High dose intravenous immunoglobulin (IVIG) are widely used after kidney transplantation and its biological effect on T and B cell phenotype in the context of maintenance immunosuppression was not documented yet. We designed a monocentric prospective cohort study of kidney allograft recipients with anti-HLA donor specific antibodies (DSA) without acute rejection on screening biopsies treated with prophylactic high-dose IVIG (2 g/kg) monthly for 2 months. Any previous treatment with Rituximab was an exclusion criterion. We performed an extensive analysis of phenotypic and transcriptomic T and B lymphocytes changes and serum cytokines after treatment (day 60). Twelve kidney transplant recipients who completed at least two courses of high-dose IVIG (2 g/kg) were included in a median time of 45 (12-132) months after transplant. Anti-HLA DSA characteristics were similar before and after treatment. At D60, PBMC population distribution was similar to the day before the first infusion. CD8+ CD45RA+ T cells and naïve B-cells (Bm2+) decreased (P = 0.03 and P = 0.012, respectively) whereas Bm1 (mature B-cells) increased (P = 0.004). RORγt serum mRNA transcription factor and CD3 serum mRNA increased 60 days after IVIG (P = 0.02 for both). Among the 25 cytokines tested, only IL-18 serum concentration significantly decreased at D60 (P = 0.03). In conclusion, high dose IVIG induced limited B cell and T cell phenotype modifications that could lead to anti-HLA DSA decrease. However, no clinical effect has been isolated and the real benefit of prophylactic use of IVIG after kidney transplantation merits to be questioned.

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.

The induction of specific and sustainable tolerance is a challenging issue in organ transplantation. The discovery of the immunosuppressive properties of apoptotic cells in animal models has paved the way for their use in human transplantation. In this work, we aimed to define a stable, reproducible, and clinically compatible production procedure of human apoptotic cells (Apo-cells). Using a clinically approved extracorporeal photopheresis technique, we have produced and characterized phenotypically and functionally human apoptotic cells. These Apo-cells have immunosuppressive properties proved in vitro and in vivo in NOD/SCID/γC mice by their capacity to modulate an allogeneic response following both a direct and an indirect antigen presentation. These results brought the rationale for the use of Apo-cells in tolerance induction protocol for organ transplantation.

Recurrence of glomerular disease after renal transplantation is a frequent cause of graft loss. Incidence, risk factors and outcome of recurrence are widely due to the underlying glomerular disease. Graft biopsy analysis is required to confirm the definitive diagnosis of recurrence and to start an appropriate therapy that, in some cases, remains challenging to prevent graft failure. Increased use of protocol biopsy and recent advances in our understanding of the pathogenesis of some glomerular diseases with the identification of some relevant biomarkers provide a unique opportunity to initiate kidney-protective therapy at early stages of recurrence on the graft. This review summarizes our current knowledge on the management of many recurrent primary and secondary glomerulonephritis after kidney transplantation. (C) 2018 Societe francophone de nephrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.

BackgroundIn kidney transplant recipients, anticardiolipin (ACL) antibodies without antiphospholipid syndrome (APS) are found in up to 38% of patients and could be associated with thrombotic events (TEs). However, the prognostic role of ACL regarding kidney transplant and patients outcomes have still not been well defined.MethodsWe conducted an observational, monocentric, retrospective cohort study including 446 kidney transplant recipients and standardized follow-up: 36-month allograft and patient survival, 12-month estimated glomerular filtration rate (eGFR) and 3- and 12-month screening biopsies.ResultsACL tests were run on 247 patients, 101 were positive (ACL+ group, 41%) and 146 were negative (ACL- group, 59%). Allografts and patient survival within 36 months as TE were similar between both groups [hazard ratio (HR) = 1.18 and HR = 0.98, respectively]. The 12-month eGFR was significantly lower in the ACL+ group [median (95% confidence interval) 48.5 (35.1-60.3) versus 51.9 (39.1-65.0) mL/min/1.73 m2, P= 0.042]. ACL+ was independently associated with eGFR decrease (P = 0.04). In 12-month screening biopsies, tubular atrophy was significantly more severe in the ACL+ group compared with the ACL- group (P = 0.02).ConclusionsACL without APS before kidney transplantation is an independent risk factor of eGFR decline within the first year post-transplant without over-incidence of TEs. Specific immunosuppressive therapy including mammalian target of rapamycin inhibitors should be discussed in the future.

