High-dimensional mass cytometry identified circulating natural killer T-cell subsets associated with protection from cytomegalovirus infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.

Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome.

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.

A comprehensive assessment of long-term SARS-CoV-2-specific adaptive immune memory in convalescent COVID-19 Solid Organ Transplant recipients.

Long-term adaptive immune memory has been reported among immunocompetent individuals up to eight months following SARS-CoV-2 infection. However, limited data is available in convalescent patients with a solid organ transplant. To investigate this, we performed a thorough evaluation of adaptive immune memory at different compartments (serological, memory B cells and cytokine [IFN-γ, IL-2, IFN-γ/IL12 and IL-21] producing T cells) specific to SARS-CoV-2 by ELISA and FluoroSpot-based assays in 102 convalescent patients (53 with a solid organ transplants (38 kidney, 5 liver, 5 lung and 5 heart transplant) and 49 immunocompetent controls) with different clinical COVID-19 severity (severe, mild and asymptomatic) beyond six months after infection. While similar detectable memory responses at different immune compartments were detected between those with a solid organ transplant and immunocompetent individuals, these responses were predominantly driven by distinct COVID-19 clinical severities (97.6%, 80.5% and 42.1%, all significantly different, were seropositive; 84% vs 75% vs 35.7%, all significantly different, showed IgG-producing memory B cells and 82.5%, 86.9% and 31.6%, displayed IFN-γ producing T cells; in severe, mild and asymptomatic convalescent patients, respectively). Notably, patients with a solid organ transplant with longer time after transplantation did more likely show detectable long-lasting immune memory, regardless of COVID-19 severity. Thus, our study shows that patients with a solid organ transplant are capable of maintaining long-lasting peripheral immune memory after COVID-19 infection; mainly determined by the degree of infection severity.

Immune responses following tocilizumab therapy to desensitize HLA-sensitized kidney transplant candidates.

Kidney transplant candidates (KTCs) who are HLA highly sensitized (calculated panel-reactive alloantibodies >95%) have poor access to deceased kidney transplantation. In this single-center prospective study, 13 highly sensitized desensitization-naïve KTCs received IV tocilizumab (8 mg/kg) every 4 weeks. We evaluated tolerability as well as immune responses, that is, T cell, B cell, T follicular helper (Tfh) subsets, blood cytokines (IL-6, soluble IL-6 receptor-sIL-6R-, IL-21), blood chemokines (CXCL10, CXCL13), and anti-HLA alloantibodies. Tocilizumab treatment was well-tolerated except in one patient who presented spondylodiscitis, raising a note of caution. Regarding immune parameters, there were no significant changes of percentages of lymphocyte subsets, that is, CD3+ , CD3+ /CD4+ , CD3+ /CD8+ T cells, and NK cells. This was also the case for Tfh cell subsets, B cells, mature B cells, plasma cells, pre-germinal center (GC) B cells, and post-GC B cells, whereas we observed a significant increase in naïve B cells (p = .02) and a significant decrease in plasmablasts (p = .046) over the tocilizumab treatment course. CXCL10, CXCL13, IL-21, total IgG, IgA, and IgM levels did not significantly change during tocilizumab therapy; conversely, there was a significant increase in IL-6 levels (p = .03) and a huge increase in sIL-6R (p = .00004). There was a marginal effect on anti-HLA alloantibodies (class I and class II). To conclude in highly sensitized KTCs, tocilizumab as a monotherapy limited B cell maturation; however, it had almost no effect on anti-HLA alloantibodies.

The Mayo Adhesive Probability score can help predict intra- and postoperative complications in patients undergoing laparoscopic donor nephrectomy.

