 5164, CNRS, Bordeaux University, Bordeaux, France.

Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αβ and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients.
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http://dx.doi.org/10.1111/imr.12922DOI Listing
November 2020

A Randomized Prospective Study Comparing Anti-T-Lymphocyte Igs to Basiliximab in Highly Sensitized Kidney Transplant Patients.

Kidney Int Rep 2020 Aug 2;5(8):1207-1217. Epub 2020 Jun 2.

Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France.

Background: Two prospective studies that were performed before the era of highly sensitive solid-phase assays have shown a lower incidence of acute rejection in highly sensitized kidney-transplant patients given polyclonal antibodies compared with those given anti-CD25 monoclonal antibodies.

Methods: This prospective pilot randomized French multicenter study aimed to compare anti-T-lymphocyte Ig (ATLG) ( = 32) and basiliximab ( = 27) in highly sensitized kidney-transplant patients without preformed donor-specific antibodies (pDSAs) as assessed by a Luminex Single-Antigen flow bead assay. Only patients with a calculated panel reactive antibody ≥50%, with at least 1 antibody with a mean fluorescence intensity ≥5000 and without a historical pDSA and without a pDSA on the day of transplantation were included.

Results: Treatment failure as defined by biopsy-proven acute rejection, patient lost to follow-up, graft loss, and death was observed in 18.8% (95% confidence interval [CI], 8.9%-37.1%) and 18.8% (95% CI, 8.9%-37.1%) in patients who received ATLG and 14.8% (95% CI, 5.8%-34.8%) and 28.2% (95% CI, 14.2%-51.2%) of patients who received basiliximab, respectively at 6 ( = 0.66) and 12 ( = 0.62) months post-transplantation. One T cell-mediated rejection was observed in ATLG-treated patients (3.1%). One antibody-mediated rejection due to a donor-specific antibody (DSA) occurred in basiliximab-treated patients (3.7%). Patient survival, graft survival, kidney parameters, and infection rate were similar in the 2 groups.

Conclusion: This pilot study indicates that in highly sensitized kidney-transplant patients without pDSAs, both ATLG and basiliximab can be used efficiently and safely. However, because of the lack of power, these results should be interpreted with caution.
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http://dx.doi.org/10.1016/j.ekir.2020.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403559PMC
August 2020

Distribution of Donor-Specific Antibody Subclasses Quantified by Mass Spectrometry: High IgG3 Proportion Is Associated With Antibody-Mediated Rejection Occurrence and Severity.

Front Immunol 2020 2;11:919. Epub 2020 Jun 2.

Department of Nephrology, Dialysis and Transplantation, Montpellier University Hospital, University of Montpellier, Montpellier, France.

Donor-specific antibodies (DSAs) are the main risk factor for antibody-mediated rejection (ABMR) and graft loss but could have variable pathogenicity according to their IgG subclass composition. Luminex-based test might lack sensitivity for the detection of IgG subclasses and this test does not allow quantifying the relative abundance of each IgG subclass. We investigated the precise repartition of each DSA subclass and their role in ABMR occurrence and severity, using an innovative mass spectrometry-based method. Between 2014 and 2018, we enrolled 69 patients who developed DSA ( = 29 without ABMR, and = 40 with ABMR) in two transplant centers. All IgG subclasses were detected in every samples tested: 62.7% were IgG1, 26.6% were IgG2, 6.6% were IgG3, and 4.2% were IgG4. The IgG3 proportion was significantly higher in the ABMR+ compared to the ABMR- group (8.4% vs. 5.6%, = 0.003). The proportion of IgG1, IgG2, and IgG4 of DSA was similar between the two groups. Higher IgG3 level was associated with higher C4d deposition, higher microvascular inflammation scores, and glomerular filtration rate decline >25%. IgG3 proportion was not correlated with DSA MFI. Multivariate analysis showed that proteinuria and high level of IgG3 DSA were the only two factors independently associated with ABMR. In conclusion, DSA are always composed of the four IgG subclasses, but in different proportions. High IgG3 proportion is associated with ABMR occurrence and severity and with poorer outcome, independently of DSA MFI.
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http://dx.doi.org/10.3389/fimmu.2020.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326073PMC
June 2020

Poor kidney graft survival in anorexia nervosa patients.