La récidive d’une glomérulopathie après transplantation rénale est une cause fréquente de perte du greffon. L’incidence, les facteurs de risque et l’issue de la récurrence sont largement liés à la maladie glomérulaire sous-jacente. L’analyse de la biopsie du greffon est nécessaire afin de confirmer le diagnostic définitif de récidive et initier une thérapie appropriée qui reste dans certains cas un véritable challenge pour prévenir l’échec de la greffe. L’utilisation croissante des biopsies de protocole et les progrès récents dans notre compréhension de la pathogénie de certaines maladies glomérulaires avec l’identification de certains biomarqueurs d’intérêt offrent une occasion unique d’initier une thérapie de protection rénale aux stades précoces de la récidive sur la greffe. Cette revue résume nos connaissances actuelles sur la prise en charge de nombreuses glomérulonéphrites primaires et secondaires récurrentes après transplantation rénale.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Truncation of C-mip (Tc-mip), a new proximal signaling protein, induces c-maf Th2 transcription factor and cytoskeleton reorganization. Philippe Grimbert, Asta Valanciute, Vincent Audard, André Pawlak, Sabine Le Gouvello, Philippe Lang, Patrick Niaudet, Albert Bensman, Georges Guellaën, Djillali Sahali

BACKGROUND:Our understanding of the pathophysiologic processes underlying sickle cell nephropathy remains incomplete. We performed a pilot study to investigate the potential value of magnetic resonance imaging (MRI) for the assessment of kidney oxygenation and detection of potential changes to tissue perfusion and cellular integrity during a vaso-occlusive crisis.STUDY DESIGN:A case-control study.SETTING & PARTICIPANTS:10 homozygous patients with sickle cell disease (SCD), without kidney disease (based on estimated glomerular filtration rate and albuminuria), underwent renal MRI during a vaso-occlusive crisis episode. The imaging data obtained were compared with those for a second MRI performed at steady state (median, 56 [IQR, 37-72] days after the vaso-occlusive crisis MRI). The control group consisted of 10 apparently healthy individuals.MEASUREMENTS:Deoxyhemoglobin level assessed by R2* value was calculated using the blood oxygen level-dependent technique. The intravoxel incoherent motion diffusion-weighted imaging technique was used to calculate D, D*, and F parameters.RESULTS:Median medullary R2* values on steady-state MRI were significantly higher for patients with SCD than for controls (P=0.01) and did not change significantly during the vaso-occlusive crisis. No significant differences in median cortical R2* values were observed. Both cellular integrity (D) and local perfusion (D* and F) were significantly altered in medullary and cortical areas during vaso-occlusive crises in comparison to steady state in patients with SCD. These parameters did not differ significantly between patients with SCD assessed at steady state and the control group.LIMITATIONS:Small sample size, estimation of glomerular filtration rate according to CKD-EPI creatinine equation without adjustment for race.CONCLUSIONS:Deoxyhemoglobin levels in the medullary area are higher in patients with SCD, during vaso-occlusive crises and at steady state, than in controls. Alterations to the tissue perfusion and cellular integrity of renal parenchyma are a common finding during vaso-occlusive crises that provide additional evidence that a vaso-occlusive crisis may be associated with subclinical kidney injury detectable on MRI.