PURPOSE: Living donor nephrectomy is a high-stake procedure involving healthy individuals, therefore every effort should be made to define each patient's individualized risk and improve potential donors' information. The aim of this study was to evaluate the interest of the Mayo adhesive probability (MAP) score, an imaging-based score initially designed to estimate the risk of adherent perinephric fat in partial nephrectomy, to predict intra- and postoperative complications of living donor nephrectomy. MATERIALS AND METHODS: We retrospectively reviewed the imaging, clinical, and follow-up data of 452 kidney donors who underwent laparoscopic donor nephrectomy in two academic centers. RESULTS: Imaging and follow-up data were available for 307 kidney donors, among which 44 (14%) had a high MAP score (≥ 3). Intraoperative difficulties were encountered in 50 patients (16%), including difficult dissection (n = 35) and bleeding (n = 17). Conversion to open surgery was required for 13 patients (4.2%). On multivariate analysis, a MAP score ≥ 3 was significantly associated with the risk of intraoperative difficulty [OR 14.12 (5.58-35.7), p < 0.001] or conversion to open surgery [OR 18.96 (3.42-105.14), p = 0.0042]. Postoperative complications were noted in 99 patients (32%), including 12 patients (3.9%) with Clavien-Dindo grade III-IV complications. On multivariate analysis, a high MAP score was also associated with the risk of postoperative complications [OR 2.55 (1.20-5.40), p = 0.01]. CONCLUSIONS: In this retrospective bicentric study, a high MAP score was associated with the risk of intra- and postoperative complications of laparoscopic donor nephrectomy. The MAP score appears of interest in the living donor evaluation process to help improve donors' information and outcomes.

Outcomes in Living Donor Kidney Transplantation: The Role of Donor's Kidney Function.

INTRODUCTION: Living donor kidney transplant (LDKT) is one of the best therapeutic options for end-stage kidney disease (ESKD). Guidelines identify different estimated glomerular filtration rate (eGFR) thresholds to determine the eligibility of donors. The aim of our study was to evaluate whether pretransplant donor eGFR was associated with kidney function in the recipient. METHODS: We retrospectively studied LDKT recipients who received a kidney graft between September 1, 2005, and June 30, 2016 in the same transplant center in France and that had eGFR data available at 3, 12, 24, and 36 months posttransplant. RESULTS: We studied 90 donor-recipient pairs. The average age at time of transplant was 51.47 ± 10.95 for donors and 43.04 ± 13.52 years for recipients. Donors' average eGFR was 91.99 ± 15.37 mL/min/1.73 m2. Donor's age and eGFR were significantly correlated (p < 0.0001, r2 0.023). Donor's age and eGFR significantly correlated with recipient's eGFR at 3, 12, and 24 months posttransplant (age: p < 0.001 at all intervals; eGFR p = 0.001, 0.003, and 0.016, respectively); at 36 months, only donor's age significantly correlated with recipient's eGFR. BMI, gender match, and year of kidney transplant did not correlate with graft function. In the multivariable analyses, donor's eGFR and donor's age were found to be associated with graft function; correlation with eGFR was lost at 36 months; and donor's age retained a strong correlation with graft function at all intervals (p < 0.001). CONCLUSIONS: Donor's eGFR and age are strong predictors of recipient's kidney function at 3 years. We suggest that donor's eGFR should be clinically balanced with other determinants of kidney function and in particular with age.

Treatment of refractory myasthenia gravis by double-filtration plasmapheresis and rituximab: A case series of nine patients and literature review.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease mediated by circulating autoantibodies (anti-AchR, anti-MuSK, etc.). More than 20% of myasthenic patients are refractory to conventional treatments (plasma exchange, IVIg, steroids, azathioprine, mycophenolate mofetil). Rituximab (B-lymphocyte-depleting anti-CD20) and apheresis (double-filtration plasmapheresis [DFPP] and immunoadsorption [IA]) are interesting therapeutic alternatives. METHODS: This monocentric pilot study included nine refractory myasthenic patients (March 2018 to May 2020) treated by DFPP and/or IA associated with rituximab (375 mg/m2 ). Clinical responses were assessed using the Myasthenia Gravis Foundation of America (MGFA) score. RESULTS: Average age of patients was 53 ± 17 years. Gender ratio (M/F) was 3:6. The combination of apheresis and rituximab reduced median MGFA score from IV to II after 12 months of follow-up. Clinical improvement assessed by MGFA score was sustained in the long-term for all patients, during an average follow-up of 14 ± 9 months, allowing them to be self-sufficient and out sick-leave. The median number of apheresis sessions was 7 (5-30). The dose of prednisolone was reduced in two patients from 40 mg/d and 30 mg/d to 7.5 mg/d and 10 mg/d, respectively. It was stopped in a patient who was taking 30 mg/d. No infectious, bleeding, or thrombosis complications were noted. CONCLUSION: The combination of rituximab and DFPP was effective to treat refractory MG.

How to improve clotting factors depletion in double-filtration plasmapheresis.

BACKGROUND: Double-filtration plasmapheresis (DFPP), a selective therapeutic apheresis, can deplete pathogenic antibodies/substances, but also important coagulation factors. AIM: To determine if the use of a separator filter with different characteristics (CascadefloEC-50 W) as compared to the reference filter (PlasmafloOP-08 W) is as efficient in terms of immunoglobulin loss, but can reduce coagulation factor losses and have similar tolerability. PATIENTS/METHODS: This is a single-center prospective study including 14 patients divided into two groups (7 each): that is, group1 = CascadefloEC-50 W and group2 = PlasmafloOP-08 W. We measured immunoglobulins, lipid profiles, blood-cell counts, hemostasis (prothrombin time, activated partial thromboplastin time), coagulation factors, and natural anticoagulants at before and after the first DFPP-session. RESULTS: In group 1, the loss of coagulation factors was significantly reduced as compared to group 2 for proteins with a molecular weight of >150 kDa: there was, respectively, an average decrease of 70% vs 31% for fibrinogen (P = 0.004), 66% vs 21% for factor V (P = 2.16e-07), 60% vs 32% for factor XI (P = 6.96e-06), 75% vs 17% for XIII-antigen (P = 0.0002), and 47% vs 0% for VWF-antigen(P = 0.02). The decrease in post-session IgG was, on average, 45% in group 1 and 50% in group 2 (P = 0.13). Those results remained significant even when adjusted to the treated-plasma volume and the pre-DFPP factor values. CONCLUSION: DFPP, using a CascadefloEC-50W as a first-filter, reduces efficiently IgGs similarly to PlasmafloOP-08W but spares clotting factors.

Fibrinogen reconstitution after therapeutic apheresis: Comparison of double-filtration plasmapheresis, plasma exchange, and immunoadsorption.

BACKGROUND: Fibrinogen reconstitution after therapeutic apheresis has been poorly studied. Apheresis modalities, for example, plasma exchange (PE), double-filtration plasmapheresis (DFPP), or selective immunoadsorption (IA), may have different impacts. METHODS: We retrospectively investigated therapeutic apheresis sessions performed at our center across four modalities (PE, DFPP, and IA with or without plasma filtration). Fibrinogen levels were assessed at the beginning and end of each apheresis session, and immediately before the subsequent session. We adjusted measurements on hematocrit values to account for hemoconcentration. RESULTS: Between January 10, 2016 and March 2, 2020, we included 90 patients for a total of 754 apheresis sessions (PE: 35; DFPP: 351; IA only: 109; IA + plasma filtration: 259). Each patient received a median of five sessions (1Q 3; 3Q 9); median plasma volume treated was 5.5 L (1Q 4.3 L; 3Q 7.0 L). Within a session, DFPP and PE induced a significantly greater depletion of fibrinogen than both IA modalities, even after adjustment for the treated plasma volume. Median fibrinogen reconstitution was 0.8 (0.4-1.2) g/L (median time between sessions: 38 hours). In multivariate analysis, fibrinogen reconstitution was significantly associated with intersession time (+0.66 g/L/log-hour P < .001), apheresis modality (ANOVA; P < .001), initial fibrinogen concentration (+0.15 g/L per gram of fibrinogen; P < .001), and the last fibrinogen concentration from the previous apheresis session (-0.14 g/L per gram of fibrinogen; P < .001). In a model that considered hemoconcentration, the results were unchanged. CONCLUSIONS: We demonstrate that fibrinogen reconstitution was highly variable between patients and apheresis sessions. Apheresis modalities had a significant impact on fibrinogen reconstitution, regardless of hemoconcentration.

