Harnessing Immune Cell Metabolism to Modulate Alloresponse in Transplantation.

Immune cell metabolism plays a pivotal role in shaping and modulating immune responses. The metabolic state of immune cells influences their development, activation, differentiation, and overall function, impacting both innate and adaptive immunity. While glycolysis is crucial for activation and effector function of CD8 T cells, regulatory T cells mainly use oxidative phosphorylation and fatty acid oxidation, highlighting how different metabolic programs shape immune cells. Modification of cell metabolism may provide new therapeutic approaches to prevent rejection and avoid immunosuppressive toxicities. In particular, the distinct metabolic patterns of effector and suppressive cell subsets offer promising opportunities to target metabolic pathways that influence immune responses and graft outcomes. Herein, we review the main metabolic pathways used by immune cells, the techniques available to assay immune metabolism, and evidence supporting the possibility of shifting the immune response towards a tolerogenic profile by modifying energetic metabolism.

Imlifidase for Kidney Transplantation of Highly Sensitized Patients With a Positive Crossmatch: The French Consensus Guidelines.

Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.

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.

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.

CMV-infected kidney grafts drive the expansion of blood-borne CMV-specific T cells restricted by shared class I HLA molecules via presentation on donor cells.

We aimed to determine the role of cytomegalovirus (CMV)-infected donor cells in the development of a CMV-specific immune response in kidney transplant recipients. We assessed the CMV pp65-specific immune response by using interferon-É£ ELISPOT and dextramers in peripheral blood mononuclear cells from 115 recipients (D+R- 31, D+R + 44, D-R + 40) late after transplantation (mean 59 ± 42 months). Receiving a kidney from a D+ donor resulted in a higher number of IFN-É£-producing anti-CMV T cells (P = .004). This effect disappeared with the absence of shared HLA class I specificities between donors and recipients (P = .430). To confirm the role of donor cells in stimulating the expansion of newly developed CMV-specific CD8+ T cells after transplantation, we compared the number of HLA-A2-restricted CMV-specific CD8+ T cells in primo-infected recipients who received an HLA-A2 or non-HLA-A2 graft. The median of anti-CMV pp65 T cells restricted by HLA-A2 was very low for patients who received a non-HLA-A2 graft vs an HLA-A2 graft (300 [0-14638] vs. 17972 [222-85594] anti-CMV pp65 CD8+ T cells/million CD8+ T cells, P = .001). This adds new evidence that CMV-infected kidney donor cells present CMV peptides and drive an inflation of memory CMV-specific CD8+ T cells, likely because of frequent CMV replications within the graft.

From the Clinical to the Bench: Exploring the Insulin Modulation Effects of Tacrolimus and Belatacept.

Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show that late conversion from CNIs to belatacept, a costimulation blocker, improves HbA1c in kidney transplant recipients with PTD or de novo diabetes. This study investigates whether the observed effects on PTD stem solely from CNI withdrawal or if belatacept influences PTD independently. The study assessed the impact of tacrolimus and belatacept on insulin secretion in MIN6 cells (a beta cell line) and rat islets. Tacrolimus and belatacept were administered to the cells and islets, followed by assessments of cell viability and insulin secretion. Tacrolimus impaired insulin secretion without affecting cell viability, while belatacept showed no detrimental effects on either parameter. These findings support clinical observations of improved HbA1c upon switching from tacrolimus to belatacept. Belatacept holds promise in islet or pancreas transplantation, particularly in patients with unstable diabetes. Successful cases of islet transplantation treated with belatacept without severe hypoglycemia highlight its potential in managing PTD. Further research is needed to fully understand the metabolic changes accompanying the transition from CNIs to belatacept. Preserving insulin secretion emerges as a promising avenue for investigation in this context.

Cytomegalovirus detection is associated with ICU admission in non-AIDS and AIDS patients with Pneumocystis jirovecii pneumonia.

OBJECTIVES: Cytomegalovirus (CMV) is frequently detected in lung and/or blood samples of patients with Pneumocystis jirovecii pneumonia (PJP), although this co-detection is not precisely understood. We aimed to determine whether PJP was more severe in case of CMV detection. METHODS: We retrospectively included all patients with a diagnosis of PJP between 2009 and 2020 in our centre and with a measure of CMV viral load in blood and/or bronchoalveolar lavage (BAL). PJP severity was assessed by the requirement for intensive care unit (ICU) admission. RESULTS: The median age of the 249 patients was 63 [IQR: 53-73] years. The main conditions were haematological malignancies (44.2%), solid organ transplantations (16.5%), and solid organ cancers (8.8%). Overall, 36.5% patients were admitted to ICU. CMV was detected in BAL in 57/227 patients; the 37 patients with viral load ≥3 log copies/mL were more frequently admitted to ICU (78.4% vs 28.4%, p<0.001). CMV was also detected in blood in 57/194 patients; the 48 patients with viral load ≥3 log copies/mL were more frequently admitted to ICU (68.7% vs 29.4%, p<0.001). ICU admission rate was found to increase with each log of BAL CMV viral load and each log of blood CMV viral load. CONCLUSIONS: PJP is more severe in the case of concomitant CMV detection. This may reflect either the deleterious role of CMV itself, which may require antiviral therapy, or the fact that patients with CMV reactivation are even more immunocompromised.

Evaluation of Torque Teno Virus DNA Load as a Predictive Biomarker in Kidney Transplant Recipients Converted from Calcineurin Inhibitors to Belatacept.

Introduction: Belatacept is a relevant alternative to calcineurin inhibitors (CNIs) after kidney transplantation (KT). Circulating Torque Teno virus (TTV) DNA load is correlated to infections and rejection risks post-KT in patients treated with CNIs. The aim of this study was to assess the TTV DNA load profile in kidney transplant recipients converted from CNIs to belatacept and explore its use as a predictive biomarker. Methods: Sixty-eight single-center kidney transplanted recipients who were converted from CNIs to belatacept between June, 2015 and December, 2020 were included in this study. Whole blood TTV DNA load was measured before, at 3, 6, and 12 months post-belatacept conversion. Our primary end point was to assess the TTV DNA load profile and correlate the results with rejection and opportunistic infection (OPI). Results: TTV DNA load remained stable after belatacept conversion, that is, 3.8 (3.1-4.9), 4.4 (3.2-5.4), 4.0 (3.0-5.7) and 4.2 (3.0-5.2) log10 copies/ml at baseline, 3, 6, and 12 months, respectively. No correlation was found between TTV DNA load and post-KT complications. Chronic allograft dysfunction at 1 year postconversion was associated with a lower TTV DNA load after 6 and 12-months (P = 0.014 and P = 0.021, respectively). A higher TTV DNA load was found in older patients and in those with higher body mass index (BMI) (P = 0.023 and P = 0.005, respectively). Conclusion: Conversion from CNIs to belatacept did not affect TTV DNA load. OPIs or acute rejection occurrences were not associated with TTV DNA load. However, low TTV (lTTV) DNA load after 6 months postconversion may be a promising tool to predict graft dysfunction risk at 1-year postconversion.

Is There a Place for Apheresis in the Management of Idiopathic Membranous Nephropathy? A Report of Three Cases and Literature Review.

Membranous nephropathy constitutes approximately 20% of adult nephrotic syndrome cases. In approximately 80% of cases, membranous nephropathy is primary, mediated by IgG autoantibodies primarily targeting podocyte antigens (PLA2R, THSD7A, etc.). The treatment involves a combination of corticosteroids and cyclophosphamide or anti-CD20-based therapies, e.g., rituximab. In the event of significant proteinuria and in order to avoid the urinary elimination of rituximab, therapeutic apheresis, in particular semi-specific immunoadsorption, may be an option allowing for a reduction in proteinuria and autoantibodies before initiating treatment with rituximab. We present the preliminary experience of three patients treated with semi-specific immunoadsorption for primary membranous nephropathy between January 2021 and March 2023. Two patients were anti-PLA2R-autoantibody-positive and one was seronegative. The average age was 59 ± 17 years. Semi-specific immunoadsorption did not reduce albuminuria, but it, nevertheless, led to an increase in serum albumin, contributing to the regression of edema. It effectively eliminated anti-PLA2R autoantibodies in the two anti-PLA2R-positive patients. Consequently, apheresis may not induce a rapid reduction in proteinuria, but could contribute to a more accelerated remission when combined with the anti-CD20 treatment.

Imlifidase therapy: exploring its clinical uses.

INTRODUCTION: Imlifidase, the IgG-degrading enzyme derived from Streptococcus pyogenes, can cleave all four human IgG subclasses with precise specificity. All IgG molecules can be inactivated for ~1-to-2 weeks, until new IgG synthesis is detected. AREAS COVERED: Imlifidase was first studied for the desensitization of highly HLA-sensitized patients to enable kidney transplantation. It is currently being evaluated for kidney transplant recipients who have antibody-mediated rejection (AMR), those with acute kidney injury in the setting of anti-glomerular basement membrane disease, and those with Guillain-Barré syndrome. In 2020, imlifidase received conditional approval from the European Medicines Agency for use to desensitize deceased-donor kidney transplant recipients with a positive crossmatch. Literature search through PubMed revealed that so far, 39 crossmatched-positive patients, i.e. in the presence of donor-specific alloantibodies (DSA) on the transplantation day, have received imlifidase prior to kidney transplantation in four single-arm, open-label, phase II studies. Results at 3-year follow-up are good, i.e. allograft survival is 84%, despite 38% of patients presenting with acute AMR. Mean estimated glomerular filtration rate at 3 years was 55 mL/min/1.73 m2. EXPERT OPINION: The major hurdle now is how to prevent/avoid DSA rebound within days 5-15 post-transplantation. Thus, imlifidase represents a major breakthrough for highly HLA-sensitized kidney transplant candidates, particularly those that have calculated panel-reactive alloantibodies of ≥90%.

Desensitization in Crossmatch-positive Kidney Transplant Candidates.

Access to kidney transplantation is limited by HLA-specific sensitization. Desensitization strategies enable crossmatch-positive kidney transplantation. In this review, we describe clinical experience gained over the last 20 y using desensitization strategies before kidney transplantation and describe the different tools used (both drugs and apheresis options), including IVIg, rituximab, apheresis techniques, interleukin-6 interference, proteasome inhibition, enzymatic degradation of HLA antibodies, complement inhibition, and B cytokine interference. Although access to transplantation for highly sensitized kidney transplantation candidates has been vastly improved by desensitization strategies, it remains, however, limited by the recurrence of HLA antibodies after transplantation and the occurrence of antibody-mediated rejection.