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.

Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

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.

Clinical description of the broad range of neurological presentations of COVID-19: A retrospective case series.

BACKGROUND: Neurological disorders associated with SARS-CoV-2 infection represent a clinical challenge because they encompass a broad neurological spectrum and may occur before the diagnosis of COVID-19. METHODS: In this monocentric retrospective case series, medical records from patients with acute neurological disorders associated with SARS-CoV-2 infection from medicine departments of an academic center in Paris area were collected between March 15th and May 15th 2020. Diagnosis of SARS-CoV-2 was ascertained through specific RT-PCR in nasopharyngeal swabs or based on circulating serum IgG antibodies. RESULTS: Twenty-six patients diagnosed with SARS-CoV-2 infection presented with neurological disorders: encephalitis (N=8), encephalopathy (N=6), cerebrovascular events (ischemic strokes N=4 and vein thromboses N=2), other central nervous system (CNS) disorders (N=4), and Guillain-Barré syndrome (N=2). The diagnosis of SARS-CoV-2 was delayed on average 1.6 days after the onset of neurological disorder, especially in case of encephalitis 3.9 days, encephalopathy 1.0 day, and cerebrovascular event 2.7 days. CONCLUSIONS: Our study confirms that COVID-19 can yield a broad spectrum of neurological disorders. Because neurological presentations of COVID-19 often occur a few days before the diagnosis of SARS-COV-2 infection, clinicians should take preventive measures such as patient isolation and masks for any new admission to avoid nosocomial infections. Anti-SARS-CoV2 antibody detection in RT-PCR SARS CoV-2 negative suspected cases is useful to confirm a posteriori the diagnosis of atypical COVID-19 presentations.

[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.

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.

[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.

Renal transplantation in HIV-infected patients: the Paris experience.

Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.

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.

Postnatal development of fiber type composition in rabbit jaw and leg muscles.

We examined the difference in fiber type composition and cross-sectional areas during postnatal development in male rabbit jaw muscles and compared these with changes in leg muscles. The myosin heavy chain (MyHC) content of the fibers was determined by immunohistochemistry. No fiber type difference was found between the jaw muscles in 20-week-old rabbits. However, the way this adult fiber type composition was reached differed between the muscles. The deep temporalis, medial pterygoid, and superficial masseter displayed an increase in alpha fibers during early and a decrease during late postnatal development. Other jaw muscles displayed an increase in alpha fibers during early development only. In contrast, alpha fibers were not found in the soleus, in which fiber type changes were completed at week 4. The gastrocnemius muscle did not change its fiber type composition. Initially, fibers in jaw-opening muscles had larger cross-sectional areas than in other muscles, but they increased less during development. Although there were no large differences in the fiber type composition of muscles in young adult rabbits, large differences were found in the jaw muscles, but not in the leg muscles, during development. In part, these developmental changes in fiber percentages within the jaw muscles can be explained by functional modifications in this muscle group. In the present study, the deep temporalis, medial pterygoid, and superficial masseter showed the most dramatic percent changes in fibers during postnatal development.

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.

Outcome of renal transplantation in eight patients with Candida sp. contamination of preservation fluid.

The complications of kidney graft preservation fluid infected by Candida sp. may range in severity from trivial infections to life-threatening complications, including graft arteritis and anastomotic rupture. Mandatory nephrectomy has recently been proposed as a means of preventing arterial wall rupture in such cases. We describe the clinical features and outcome of renal transplantation from a cadaveric donor in eight recipients with preservation fluid testing positive for Candida sp. Six patients were treated with antifungal drugs. After 1-2 years of follow-up, including regular imaging, none of the patients had developed arterial aneurysm, and all had a functional allograft and were alive. The contamination of renal graft preservation fluid with Candida sp. may be uneventful and should not systematically lead to removal of the graft. Until other risk factors for vascular complications have been determined, early antifungal treatment and repeated radiological monitoring are advisable for the prevention and/or early detection of such complications.

Failure of anti-CD20 monoclonal antibody therapy to prevent antibody-mediated rejection in three crossmatch-positive renal transplant recipients.

There is no optimal desensitization protocol for cadaveric renal transplant recipients who display high levels of donor-specific alloantibodies as defined by a positive T- or B-cell cytotoxic crossmatch. We used anti-CD20 monoclonal antibodies (Rituximab) to try to prevent antibody-mediated rejection in three crossmatch-positive renal transplants recipients (standard and sensitized techniques). The three patients received a first, second, or third cadaveric donor renal transplant. Patient one had an historical positive T- and B-cell cytotoxicity crossmatch: negative T- and B-cell cytotoxicity crossmatch at the day of transplantation. The panel reactive antibody (PRA) level was 100%. Patients 2 and 3 showed positive B-cell cytotoxicity crossmatches: historical and on the day of transplantation; PRA levels were 50% and 71%, respectively. All recipients were treated pretransplant with rituximab (375 mg/m(2)) and 4 days of intravenous immunoglobulin (0.5 g/kg body weight) per day posttransplant plus 5 days of thymoglobulin. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisone. Antibody-mediated rejection occurred in all patients at day 6, day 10, or 8 months after renal transplantation. For patient 1, the rejection was not reversible and the graft was lost at day 15. Patient 2 had poor renal function with an MDRD estimate of glomerular filtration rate at 36 mL/min/1.73 m(2) at 18 months posttransplantation, and the graft of patient 3 was lost at 9 months posttransplantation due to resistant antibody-mediated rejection with thrombotic microangiopathy. In these three cases of crossmatch-positive patients, rituximab failed to prevent antibody-mediated rejection. Others studies will be needed to determine the place of rituximab in these patients.