Eat Weight Disord 2020 Jul 15. Epub 2020 Jul 15.

Service de Néphrologie Transplantation Dialyse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Background: Anorexia nervosa is a condition associated with poor outcomes in a variety of circumstances such as recurrence of eating disorders, psychiatric disorders, and organ damage.

Objective: In the present study, we first sought to determine the 5-year kidney graft survival in patients with anorexia nervosa and then to evaluate the BMI course and medical complications.

Methods: In this multicenter, retrospective, case-control study, we analyzed the impact of anorexia nervosa on graft outcomes compared to transplant recipients with low or normal BMI.

Results: We enrolled 137 women in this study: 19 with anorexia nervosa, 59 with low BMI (BMI < 18.5 kg/m), and 59 with normal BMI (18.5-24.9 kg/m). Anorexia nervosa was significantly associated with lower graft survival compared to either of the other groups (hazard ratio 5.5 [95% CI 3.4-8.9], p = 0.005); there was no difference in graft survival between patients with low or normal BMI. Cardiovascular complications were more frequent in the anorexia nervosa group (37%) than in patients with low (6%) or normal BMI (7%) (p = 0.001).

Conclusion: We conclude that patients with anorexia nervosa should be considered a high-risk group.

Level Of Evidence: Level III, evidence obtained from well-designed cohort or case-control analytic studies.
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http://dx.doi.org/10.1007/s40519-020-00959-8DOI Listing
July 2020

Characterization of a Unique γδ T-Cell Subset as a Specific Marker of Cytomegalovirus Infection Severity.

J Infect Dis 2021 Feb;223(4):655-666

Univ. Bordeaux, CNRS, ImmunoConcEpT, Bordeaux, France.

Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the Vγ9posVδ2pos T cells that respond to phosphoantigens but not to CMV. A third Vγ9negVδ2pos subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these Vγ9negVδ2pos T cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδ T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2pos T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T cells responded specifically to CMV-infected cells in a T-cell receptor-dependent manner and through strong interferon γ production. Finally, Vγ9negVδ2pos T cells were the only γδ T-cell subset in which expansion was tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T cells as an immune marker for CMV disease severity in immunocompromised patients.
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http://dx.doi.org/10.1093/infdis/jiaa400DOI Listing
February 2021

The FcγRIIIA-158 VV genotype increased the risk of post-transplant lymphoproliferative disorder in T-cell-depleted kidney transplant recipients - a retrospective study.

Transpl Int 2020 Aug 14;33(8):936-947. Epub 2020 May 14.

EA7501 « Groupe Innovation et Ciblage Cellulaire » team « Fc Receptors, Antibodies and Microenvironment », University of Tours, Tours, France.

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication in organ transplant recipients. The use of T lymphocyte-depleting antibodies (TLDAb), especially rabbit TLDAb, contributes to PTLD, and the V158F polymorphism of Fc gamma receptor IIIA (FcγRIIIA) also named CD16A could affect the concentration-effect relationship of TLDAb. We therefore investigated the association of this polymorphism with PTLD in kidney transplant recipients. We characterized the V158F polymorphism in two case-control cohorts (discovery, n = 196; validation, n = 222). Then, we evaluated the binding of rabbit IgG to human FcγRIIIA-158V and FcγRIIIA-158F. The V158F polymorphism was not linked to PTLD in the overall cohorts, but risk of PTLD was increased in VV homozygous recipients receiving TLDAb compared with F carriers in both cohorts, especially in recipients receiving TLDAb without muromonab (discovery: HR = 2.22 [1.03-4.76], P = 0.043, validation: HR = 1.75 [1.01-3.13], P = 0.049). In vitro, we found that the binding of rabbit IgG to human NK-cell FcγRIIIA was increased when cells expressed the 158-V versus the 158-F allotype. While the 158-V allotype of human FcγRIIIA binds rabbit immunoglobulin-G with higher affinity, the risk of PTLD was increased in homozygous VV kidney transplant recipients receiving polyclonal TLDAb.
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http://dx.doi.org/10.1111/tri.13624DOI Listing
August 2020

An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation.

Transpl Int 2020 Jul 5;33(7):786-795. Epub 2020 May 5.

Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.

The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.
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http://dx.doi.org/10.1111/tri.13613DOI Listing
July 2020

Effect of mTOR inhibitors during CMV disease in kidney transplant recipients: Results of a pilot retrospective study.

Microbiol Immunol 2020 Jul 30;64(7):520-531. Epub 2020 Apr 30.

Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.

mTOR inhibitors exert a preventive effect on cytomegalovirus (CMV) disease in CMV seropositive (R+) kidney transplant recipients, but their impact during the curative treatment of CMV disease in high-risk kidney transplant recipients has not been investigated. We aimed to evaluate the efficacy and tolerance of mTOR inhibitors compared with mycophenolic acid in 63 consecutive kidney transplant recipients (80% of D+R-) suffering from CMV disease with a persistent or a recurrent CMV DNAemia. In this monocentric retrospective study, 16 had their treatment converted to mTOR inhibitors and 47 did not. The Kaplan-Meier curves did not show any significant differences in CMV DNAemia eradication (77% vs. 88% respectively; hazard ratio (HR), 1.648 [95% confidence interval (CI), 0.913-2.973]; log-rank test, P = .132), DNAemia recurrence (36% vs. 47%; HR, 1.517 [95% CI, 0.574-4.007]; log-rank test, P = .448) and CMV clinical recurrence (17% vs. 27%; HR, 1.375 [95% CI, 0.340-5.552]; log-rank test, P = .677) between patients who received mTOR inhibitors and those who did not. These results were confirmed in uni- and multivariate time-dependent Cox regressions. In summary, conversion from mycophenolic acid to mTOR inhibitors seems inadequate for improving CMV clearance or in better preventing CMV recurrences during severe or persistent CMV disease.
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http://dx.doi.org/10.1111/1348-0421.12794DOI Listing
July 2020

Reassessment of the clinical impact of preformed donor-specific anti-HLA-Cw antibodies in kidney transplantation.

Am J Transplant 2020 05 18;20(5):1365-1374. Epub 2020 Jan 18.

Laboratoire d'Immunologie et Immunogénétique, CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France.

Anti-denatured HLA-Cw antibodies are highly prevalent, whereas anti-native HLA-Cw antibodies seem to lead to random flow cytometry crossmatch results. We aimed to reassess crossmatch prediction for anti-HLA-Cw using 2 types of single antigen flow beads (classical beads and beads with diminished expression of denatured HLA), and to compare the pathogenicity of preformed anti-denatured and anti-native HLA-Cw antibodies in kidney transplantation. We performed 135 crossmatches with sera reacting against donor HLA-Cw (classical beads fluorescence ≥500); only 20.6% were positive. Forty-three (31.6%) were anti-denatured HLA antibodies (beads with diminished expression of denatured HLA fluorescence <300); all were crossmatch negative. The correlation between classical beads fluorescence and the crossmatch ratio was low (ρ = 0.178), and slightly higher with beads with diminished expression of denatured HLA (ρ = 0.289). We studied 52 kidney recipients with preformed anti-HLA-Cw donor-specific antibodies. Those with anti-native HLA antibodies experienced more acute and chronic antibody-mediated rejections (P = .006 and .03, respectively), and displayed a lower graft survival (P = .04). Patients with anti-native HLA-Cw antibodies more frequently had previous sensitizing events (P < .000001) or plausibility of their antibody profile according to known anti-native HLA-Cw eplets (P = .0001). Anti-native but not anti-denatured HLA-Cw antibodies are deleterious, which underscores the need for reagents with diminished expression of denatured HLA.
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http://dx.doi.org/10.1111/ajt.15766DOI Listing
May 2020

A prospective comparison of dynamic contrast-enhanced MRI and Cr-EDTA clearance for glomerular filtration rate measurement in 42 kidney transplant recipients.

Eur J Radiol 2019 Aug 4;117:209-215. Epub 2019 Feb 4.

Centre Hospitalier Universitaire de Bordeaux, Service de Radiologie et d'Imagerie Diagnostique et Interventionnelle de l'Adulte, Groupe Hospitalier Pellegrin, France.

Objectives: To evaluate the performance of dynamic contrast-enhanced MRI measurement of glomerular filtration rate (GFR) compared with the reference standard technique of urinary clearance of Cr-EDTA.

Patients And Methods: All kidney transplant recipients (KTRs) with an indication for non-urgent contrast-enhanced MRI at our institution were prospectively included between 2008 and 2012. Renographies were acquired by low-dose dynamic contrast-enhanced MRI (DCE-MRI) then fitted with a two-compartment pharmacokinetic model. MR-GFR was compared with reference isotopic measurements using Bland-Altman diagrams, intraclass correlation coefficient (ICC) and concordance rates.

Results: Forty-two KTRs (mean age 51.5 years, 26-74) were analyzed. Mean estimated GFR was 48.5 ± 27 mL/min/1.73m (24-178 mL/min). The mean bias was +13.2 mL/min (6.4-20.0, +36.9%) ranging from -31.0 mL/min (-41.7%) to +101.4 mL/min (+89.2%) with a large variability (standard-deviation: 22.3 mL/min; limits of agreement: [-30.6 (-43.3--18.9); +57.0 (45.3-68.7)]). The ICC was 0.32 (0.02-0.56) and the concordance rate was 28.6% (14.9-42.2).

Conclusions: The large variability of MR-GFR compared with the reference technique precludes its use in KTRs, whose anatomical peculiarities make standardization of arterial input function (AIF) difficult.
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http://dx.doi.org/10.1016/j.ejrad.2019.02.002DOI Listing
August 2019

Different impact of rATG induction on CMV infection risk in D+R- and R+ KTRs.

J Infect Dis 2019 07;220(5):761-771

Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.

Background: Rabbit antithymocyte globulin (rATG) induction is associated with profound immunosuppression, leading to a higher risk of cytomegalovirus (CMV) infection compared with anti-interleukin 2 receptor antibody (anti-IL-2RA). However, this risk, depending on the baseline CMV serological recipient/donor status, is still controversial.

Methods: The CMV DNAemia-free survival between rATG- and anti-IL-2RA-treated patients was analyzed in donor-positive/recipient-negative (D+R-) and recipient-positive (R+) patients in 1 discovery cohort of 559 kidney transplant recipients (KTRs) and 2 independent cohorts (351 and 135 kidney KTRs). The CMV-specific cell-mediated immunity (CMI) at baseline and at different time points after transplantation was assessed using an interferon γ enzyme-linked immunosorbent spot assay.

Results: rATG increased the risk of CMV DNAemia in R+ but not in D+R- KTRs. In R+ CMI-positive (CMI+) patients, the CMV DNAemia rate was higher in rATG-treated than in anti-IL-2RA-treated patients; no difference was observed among R+ CMI-negative (CMI-) patients. Longitudinal follow-up demonstrated a deeper depletion of preformed CMV CMI in R+ rATG-treated patients.

Conclusions: D+R- KTRs have the highest risk of CMV DNAemia, but rATG adds no further risk. Among R+ KTRs, we described 3 groups, the least prone being R+CMI+ KTRs without rATG, then R+CMI+ KTRs with rATG, and finally R+CMI- KTRs. CMV serostatus, baseline CMV-specific CMI, and induction therapy may lead to personalized preventive therapy in further studies.
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http://dx.doi.org/10.1093/infdis/jiz194DOI Listing
July 2019

Single-cell RNA sequencing unveils the shared and the distinct cytotoxic hallmarks of human TCRVδ1 and TCRVδ2 γδ T lymphocytes.

Proc Natl Acad Sci U S A 2019 06 22;116(24):11906-11915. Epub 2019 May 22.

Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, 31100 Toulouse, France;

γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In -distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets form close yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV and CMV donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.
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http://dx.doi.org/10.1073/pnas.1818488116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576116PMC
June 2019

Late vs early-onset CMV infections in kidney transplantation, still a topical issue, reply to Ono et al.

Transpl Infect Dis 2019 08 22;21(4):e13103. Epub 2019 May 22.

Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin University Hospital, Bordeaux, France.

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http://dx.doi.org/10.1111/tid.13103DOI Listing
August 2019

An open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients.

Kidney Int 2019 07 27;96(1):231-244. Epub 2019 Feb 27.

Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

This is a randomized trial (ATHENA study) in de novo kidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novo kidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novo kidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.
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http://dx.doi.org/10.1016/j.kint.2019.01.041DOI Listing
July 2019

Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression.

Kidney Int 2019 06 5;95(6):1471-1485. Epub 2019 Mar 5.

Laboratoire d'Immunologie et Histocompatibilité Hôpital Saint-Louis, Paris, France; INSERM UMRs 1160, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.

Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.
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http://dx.doi.org/10.1016/j.kint.2018.12.029DOI Listing
June 2019

C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection.

Front Immunol 2019 8;10:235. Epub 2019 Mar 8.

University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France.

C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival ( = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.
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http://dx.doi.org/10.3389/fimmu.2019.00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418012PMC
May 2020

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.

J Am Soc Nephrol 2019 04 8;30(4):692-709. Epub 2019 Mar 8.

Paris Descartes, Sorbonne Paris Cité University, Paris, France;

Background: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.

Methods: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.

Results: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.

Conclusions: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant.
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http://dx.doi.org/10.1681/ASN.2018080868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442343PMC
April 2019

Impact of estimation versus direct measurement of predonation glomerular filtration rate on the eligibility of potential living kidney donors.

Kidney Int 2019 04 26;95(4):896-904. Epub 2019 Feb 26.

Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, Jean Monnet University, COMUE Université de Lyon, Lyon, France.

While direct measurements of glomerular filtration rate (GFR) provide the most accurate evaluation of pre-donation kidney function, guidelines do not systematically require the use of a reference method. We evaluated whether and to what extent relying upon creatinine-based estimating equations (eGFR) rather than direct measurement of GFR (mGFR) alters the selection of potential living donors. We compared the impact of 4 equations (the MDRD study equation, the CKD-EPI equation, the revised Lund-Malmö equation, and the full age spectrum [FAS] equation) on the evaluation of 2733 potential donors with GFR measured by reference methods. We also considered the impact of using either absolute or age-adapted GFR thresholds. The CKD-EPI and FAS equations had the best performances (P10 of 50.6% and 47.8%; P30 of 94.4% and 93.1%, respectively) and led to the lowest proportion of improperly evaluated candidates. Misclassification was more frequent when GFR adequacy was defined as an absolute threshold of 90 ml/min/1.73m as compared to an age-adapted definition (26% and 5%, respectively). Interpretation of eGFR according to an absolute threshold of 90 ml/min/1.73m identified 1804 candidates eligible to donate, compared to 2648 when mGFR was interpreted with age-adapted thresholds. We conclude that creatinine-based estimates cannot substitute for direct GFR measurement to evaluate candidates for kidney donation. When reference methods for direct GFR measurement are not available, our data suggest that a strategy based on age-adapted eGFR values estimated with either the CKD-EPI or FAS equation should be preferred.
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http://dx.doi.org/10.1016/j.kint.2018.11.029DOI Listing
April 2019

The age-calibrated measured glomerular filtration rate improves living kidney donation selection process.

Kidney Int 2018 09;94(3):616-624

Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, Jean Monnet University, Communauté d'Universités et Etablissements Université de Lyon, Lyon, France.