BACKGROUND AND OBJECTIVES:Post-transplant lymphoproliferative disorders arising after kidney transplantation portend an increased risk of morbidity and mortality. Retransplantation of patients who had developed post-transplant lymphoproliferative disorder remains questionable owing to the potential risks of recurrence when immunosuppression is reintroduced. Here, we investigated the feasibility of kidney retransplantation after the development of post-transplant lymphoproliferative disorder. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We reviewed the data from all patients who underwent kidney retransplantation after post-transplant lymphoproliferative disorder in all adult kidney transplantation centers in France between 1998 and 2015. RESULTS:We identified a total of 52 patients with kidney transplants who underwent 55 retransplantations after post-transplant lymphoproliferative disorder. The delay from post-transplant lymphoproliferative disorder to retransplantation was 100±44 months (28-224); 98% of patients were Epstein-Barr virus seropositive at the time of retransplantation. Induction therapy for retransplantation was used in 48 patients (i.e., 17 [31%] patients received thymoglobulin, and 31 [57%] patients received IL-2 receptor antagonists). Six patients were also treated with rituximab, and 53% of the patients received an antiviral drug. The association of calcineurin inhibitors, mycophenolate mofetil, and steroids was the most common maintenance immunosuppression regimen. Nine patients were switched from a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. One patient developed post-transplant lymphoproliferative disorder recurrence at 24 months after retransplantation, whereas post-transplant lymphoproliferative disorder did not recur in 51 patients. CONCLUSIONS:The recurrence of post-transplant lymphoproliferative disorder among patients who underwent retransplantation in France is a rare event.

Solid organ transplantation societies recommend a relative contraindication of transplantation for people with bipolar or psychotic disorders. Very few data are available on the outcome of kidney transplantation and the increased risk of kidney disease in those patients. We conducted a retrospective multicenter cohort study (1979-2014) including kidney allograft recipients with either bipolar (BD) or psychotic disorders prior to transplant. Objectives were kidney allograft and patient outcomes compared to a matched control group without psychiatric disorders and the evolution of psychiatric disorder at 60months after transplantation. Forty-seven patients including 25 women were identified, 34 with BD and 13 with psychotic disorder. Patients' overall cumulative death rates at 60months were not significantly different in both groups [12.2%; 95% confidence interval: (4.5-24.1) in the group with psychiatric disorder versus 5.2%; (1.7-11.7) in control group P=0.11] as for cumulative allograft loss rates [11.7% (3.5-25.2) vs. 9.4% (4.4-16.8) in control group (P=0.91)]. Twenty-three patients (16 with BD and seven with psychotic disorder) experienced at least one psychiatric relapse [incidence rate: 1.8/100 persons- months; 95% CI; (1.2-2.7)] totaling 13 hospitalizations within 60months of follow-up. Four patients stopped immunosuppressive therapy leading to allograft loss in three. Our study suggests that patients with BD or psychotic disorders have to be considered for renal transplantation with close psychiatric follow-up after transplant.

Background Treatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly specified in the absence of randomized trials. Methods In this phase III, multicenter, double-blind, placebo-controlled trial, we randomly assigned patients with biopsy-proven AMR to receive rituximab (375 mg/m2) or placebo at day 5. All patients received PE, IVIg, and CS. The primary endpoint was a composite of graft loss or no improvement in renal function at day 12. Results Among the 38 patients included, at 1 year, no deaths occurred, but 1 graft loss occurred in each group. The primary endpoint frequency was 52.6% (10/19) and 57.9% (11/19) in the rituximab and placebo groups, respectively (P = 0.744). Renal function improved in both groups, as soon as day 12 with no difference in serum creatinine level and proteinuria at 1, 3, 6, and 12 months. Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups. Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months, with no significant difference between groups but with a trend in favor of the rituximab group. Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12, with no significant difference between them but with a trend in favor of the rituximab group at 12 months. Conclusions After 1 year of follow-up, we observed no additional effect of rituximab in patients receiving PE, IVIg, and CS for AMR. Nevertheless, our study was underpowered and important differences between groups may have been missed. Complementary trials with long-term follow-up are needed.

Introduction: Predominantly monotypic plasma cell infiltrates are an uncommon renal finding in patients with malignant lymphoplasmacytic proliferation.Case presentation: We report the case of a 52-year-old man with chronic kidney disease and significant proteinuria associated with a monoclonal immunoglobulin spike (lgGK). Kidney biopsy revealed the presence of atypical multinucleated CD138(+) plasma cells with voluminous nuclei stained exclusively with a kappa antibody. Electron microscopy showed mesangial and segmental parietal electron-dense, nonorganized hyaline deposits without immunogold labeling for the kappa light chain. The bone marrow aspirate revealed 6% of apparently mature plasmocytes without dystrophy. We therefore concluded that the patient had an indolent multiple myeloma with specific renal involvement in the form of malignant monotypic interstitial plasmacytic infiltration. We initiated a specific chemotherapy regimen including bortezomib cyclophosphamide dexamethasone. After 4 months of follow-up, creatinine levels had improved slightly and free kappa light-chain levels had decreased significantly within the normal range.Conclusion: This case highlights the need to consider neoplastic interstitial plasma cell infiltration systematically in patients diagnosed with an apparently benign monoclonal gammopathy and to consider adaptation of the chemotherapy regimen, to improve renal function.

The analysis of anti-HLA sensitization at the time of and following allograft nephrectomy may help clinicians to define better both the indications for nephrectomy and preventive therapeutic strategies. We carried out a retrospective analysis of anti-HLA antibodies in 63 clinically indicated nephrectomies (baseline and three and 12 months after) according to the time elapsed since transplantation (six months) and clinical background. An intervention study included 10 patients without donor-specific antibodies (DSA) at the time of nephrectomy treated with high-dose intravenous immunoglobulin (IVIG) (1.5 g/kg). Early nephrectomies were performed in 15 patients (24%). Among the late nephrectomies, 14 patients (22%) were asymptomatic and 34 (54%) had graft intolerance syndrome (GIS). At baseline, anti-HLA sensitization was significantly lower in the early and late asymptomatic groups than in the GIS group, but increased considerably within the three months following surgery. In the group of 10 patients treated with IVIG, only the number of class I non-DSA increased in the three months after surgery, whereas in the control group (N = 13), all anti-HLA variables increased significantly. All patients undergoing a clinically indicated allograft nephrectomy become highly sensitized within the 12 months after surgery. In patients without DSA before nephrectomy, high doses of IVIG may prevent anti-HLA sensitization.

We performed a retrospective study to assess the changes in clinical, biological and heart echocardiographic parameters in 32 sickle cell disease ( SCD ) patients beginning haemodialysis. Acute SCD ‐related complications were similar at 6 months before and 6 months after the initiation of haemodialysis. Median haemoglobin level did not change significantly, but the need for blood transfusions increased ( P < 0·001). The 5‐year incidence of death was higher in SCD patients ( P < 0·0001). The 5‐year likelihood of receiving a renal graft was lower in SCD patients ( P = 0·022). Our findings suggest that SCD patients have poorer survival and a lower likelihood of receiving a renal graft.

After kidney transplantation, C4d is an incomplete marker of acute antibody- mediated rejection (AMR) and C1q- binding donor- specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q- binding impact on allograft survival. We compared clinical, histological and serological features of C4d- and C4d+ AMR, C1q+ and C1q- DSA AMR and analysed C4d and C1q- binding impact on allograft survival. Among 500 for- cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.116.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q- AMR.

Calciphylaxis is a small vessel vasculopathy, characterized by medial wall calcification that develops in a few patients with chronic renal failure. The prognosis of skin calciphylaxis has improved considerably since the introduction of sodium thiosulfate (STS), but it remains unclear whether this therapy is effective against organ lesions related to calciphylaxis. Pulmonary calciphylaxis is a usually fatal medical condition that may occur in association with skin involvement in patients with end-stage renal disease.We report here the case of a 49-year-old woman homozygous sickle cell disease patient on chronic hemodialysis with biopsy-proven systemic calciphylaxis involving the lungs and skin. On admission, ulcerative skin lesions on the lower limbs and bilateral pulmonary infiltrates on chest computerized tomography scan were the main clinical and radiological findings. Skin and bronchial biopsies demonstrated calciphylaxis lesions. The intravenous administration of STS in association with cinacalcet for 8 consecutive months led to a clear improvement in skin lesions and thoracic lesions on chest computerized tomography scan.This case suggests for the first time that organ lesions related to calciphylaxis, and particularly lung injury, are potentially reversible. This improvement probably resulted from the combination of 3 interventions (more frequent dialysis, cinacalcet, and STS), rather than the administration of STS alone.