Comparison of three modalities of plasmapheresis on coagulation: Centrifugal, single-membrane filtration, and double-filtration plasmapheresis.

BACKGROUND: Plasmapheresis can deplete pathogenic antibodies and allow ABO- and/or HLA-incompatible transplantation. AIM: To determine the impacts of three modalities of plasmapheresis (centrifugal plasmapheresis [cTPE], single-filtration plasmapheresis [mTPE], double-filtration plasmapheresis [DFPP]) on hemostasis parameters and thrombin generation. MATERIALS/METHODS: Prospective, comparative study on 21 patients that received three modalities of plasmapheresis (7 patients/group). Hemostasis (prothrombin time [PT], activated partial thromboplastin time [aPTT], procoagulant factors and natural anticoagulants) were measured before and after the first plasmapheresis session. Thrombin generation was also assessed in platelet-poor plasma using an STA-Genesia (Stago) analyzer and Thromboscreen reagents (Stago) in 4-5 patients from each group. RESULTS: Both cTPE and mTPE resulted in high decreases in proteins, whatever their molecular weights. Median post/pre ratios were 0.27 to 0.55 for cTPE for most proteins (except FVIII [0.64] and VWF [0.57]). Median post/pre-ratios of mTPE were 0.28 to 0.56 for all proteins. DFPP decreased high-molecular-weight proteins (fibrinogen, FV, FVIII, FXI, VWF) and proteins strongly bound to large molecules (protein SandTFPI). Median post/pre ratios with cTPE and mTPE were similar to DFPP for fibrinogen and FXIII. Regarding thrombin generation, cTPE and mTPE did not significantly modify endogenous thrombin potential (ETP) and DFPP induced a slight decrease in ETP (median post/pre ratio at 0.73) in the absence of thrombomodulin. ETP inhibition by thrombomodulin was decreased for all procedures. CONCLUSIONS: DFPP depleted high molecular-weight proteins in contrast to cTPE and mTPE, which significantly decreased all proteins. Regarding thrombin generation, depletion of procoagulant factors was counterbalanced by a decrease in some natural anticoagulants whatever plasmapheresis method used; with all methods, fibrinogen and FXIII were highly depleted.

Treatment of antibody-mediated rejection with double-filtration plasmapheresis, low dose IVIg plus rituximab after kidney transplantation.

Antibody-mediated rejection (ABMR) at early or late post-transplantation remains challenging. We performed a single-center single-arm study where four cases of acute ABMR and nine cases of chronic active ABMR (defined by Banff classification) were treated with double-filtration plasmapheresis (two cycles of three consecutive daily sessions with a 4-day gap between). At the end of the third and sixth DFPP sessions, the patients received rituximab 375 mg/m2 . After a median follow-up of 1078 (61-1676) days, kidney-allograft survival was 50%. Before DFPP/rituximab therapy, the median donor-specific alloantibody (DSA) mean fluorescence intensity (MFI) was 9160 (4000-15 400); 45 days (D45) later it had significantly decreased to 7375 (215-18 100) (P = .018). In addition, at one-year (Y1) post-therapy, MFI had decreased further, that is, 4060 (400-7850) (P = .001). In two patients, DSA MFIs decreased and remained below 2000. The slope of estimated glomerular-filtration rate within the 6 months preceding intervention was -1.18 mL/min/month and remained unchanged at -1.29 mL/min/month within the year after intervention. Proteinuria remained unchanged. Baseline Banff scores on repeat allograft biopsies (post-therapy D45, Y1) did not show any improvement. Side-effects were mild to moderate. We conclude that the combined DFPP/rituximab significantly decreased DSAs in ABMR kidney-transplant recipients but did not improve renal function or renal histology at 1-year follow-up.

Isoagglutinin removal by plasma centrifugation or filtration (single or double): A prospective study in a single center.

INTRODUCTION: ABO-incompatible (ABOi) kidney transplantation, a well-established procedure, has good long-term results provided pretransplant desensitization that includes immunosuppression and apheresis. OBJECTIVE: To compare, within the first pretransplant apheresis session given to 29 ABOi kidney-transplant candidates, the effect on isoagglutinin titers (both IgG and IgM isotypes) of three modalities: centrifugation therapeutic plasmapheresis (cTP; n = 10), filtration TP (fTP; n = 9), and double-filtration plasmapheresis (DFPP; n = 10). RESULTS: The three groups were comparable according to baseline demographics. Treated plasma volumes were similar across the three groups, that is, 4111 ± 403 mL (cTP), 3861 ± 282 mL (fTP), and 3699 ± 820 mL (DFPP): that is, 54 ± 7, 53 ± 7, and 53 ± 10 mL/kg respectively. One session of centrifugation or filtration TP reduced IgG anti-A/anti-B isoagglutinin titer by ~4, whereas one DFPP session reduced it by ~2. One session of cTP reduced IgM anti-A isoagglutinin titer by a little less than 4, whereas fTP and DFPP sessions reduced it by ~3. There were no statistical differences across the three groups regarding isoagglutinin rebound (IgG and IgM). However, isoagglutinin IgG rebound was >4 dilutions for anti-B titers compared with ~2 dilutions for anti-A titers. The median decreases in IgG level were -3.9 g/L (DFPP), -5.9 g/L (cTP), and - 6.06 g/L (fTP) (p = ns). Median fibrinogen depletions were ~ 60% (fTP), 64% (DFPP), and 76% (cTP). CONCLUSIONS: Isoagglutinin depletions within the first apheresis session were similar across cTP, fTP, and DFPP: this was numerically lower for DFPP.

Immunoadsorption for Recurrent Primary Focal Segmental Glomerulosclerosis on Kidney Allografts: A Single-Center Experience and Literature Review.

INTRODUCTION: Primary focal and segmental glomerulosclerosis (FSGS) frequently reoccurs on kidney transplants and may lead to premature allograft loss. There are no guidelines for treating FSGS recurrence on allografts; treatment is based on apheresis (plasma exchange plasmapheresis [PP], semi-specific immunoadsorption [IA] with reusable columns) plus rituximab. OBJECTIVE: We aimed to assess the efficacy of IA to treat recurrent FSGS. METHODS: We report on 7 patients with recurrent FSGS on kidney allograft (proteinuria ≥3 g/g of urinary creatinine or ≥3 g/day); they all received IA. Our primary objective was to reduce proteinuria by >50%. Patients' mean age was 45 ± 10 years. Postoperative immunosuppression relied on steroids, mycophenolate mofetil, tacrolimus, with an induction therapy of basiliximab or antithymocyte globulins. Prophylaxis to prevent FSGS recurrence was either rituximab alone (n = 3), rituximab plus either PP or IA (n = 3), or no treatment (n = 1). Mean follow-up was 20 ± 13 months. There was a median of 72 (14-101) IA sessions per patient, that is, a mean of 14 ± 1 sessions per IA column. RESULTS: At 12 months after starting IA, all patients had partial (n = 6) or complete (n = 1) remission, and allograft survival was 100%. The mean reduction in proteinuria within an IA session was 45 ± 15%. At last follow-up, 2 patients are in remission without IA, 3 patients are in partial remission that is IA dependent, and 2 patients lost their allograft due to FSGS recurrence. The most frequent adverse event was cytomegalovirus reactivation (n = 13), which subsided after valganciclovir therapy. CONCLUSIONS: We show that recurrence of FSGS can be controlled long term with IA plus rituximab. However, some patients remained dependent on IA.

Effect of immunoadsorption alone or combined with membrane filtration on hemostasis parameters.

INTRODUCTION: ABO- or HLA-incompatible kidney transplantation is possible thanks to pretransplant antibody-depletion achieved by extracorporeal-treatment modalities. These methods induce depletion of some plasma proteins and may also impact on proteins involved in hemostasis. METHODS: To determine the impact of one session of immunoadsorption (IA) alone or combined with membrane filtration (MF) on clotting factors and natural anticoagulants, we performed a prospective, observational study on 13 patients waiting for HLA-/ABO-incompatible kidney transplants. Plasma hemostasis parameters were measured before and immediately after a first session of IA alone in six patients and of IA + MF in seven patients. RESULTS: IA alone induced depletion of fibrinogen and factor XIII (FXIII) whereas IA + MF caused greater depletion of all high-molecular-weight hemostatic proteins (fibrinogen, FV, FVIII, FXI, FXIII, von-Willebrand factor [VWF]). After an IA session, median reductions were 30% for fibrinogen and 43% for FXIII compared to baseline values. After a session of IA + MF, median decreases were 70% for fibrinogen, 54% for FV, 56% for FVIII, 37% for FXI, 78% for FXIII, and 62% for VWF. Noticeably, levels of low-molecular-weight factors (<100 kDa) were far less decreased than high-molecular-weight proteins with IA + MF, except for protein S and the tissue factor pathway inhibitor, which are known to be partially physiologically bound to high-molecular-weight molecules. CONCLUSIONS: IA and IA + MF induced significant depletion of some proteins implicated in the hemostatic process; however, IA + MF resulted in stronger modifications to hemostasis parameters than IA alone. This may have potential clinical implications regarding bleeding risk, and particularly depletion of fibrinogen and FXIII.

Aortic bypass surgery for asymptomatic patients awaiting a kidney transplant: A word of caution.

INTRODUCTION: In the presence of severe aorto-iliac calcification, aortic bypass surgery can be mandatory to allow kidney transplantation. The aim of our study was to evaluate the safety and outcomes of this strategy among asymptomatic patients. MATERIALS AND METHODS: We retrospectively reviewed the files of all patients that had undergone vascular bypass surgery prior to kidney transplantation between November 2004 and March 2016. All patients undergoing aortic bypass surgery prior to kidney transplantation without any vascular-related symptoms were included. RESULTS: Twenty-one asymptomatic patients were included. Ten patients (48%) have not received a kidney transplant. Four patients died before kidney transplantation, including 2 deaths related to the bypass surgery (9.5%). Early post-operative morbidity involved 11 cases. Eleven patients (52%) were transplanted. Transplanted patients were significantly younger (median age 60 [56-61] vs 67 [60-72] years, P = .04) at the time of bypass and were less frequently treated for coronary heart disease (9% vs 50%, P = .06). CONCLUSION: Aortic bypass surgery performed prior to kidney transplantation among asymptomatic patients has significant mortality and morbidity rates. When transplantation is possible, the results are satisfying. Larger studies are required to define the selection criteria, such as age and coronary heart disease.

Reducing Fibrinogen and Factor XIII Using Double-Filtration Plasmapheresis for Antibody-Mediated Rejection: Predictive Models.

BACKGROUND/AIMS: Antibody-mediated rejection (AMR) is related to circulating donor-specific anti-human leukocyte antigen alloantibodies (DSAs). DSAs can be removed by apheresis, for example, double-filtration plasmapheresis (DFPP). However, DFPP removes some clotting factors (fibrinogen and factor XIII [FXIII]). METHODS: This was a prospective trial including 6 DSA-mediated AMR kidney transplant recipients. Patients received 2 cycles of 3-4 consecutive DFPP sessions followed by 1 injection of rituximab (break of 4-5 days between the 2 cycles). We monitored fibrinogen and FXIII levels before and after each session of DFPP. RESULTS: Overall, fibrinogen and FXIII levels were significantly decreased after each session, and were significantly reduced between the very first and very last sessions. In addition, we established a model that predicted fibrinogen and FXIII values after each session and after 2 cycles. CONCLUSION: We established a model in order to predict fibrinogen and FXIII depletion after DFPP sessions; it may help clinicians supplement fibrinogen and/or FXIII when appropriate.

