Beyond the First Year: Epidemiology and Management of Late-Onset Opportunistic Infections After Kidney Transplantation.

Late opportunistic infections (OI) occurring beyond the first year after kidney transplantation (KT) are poorly described and not targeted by prophylactic strategies. We performed a ten-year retrospective monocentric cohort study describing epidemiology, risk factors and impact of late OI occurring 1 year after KT. We included clinically symptomatic OI requiring treatment besides BK virus nephropathy. Control groups included early OI occurring in the first year after KT, and KT recipients without OI since KT and alive with a functional allograft at 1 year. Among 1066 KT recipients, 185 (19.4%) presented a first episode of OI 21.0 (8.0-45.0) months after KT: 120 late OI (64.9%) and 65 early OI (35.1%). Late OI were mainly viral (N = 83, 69.2%), mostly herpes zoster (HZ) (N = 36, 43.4%). Pneumocystis represented most late fungal infections (N = 12/25, 48%). Compared to early OI, we reported more pneumocystis (p = 0.002) and less invasive aspergillosis (p = 0.01) among late OI. Patients with late OI were significatively younger at KT (54.0 ± 13.3 vs. 60.2 ± 14.3 years, p = 0.05). Patient and allograft survival rates between late OI and control groups were similar. Only age was independently associated with mortality. While late OI were not associated with higher mortality or graft loss, implementing prophylactic strategies might prevent such infections.

Robotic-assisted laparoscopy living donor nephrectomy: Technique and results of a monocentric retrospective series.

INTRODUCTION: Robot-assisted nephrectomy for living kidney donation (LKD) has been described in the literature as a safe and reproducible technique in high volume centers with extensive robotic surgery experience. Any surgical procedure in a healthy individual ought to be safe in regards to complications. The objective of this study was to evaluate the Robotic-assisted Living Donor Nephrectomy (RLDN) experience in a robotic surgery expert center. METHODS: This is a retrospective study from 11/2011 and 12/2019. In total, 118 consecutive Living Donor (LD) kidney transplants were performed at our institution. All the procedures were performed by robotic-assisted laparoscopic approach. Extraction was performed by iliac (IE), vaginal (VE) or umbilical extraction (UE). The left kidney was preferred even if the vascular anatomy was not modal. RESULTS: For donors: the median operative time was 120min with 50mL of blood loss. The median warm ischemia time was 4min, with a non-significant shorter duration with the UE (4min) in comparison with IE or VE (5min). Nine patients had postoperative complications including 1 grade II (blood transfusion) and 1 grade IIIb (vaginal bleeding after VE). None of our procedures were converted to open surgeries and no deaths were reported. For the recipients: 1.7% presented delayed graft function; their median GFR at 1 year was 61mL/min/1.73m2. CONCLUSION: RLDN in an expert center appears to be a safe technique. The advantages of the robot device in terms of ergonomy don't hamper the surgical outcomes. Donor, recipient and graft survivals seem comparable to the reported laparoscopic outcomes in the literature.

[Evaluation of single kidney graft outcome in patients initially programmed for a dual kidney graft transplantation]. / Évaluation de greffons de bigreffe transplantés en monogreffe.

INTRODUCTION: Kidney transplantation is championed as the gold standard treatment for patients with end-stage kidney disease. According to the biomedical agency, there is an increasing number of patients waiting for kidney transplantation. Faced with organ shortage, the use of marginal grafts may well increase the number of available kidney grafts. Occasionally, during dual kidney graft transplantation, the poor quality of one of the two grafts, or other specific circumstances, may lead to transplantation of only one of the two grafts. We have compared patient outcome concerning single kidney transplantation from an initial dual kidney graft with respect to dual kidney graft transplantation. MATERIAL: Among 67 patients enrolled for a dual kidney graft, 39 dual kidney grafts (group 1) were compared with 12 grafts performed with only one of the two kidneys of a dual kidney graft (group 2) as well as 15 grafts performed following a classic kidney graft protocol (group 3). RESULTS: The survival of grafts was respectively for groups 1, 2 and 3 of 100%, 72,5% and 75,4% (P=0.17). The survival of patients was respectively for groups 1, 2 and 3 of 78.3%, 89.9% and 87.8% (P=0.47). CONCLUSION: Our study suggests that transplantation of a single kidney, initially proposed as dual kidney graft candidate, has satisfying results in terms of graft survival and patient mortality at the expense of poorer renal function in comparison to dual kidney graft. Indeed, there was no significant difference in the survival of patients and grafts. This seems promising taking into consideration that the aim of transplantation in elderly recipients is primarily to avoid dialysis, rather than having optimal post-transplantation kidney function. LEVEL OF EVIDENCE: 4.