Recommendations on the glomerular filtration rate (GFR) threshold compatible with living kidney donation are not agreed upon. The recent KDIGO guidelines suggested a reset of the conventional cutoff value of 80 to 90 mL/min/1.73 m. While GFR physiologically declines with age, it is unclear whether and how age should be taken into account for selecting acceptable pre-donation GFR. In this multicenter retrospective study encompassing 2007 kidney donors in France, we evaluated the impact of age using two threshold measured GFR (mGFR)s (80 and 90 mL/min/1.73 m). Three groups of donors were defined according to baseline mGFR: below 80, 80-89.9 and 90 mL/min/1.73 m or more. Thirty-two percent of donors were selected despite an mGFR below 90 mL/min/1.73 m. Donors with the lowest mGFR were significantly older (60 ± 9 vs. 47 ± 11 years) and this applied to both male and female donors. The lifetime-standardized renal reserve, defined as the pre-donation mGFR value divided by the expected number of remaining years of life, was similar irrespective of baseline mGFR groups. Similar results were obtained when eGFR was used instead of mGFR. Finally, in a subgroup of 132 donors with repeated mGFR five years after donation, the magnitude of mGFR decrease was similar in all groups (-34.3%, -33.9%, and -34.9% respectively). Thus, the decision to accept individuals with mGFR lower than 90 mL/min/1.73 m for kidney donation is highly dependent on the age of the candidate. Hence, threshold values lower than 90 mL/min/1.73 m are reasonable for older donors. Age-calibrated mGFR may improve efficiency of the selection process.
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http://dx.doi.org/10.1016/j.kint.2018.05.016DOI Listing
September 2018

Two cases of tacrolimus-induced neutropenia: A probably under-diagnosed cause of neutropenia after solid-organ transplantation.

Clin Transplant 2018 07 15;32(7):e13295. Epub 2018 Jun 15.

Department of Internal Medicine and Infectious Diseases, Haut-Leveque Hospital, University Hospital of Bordeaux, Pessac, France.

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http://dx.doi.org/10.1111/ctr.13295DOI Listing
July 2018

Overcoming non-specific binding to measure the active concentration and kinetics of serum anti-HLA antibodies by surface plasmon resonance.

Biosens Bioelectron 2018 Oct 7;117:191-200. Epub 2018 Jun 7.

CHU de Bordeaux, Laboratoire d'Immunologie et Immunogénétique, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France; Immuno ConcEpT, UMR CNRS 5164, 146 rue Léo Saignat, Bordeaux, France; Université de Bordeaux, 146 rue Léo Saignat, Bordeaux, France. Electronic address:

Human leukocyte antigen (HLA) donor-specific antibodies are key serum biomarkers for assessing the outcome of transplanted patients. Measuring their active concentration, i.e. the fraction that really interacts with donor HLA, and their affinity could help deciphering their pathogenicity. Surface plasmon resonance (SPR) is recognized as the gold-standard for measuring binding kinetics but also active concentrations, without calibration curves. SPR-based biosensors often suffer from non-specific binding (NSB) occurring with the sensor chip surface and the immobilized targets, especially for complex media such as human serum. In this work we show that several serum treatments such as dialysis or IgG purification reduce NSB but insufficiently for SPR applications. We then demonstrate that the NSB contribution to the SPR signal can be eliminated to determine precisely and reliably the active concentration and the affinity of anti-HLA antibodies from patients' sera. This was achieved even at concentrations close to the limit of quantification of the method, in the 0.5-1 nM range. The robustness of the assay was demonstrated by using a wide range of artificially generated NSB and by varying the density of the targets captured onto the surface. The assay is of general interest and can be used with molecules generating strong NSB, as far as a non-cognate target structurally close to the target can be captured on the same flow cell, in a different binding cycle. Compared with current fluorescence-based methods that are semi-quantitative, we expect this SPR-based assay to help better understanding anti-HLA antibodies pathogenicity and improving organ recipients' management.
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http://dx.doi.org/10.1016/j.bios.2018.06.013DOI Listing
October 2018

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

Nature 2018 06 13;558(7711):540-546. Epub 2018 Jun 13.

INSERM U1151, Institut Necker Enfants Malades, Paris, France.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
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http://dx.doi.org/10.1038/s41586-018-0217-9DOI Listing
June 2018