Peripheral vasoconstriction induced by ß-adrenoceptor blockers: a systematic review and a network meta-analysis.

AIM: Peripheral vasoconstriction has long been described as a vascular adverse effect of ß-adrenoceptor blockers. Whether ß-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to ß1 -adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta-analysis in order to assess the comparative risk of peripheral vasoconstriction of different ß-adrenoceptor blockers. METHOD: We searched for randomized controlled trials (RCTs) including ß-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of ß-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the ß-adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374). RESULTS: Among 2238 records screened, 38 studies including 57 026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with ß-adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not. CONCLUSION: Our results suggest that ß-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to ß1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of ß-adrenoceptor blockers and suggest that ß-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.

Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions.

High glucose (HG) or synthetic advanced glycation end-products (AGE) conditions are generally used to mimic diabetes in cellular models. Both models have shown an increase of apoptosis, oxidative stress and pro-inflammatory cytokine production in tubular cells. However, the impact of the two conditions combined has rarely been studied. In addition, the impact of glucose level variation due to cellular consumption is not clearly characterized in such experiments. Therefore, the aim of this study was to compare the effect of HG and AGE separately and of both on tubular cell phenotype changes in the HK2 cell line. Moreover, glucose consumption was monitored every hour to maintain the glucose level by supplementation throughout the experiments. We thus observed a significant decrease of apoptosis and H2O2 production in the HK2 cell. HG or AGE treatment induced an increase of total and mitochondrial apoptosis as well as TGF-ß release compared to control conditions; however, AGE or HG led to apoptosis preferentially involving the mitochondria pathway. No cumulative effect of HG and AGE treatment was observed on apoptosis. However, a pretreatment with RAGE antibodies partially abolished the apoptotic effect of HG and completely abolished the apoptotic effect of AGE. In conclusion, tubular cells are sensitive to the lack of glucose as well as to the HG and AGE treatments, the AGE effect being more deleterious than the HG effect. Absence of a potential synergistic effect of HG and AGE could indicate that they act through a common pathway, possibly via the activation of the RAGE receptors.

Conversion to mammalian target of rapamycin inhibitors increases risk of de novo donor-specific antibodies.

In kidney transplantation, conversion to mammalian target of rapamycin (mTOR) inhibitors may avoid calcineurin inhibitor (CNI) nephrotoxicity, but its impact on post-transplant allo-immunization remains largely unexplored. This retrospective cohort study analyzed the emergence of donor-specific antibodies (DSA) in kidney transplant recipients relative to their immunosuppressive therapy. Among 270 recipients without pretransplant immunization who were screened regularly for de novo DSA, 56 were converted to mTOR inhibitors after CNI withdrawal. DSA emergence was increased in patients who were converted to mTOR inhibitors (HR 2.4; 95% CI 1.06-5.41, P = 0.036). DSA were mainly directed against donor HLA-DQB1 antigens. The presence of one or two DQ mismatches was a major risk factor for DQ DSA (HR 5.32; 95% CI 1.58-17.89 and HR 10.43; 95% CI 2.29-47.56, respectively; P < 0.01). Rejection episodes were more likely in patients converted to mTOR inhibitors, but this difference did not reach significance (16% vs. 7.9%, P = 0.185). Concerning graft function, no significant change was observed one year after conversion (P = 0.31). In conclusion, conversion to mTOR inhibitors may increase the risk of developing class II DSA, especially in the presence of DQ mismatches: this strategy may favor chronic antibody-mediated rejection and thus reduce graft survival.