Low incidence of acute rejection within 6 months of kidney transplantation in HIV-infected recipients treated with raltegravir: the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) 153 TREVE trial.

OBJECTIVES: High rates of clinical acute rejection after kidney transplantation have been reported in people living with HIV (PLHIV), probably as a consequence of drug interactions. We therefore investigated the incidence of acute rejection within 6 months of transplantation in HIV-infected recipients treated with a protease-inhibitor-free raltegravir-based regimen. METHODS: The Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) 153 TREVE (NCT01453192) study was a prospective multicentre single-arm trial in adult PLHIV awaiting kidney transplantation, with viral load < 50 HIV-1 RNA copies/mL, CD4 T-cell count > 200 cells/µL, and HIV-1 strains sensitive to raltegravir, aiming to demonstrate 6-month clinical acute rejection rates < 30%. Time to transplantation was compared with that for uninfected subjects matched for age, sex and registration date. RESULTS: In total, 61 participants were enrolled in the study, and 26 underwent kidney transplantation. Two participants experienced clinical acute rejection, corresponding to an estimated clinical acute rejection rate of 8% [95% confidence interval (CI) 2-24%] at 6 and 12 months post-transplantation. HIV infection remained under control in all but one participant, who temporarily stopped antiretroviral treatment. Median time to transplantation was longer in PLHIV than in controls (4.3 versus 2.8 years, respectively; P = 0.002) and was not influenced by blood group. CONCLUSIONS: Acute rejection rates were low after kidney transplantation in PLHIV treated with a raltegravir-based regimen. However, PLHIV have poorer access to transplantation than HIV-uninfected individuals after registration on the waiting list.

Transcriptomic Signature of the CD24hi CD38hi Transitional B Cells Associated With an Immunoregulatory Phenotype in Renal Transplant Recipients.

The role of B cells after transplant regarding allograft rejection or tolerance has become a topic of major interest. Recently, in renal transplant recipients, a B cell signature characterized by the overexpression of CD19+ CD38hi CD24hi transitional B cells has been observed in operationally tolerant patients and in belatacept-treated patients with significantly lower incidence of donor-specific antibodies. The phenotypic and functional characterization of these transitional B cells is far from exhaustive. We present the first transcriptomic and phenotypic analysis associated with this cell phenotype. Three populations were studied and compared: (i) transitional CD24hi CD38hi , (ii) CD24+ CD38- , and (iii) CD24int CD38int B cells. Transcriptome bioinformatic analysis revealed a particular signature for the CD24hi CD38hi population. Phenotypic analysis showed that CD24hi CD38hi transitional B cells also expressed CD9, CD10, CD1b and inducible T cell costimulator ligand (ICOS-L) markers. In addition, we found enrichment of IL-10+ cells among CD24hi CD38hi cells expressing ICOS-L and CD1b, the latter showing regulatory properties. Renal transplant recipients treated with belatacept exhibited significant expression of CD1b. Our results show that transitional CD24hi CD38hi B cells exhibit a distinct and specific profile, and this could be helpful for understanding of immune-regulatory mechanisms and immune monitoring in the field of organ transplant and autoimmune disease.

Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell-Mediated Rejection.

Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell-mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell-mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il-17 and T-bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell-mediated rejection reversal (p = 0.03). The presence of IL-17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell-mediated rejection in recipients of expanded criteria allograft.

Administration of low doses of IL-2 combined to rapamycin promotes allogeneic skin graft survival in mice.

Human CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) prevent allogeneic graft rejection by inhibiting T cell activation, as has been shown in mouse models. Recently, low-dose IL-2 administration was shown to specifically activate Tregs but not pathogenic conventional T cells, leading to resolution of type 1 diabetes in nonobese diabetic mice. We therefore tested the ability of low-dose IL-2 to prevent allogeneic skin graft rejection. We found that while IL-2 alone was inefficient in preventing rejection, combined with rapamycin, IL-2 treatment promoted skin graft survival both in minor disparate and semi-allogeneic skin graft combinations. Tregs are activated by this combined treatment while conventional CD4(+) cell expansion and activation are markedly inhibited. Co-administration of anti-CD25 antibodies dramatically reduces the effect of the IL-2/rapamycin treatment, strongly supporting a central role for Treg activation. Thus, we provide the first preclinical data showing that low-dose IL-2 combined with rapamycin can significantly delay transplant rejection in mice. These findings may form the rational for clinical evaluation of this novel approach for the prevention of transplant rejection.

[Optical coherence tomography and microperimetry after internal limiting membrane peeling for epiretinal membrane]. / Micropérimétrie et OCT en face après pelage de membrane limitante interne dans la chirurgie des membranes épimaculaires.

INTRODUCTION: To evaluate the anatomical and functional consequences of internal limiting membrane (ILM) peeling in epiretinal membrane (ERM) surgery. METHODS: Retrospective single-center study including consecutive patients operated on for idiopathic ERM. The integrity of the ILM was assessed by ILM Blue® staining after removal of the ERM: either the peeling was spontaneous (group 1) or a complementary peeling was required (group 2). Pre- and post-operatively (1 and 6 months), all patients were analyzed using visual acuity, SD-OCT (Spectralis HRA OCT, Heidelberg, Germany) and microperimetry (OPKO/OTI, Miami, USA). RESULTS: Twenty-one eyes of 21 patients were included: 12 "active ILM peelings" and 9 "spontaneous peelings". In both groups, visual acuity increased significantly after surgery. Microperimetry revealed more microscotomata at 1 and 6 months for active peeling (P<0.05). Their location corresponded more often to the site where the ERM or ILM was grasped, based on surgical videos (P<0.05), and with the appearance of inner retinal defects using en face OCT. DISCUSSION: ILM peeling is frequently performed to reduce ERM recurrence. Despite lack of effect on visual acuity, active ILM peeling increases the incidence of microscotomas related to the site where the ERM or ILM is grasped. CONCLUSION: Active ILM peeling may be responsible for postoperative visual discomfort related to microscopic trauma during peeling.

Kidney transplant recipients treated with belatacept exhibit increased naïve and transitional B cells.

Phase III clinical studies have shown that kidney transplant (KT) recipients treated with the costimulation blocker belatacept exhibited a better renal allograft function and lower donor-specific anti-HLA immunization when compared to recipients treated with calcineurin inhibitors (CNI). We analyzed B cell phenotype in KT recipients treated with belatacept and stable renal function (N = 13). Results were compared to those observed in stable patients treated with CNI (N = 12), or with chronic antibody-mediated rejection (N = 5). Both transcriptional profile and phenotypic characterization of peripheral B cells were performed by real-time polymerase chain reaction and flow cytometry, respectively. In belatacept group, the frequency and absolute number of transitional B cells as defined by both phenotypes: CD19(+) CD24(hi) CD38(hi) and CD19(+) IgD(hi) CD38(hi) CD27(-) , as well as naïve B cells were significantly higher compared with CNI group. B cell activating factor (BAFF) and BAFF receptor mRNA levels were significantly lower in belatacept group than in CNI group. These results show for the first time that belatacept influences B cell compartment by favoring the occurrence of transitional B cells with potential regulatory properties, as described in operational tolerant patients. This role may explain the lower alloimmunization rate observed in belatacept-treated patients.

[Diagnostic value of multidisciplinary meetings on orbital inflammatory pathologies discussed in Nantes University Medical Center]. / Intérêt diagnostique d'une réunion de concertation multidisciplinaire des pathologies orbitaires inflammatoires au CHU de Nantes.

INTRODUCTION: Observational study of the diagnoses and the treatment modalities used for orbital inflammatory pathologies discussed in multidisciplinary meetings (MDM) in Nantes University Medical Center over 4 years. MATERIAL AND METHOD: A multidisciplinary meeting to discuss eyelid and orbital pathologies (excluding cancer) has been held in Nantes three times per year since October 2008. This retrospective study focuses on the cases of orbital inflammatory pathologies discussed at this meeting from October 2008 to October 2012 (49 cases included). RESULTS: Twenty-eight (57%) patients were diagnosed with orbital inflammation, 16 (33%) cases with isolated myositis and 5 (10%) with dacryoadenitis. In the diagnostic work-up, orbital biopsy was performed in 64% of orbital inflammation cases, 38% of myositis cases and 80% of dacryoadenitis cases. These specimens led to the diagnosis of 9 lymphomas, 2 histiocytoses and 1 metastasis. The internal medicine work-up allowed for the diagnosis of 3 granulomatoses with polyangiitis, one patient with sarcoidosis, and one patient with tuberculosis. Despite work-up, there remained 14 (29%) idiopathic orbital inflammatory syndromes (IOIS). DISCUSSION: The MDM of orbital pathology allows for the collective approach to the most difficult cases of management and is not concerned with stable orbitopathies or those presenting no diagnostic dilemma. Despite a multidisciplinary, rational etiologic work-up (frequently involving a biopsy), we find a higher rate of IOIS than reported in the literature. CONCLUSION: A multidisciplinary approach appears to be useful in improving management of orbital disease.

Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

[Organ transplantation and blood transfusion]. / Transfusion sanguine et transplantation.

Pretransplant blood transfusion remains a controversial subject and its history can summarize the last 40 years of transplantation. Until 1971, transfusions were widely used in patients awaiting transplantation, especially due to the anemia induced by the chronic renal dysfunction. Then, a noxious effect of preformed anti-HLA antibodies on renal grafts survival was reported and pretransplant transfusions were stopped. Between 1972 and 1977, improvement of renal graft survival in patients who received pretransplant transfusions was noted. Therefore, from 1978 on, a systematic policy of pretransplant transfusions was adopted by almost all centres of transplantation. During the eighties, it was again abandoned for several reasons: absence of graft survival improvement in patients treated by cyclosporine, HLA immunization leading to an increased incidence of acute graft rejection, risk of viral diseases transmission and human recombinant erythropoietin development. The lack of improvement in graft survival for ten years has been leading the transplant community to look for antigen-specific immunosuppressive strategies to achieve transplantation tolerance. Donor-specific transfusion may have clinical benefits, as long-term grafts survival improvement, through modulation of the recipient's cellular immune system and has been recently reconsidered, especially before living donor transplantation. The immunological mechanisms inducing a tolerance-gaining effect of transfusions are still misunderstood, but the recent discovery of immunomodulatory effects of the apoptotic cells present in cellular products could enlighten our comprehension of pretransplant transfusions benefits and could help to develop specific tolerance induction strategies in solid organ transplantation.

Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes.

Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain-dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal-photopheresis. Four patients were transplanted with 7- to 38-month follow-up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life.

Yeast contamination of kidney, liver and cardiac preservation solutions before graft: need for standardisation of microbial evaluation.

Contamination of preservation solution (PS) with yeasts during solid organ recovery can lead to life-threatening complications in the recipients. The prevalence of such a contamination needs to be established. From January 2004 to December 2008, we prospectively investigated the potential fungal contamination of all the PSs collected in our institution using a standardised procedure consisting in centrifugation of 10 mL PS and incubation of the pellet seeded on fungal-specific medium for 15 days at 30 degrees C. During the study period, 728 transplantations (397 kidneys, 262 livers and 69 hearts) were performed for which 659 PSs (90.5%) were available. The yeast contamination rate was 0% (0/62), 3.1% (11/356) and 4.1% (10/241) for heart, kidney and liver transplants, respectively. We identified 10 Candida albicans, five C. glabrata, two C. krusei, one C. tropicalis, one C. valida, one Pichia etchelsii and one Rhodorula sp. Routine bacterial analysis identified only five of these 21 fungal contaminations. Twenty recipients were alive after at least one year of follow-up and one died from meningeal carcinomatosis at seven months. Three patients were found to have the same species of Candida from their surgical drains but did not develop any infection or abnormalities upon ultrasound investigation. Fourteen patients received antifungal drugs. Yeast contamination occurred in 3.4% of all kidney and liver PSs tested. Its clinical consequences and therapeutic management remain to be defined. Our study also suggests that optimisation/standardisation of microbiological procedures is warranted, including analysis of large PS volume, seeding of fungal-specific medium and prolonged incubation.

Predominant Th1 and cytotoxic phenotype in biopsies from renal transplant recipients with transplant glomerulopathy.

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4+ T cells including Th1 (T-bet and INFgamma), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and RORgammat) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IF/TA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INFgamma, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.

Successful long-term outcome of the first combined heart and kidney transplant in a patient with systemic Al amyloidosis.

Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. During the follow-up period (36 months), plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission.