Publications by authors named "Paolo Malvezzi"

65 Publications

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

Kidney Blood Press Res 2021 16;46(1):84-94. Epub 2021 Feb 16.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.

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.
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http://dx.doi.org/10.1159/000512177DOI Listing
February 2021

Obinutuzumab in Kidney Transplantation: Effect on B-cell Counts and Crossmatch Tests.

Transplantation 2021 Feb 11. Epub 2021 Feb 11.

Department of Nephrology, Kasr AlAiny School of Medicine, Cairo University, Cairo, Egypt Misr International Hospital, Cairo, Egypt Cairo University Student's Hospital, Cairo, Egypt Department of Clinical Pathology, Kasr AlAiny School of Medicine, Cairo University, Cairo, Egypt National Institute of Nephrology and Urology, Cairo, Egypt Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France Université Grenoble Alpes, Grenoble, France.

Background: Resistance to the action of rituximab (RTX) has been documented in several diseases. More recently, obinutuzumab (OBZ) has shown promise where RTX has failed in oncology and lupus nephritis. Unlike RTX, OBZ is a weak activator of complement, which may avoid the false-positive complement-dependent cytotoxicity (CDC) crossmatch tests after RTX infusions.

Methods: The aim of this study was to explore the effect of OBZ on B-cell depletion in kidney-transplant candidates and its impact on crossmatch test results. We included 12 patients: who were either highly sensitized kidney-transplant candidates or kidney-transplant recipients presenting with antibody-mediated rejection. Six received OBZ and 6 received RTX. CD-19 counts, flow cytometry and CDC crossmatch tests were run immediately before and at 2 weeks after drug infusion.

Results: OBZ reduced CD-19 counts: median reduction was 98%. B-cell CDC crossmatch test results became positive following RTX infusion but were not affected by OBZ infusion.

Conclusions: OBZ effectively depleted B-cell counts in sensitized kidney-transplant candidates and, unlike RTX, had no effect on CDC crossmatch results.
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http://dx.doi.org/10.1097/TP.0000000000003686DOI Listing
February 2021

Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Results of a nationwide study.

Am J Transplant 2021 Jan 29. Epub 2021 Jan 29.

Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.

Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004-12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia <5 g/L. RTX could be used in cases of SOC failure or remission for early discontinuation of PP without increasing the risk of infection.
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http://dx.doi.org/10.1111/ajt.16504DOI Listing
January 2021

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

J Clin Apher 2021 Jan 28. Epub 2021 Jan 28.

Université Grenoble Alpes, Grenoble, France.

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.
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http://dx.doi.org/10.1002/jca.21879DOI Listing
January 2021

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

J Clin Apher 2020 Dec 21. Epub 2020 Dec 21.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble, La Tronche, France.

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/m ). 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.
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http://dx.doi.org/10.1002/jca.21868DOI Listing
December 2020

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

J Clin Apher 2021 Feb 23;36(1):149-160. Epub 2020 Nov 23.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

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.
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http://dx.doi.org/10.1002/jca.21857DOI Listing
February 2021

pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression.

Expert Rev Clin Pharmacol 2021 Jan 15;14(1):55-66. Epub 2020 Dec 15.

Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.

Introduction: Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors.

Areas Covered: We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation.

Expert Opinion: PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
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http://dx.doi.org/10.1080/17512433.2021.1851596DOI Listing
January 2021

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

World J Urol 2020 Nov 11. Epub 2020 Nov 11.

Department of Urology and Kidney Transplantation, Grenoble Alpes University Hospital, CS 10217, 38043, Grenoble Cedex 9, France.

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.
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http://dx.doi.org/10.1007/s00345-020-03513-4DOI Listing
November 2020

Opportunistic Infections and Efficacy Following Conversion to Belatacept-Based Therapy after Kidney Transplantation: A French Multicenter Cohort.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38000 Grenoble, France.

Conversion from calcineurin-inhibitors (CNIs) to belatacept can help kidney-transplant (KT) recipients avoid CNI-related nephrotoxicity. The risk of associated opportunistic infections (OPIs) is ill-defined. We conducted a multicentric cohort study across 15 French KT-centers in a real-life setting. Between 07-2010 and 07-2019, 453 KT recipients were converted from CNI- to belatacept-based therapy at 19 [0.13-431] months post-transplantation. Most patients, i.e., 332 (79.3%), were converted after 6-months post-transplantation. Follow-up time after conversion was 20.1 +/- 13 months. OPIs developed in 42(9.3%) patients after 14 +/- 12 months post-conversion. Eight patients (19%) had two OPI episodes during follow-up. Incidences of CMV DNAemia and CMV disease were significantly higher in patients converted before 6-months post-KT compared to those converted later (i.e., 31.6% vs. 11.5%; < 0.001; and 11.6% vs. 2.4%, < 0.001, respectively). Cumulative incidence of OPIs was 6.5 OPIs/100 person-years. Incidence of CMV disease was 2.8/100 person-years, of pneumocystis pneumonia 1.6/100 person-years, and of aspergillosis 0.2/100 person-years. Multivariate analyses showed that estimated glomerular filtration (eGFR) < 25 mL/min/1.73 m at conversion was independently associated with OPIs (HR = 4.7 (2.2 - 10.3), < 0.001). The incidence of EBV DNAemia was 17.3 events /100 person-years. At 1-year post-conversion, mean eGFR had significantly increased from 32.0 +/- 18 mL/min/1.73 m to 42.2 +/- 18 mL/min/1.73 m ( < 0.0001). Conversion to belatacept is an effective strategy with a low infectious risk.
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http://dx.doi.org/10.3390/jcm9113479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693007PMC
October 2020

Impact of Immunosuppressive Strategies on Post-Kidney Transplantation Thrombocytopenia.

Transplant Proc 2020 Oct 26. Epub 2020 Oct 26.

Nephrology Department, Hémodialyse, Apheresis and Renal Transplantation, CHU Grenoble-Alpes, Grenoble, France.

Background: Thrombocytopenia after kidney transplantation is a common complication, partly induced by immunosuppressive therapies. Peritransplant thrombocytopenia may cause serious hemorrhages. We assessed the incidence of early posttransplantation thrombocytopenia (defined as a platelet count of <150,000 mm or <150 G/L) in de novo kidney transplant recipients (KTRs) across 4 immunosuppressive regimens.

Methods: This was a single-center observational study that included all consecutive KTRs who received either Thymoglobulin (THY) or Grafalon (GRA) and maintenance therapy of either mycophenolate-mofetil (MMF) or everolimus (EVR), associated with tacrolimus/corticosteroids.

Results: Between July 27, 2016, and September 7, 2018, 237 KTRs were included; 64.6% experienced thrombocytopenia within the first week. Thrombocytopenia was significantly more frequent (P = .004) among GRA-treated patients (73.4%) compared to THY-treated patients (61.3%). These patients also had lower nadir platelet count (120 ± 52 vs 142 ± 48 G/L; P = .002) and lower platelet count at discharge (227 ± 94 vs 243 ± 92 G/L; P = .25). More of the GRA-EVR group had thrombocytopenia (81.0% vs 61.4% in THY-MMF, 60.9% in THY-EVR, and 69.8% in GRA-MMF; P = .081) and a worse nadir platelet count (109 ± 41 in GRA-EVR vs 141 ± 47G/L in THY-MMF, 145 ± 52 G/L in THY-EVR, and 125 ± 56 G/L in GRA-MMF; P = .011) but GRA was the only risk factor for thrombocytopenia in multivariate analyses (P = .002). Rates of hemorrhage, red blood cell transfusions, reoperations needed within the first week, delayed graft function, acute rejection, graft loss, and death did not differ between the groups after a mean follow-up of 25 ± 8 months.

Conclusions: GRA associated with EVR led to more frequent and severe thrombocytopenia, although we found no significant clinical consequences.
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http://dx.doi.org/10.1016/j.transproceed.2020.09.014DOI Listing
October 2020

Simultaneous quantification of rituximab and eculizumab in human plasma by liquid chromatography-tandem mass spectrometry and comparison with rituximab ELISA kits.

Clin Biochem 2021 Jan 20;87:60-66. Epub 2020 Oct 20.

Univ. Grenoble Alpes, INSERM, CHU Grenoble Alpes, HP2, 38000 Grenoble, France. Electronic address:

Objectives: Specific and sensitive analytical techniques to quantify therapeutic monoclonal antibodies (mAbs) are required for therapeutic drug monitoring. The quantification of mAbs has been historically performed using enzyme-linked immunosorbent assays (ELISAs), for which the limitations in terms of specificity have led to the development of alternative analytical strategies.

Methods: Here, we describe the validation of a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for the simultaneous quantification of rituximab (RTX - anti-CD20) and eculizumab (ECU - anti-C5). Sample preparation was based on our previously published method, using protein G purification and trypsin digestion. A new specific peptide for RTX, containing an N-terminal pyroglutamine and a trypsin miss-cleavage, enables better sensitivity, while peptide of ECU was chosen thanks to an in silico trypsin digestion and the Skyline® software. Full-length stable-isotope-labeled adalimumab was added to plasma samples as an internal standard. RTX in 50 human serum samples was quantified by LC-MS/MS and the concentrations obtained compared to those obtained with two commercial ELISA kits (Lisa Tracker® and Promonitor®).

Results: Calibration curves were linear from 1 to 200 µg.mL for RTX and 5 to 200 µg.mL for ECU, and within-day and between-day accuracy and precision fulfilled Food and Drug Administration validation criteria. Comparison of the LC-MS/MS method with ELISA showed a negligible bias with the Lisa Tracker® kit (4%), but significant bias with the Promonitor® assay (mean underestimation of 69% for the Promonitor® assay).

Conclusions: This new LC-MS/MS method allows the simultaneous quantification of RTX and ECU in human samples and could be used for therapeutic drug monitoring.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.10.007DOI Listing
January 2021

Cytomegalovirus disease in de novo kidney-transplant recipients: comparison of everolimus-based immunosuppression without prophylaxis with mycophenolic acid-based immunosuppression with prophylaxis.

Int Urol Nephrol 2021 Mar 15;53(3):591-600. Epub 2020 Oct 15.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, CS 10217, 38043, Grenoble Cedex 09, France.

Purpose: To compare everolimus (EVR) plus low-dose tacrolimus (TAC) with mycophenolic acid (MPA) plus standard-dose TAC with regards to rates of cytomegalovirus (CMV) disease in de novo kidney-transplant recipients (KTRs).

Methods: This single-center retrospective study included 187 de novo KTRs; 59 patients (31.6%) received EVR/low-dose TAC (group 1); 128 patients (68.4%) received MPA with standard-dose TAC (group 2). All received anti-thymocyte globulins as the induction therapy, and steroid-sparing strategy. Valganciclovir prophylaxis was mandatory for CMV D+/R- KTRs (seronegative recipients of a seropositive donor) in both groups and for R+ seropositive recipients (only in group 2).

Results: The 2-year incidence of CMV disease was low and comparable between groups: 6.8% and 7.0% in groups 1 and 2, respectively (p = 0.94). There was no statistical difference in CMV serostatus (p = 1). However, CMV disease tended to be less frequent, though not statistically different, in R+ KTRs receiving EVR without prophylaxis (3.7% vs. 8.5% in groups 1 and 2, respectively) and in patients without EVR discontinuation (2.6% vs. 6.9% in patients who did not discontinue MPA (p = 0.29). Two-year graft function was good and comparable between groups (median eGFR of 54.2 and 53.0 mL/min in groups 1 and 2, respectively; p = 0.47); incidence of immunological events was low. Significantly more patients in group 1 discontinued EVR because of adverse events than patients that discontinued MPA in group 2 (35.6% in group 1 vs. 10.2% in group 2; p < 0.001).

Conclusions: Everolimus plus low-dose TAC given to de novo KTRs was associated with low rates of CMV disease, especially in R+ patients with no CMV prophylaxis.
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http://dx.doi.org/10.1007/s11255-020-02676-8DOI Listing
March 2021

Transplantation in the era of the Covid-19 pandemic: How should transplant patients and programs be handled?

Rev Med Virol 2021 01 20;31(1):1-9. Epub 2020 Sep 20.

Service de Néphrologie, Hémodialyse, Aphérèseset Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

Due to the Covid-19 pandemic caused by SARS-CoV-2, transplant programs worldwide have been severely impacted with dwindling numbers of transplantations performed and a complete halt in several areas. In this review we examine whether SARS-CoV-2 infection presents differently in transplant recipients, whom and how we should test, how susceptible the transplant population is to overt infection and describe the range of outcomes. From retrieved published reports on SARS-CoV-2infections in 389solid organ transplant recipients reported in the literature, the overall mortality rate was 16.7% (n = 65); however for those with mild or moderate Covid-19 disease this was 2.9% and 2.3% respectively; conversely, for those with severe infection the mortality rate was 52.2%.We then address questions regarding halting transplantation programs during this pandemic, whether all human tissues being considered for transplantation are capable of transmitting the infection, and if we should alter immunosuppressive medications during the pandemic.
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http://dx.doi.org/10.1002/rmv.2149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537021PMC
January 2021

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

J Clin Apher 2020 Sep 17;35(5):444-452. Epub 2020 Aug 17.

de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble, France.

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.
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http://dx.doi.org/10.1002/jca.21825DOI Listing
September 2020

An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation.

Transpl Int 2020 Jul 5;33(7):786-795. Epub 2020 May 5.

Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.

The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.
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http://dx.doi.org/10.1111/tri.13613DOI Listing
July 2020

Predonation Single Kidney Glomerular Filtration Rate in Living Kidney Transplantation to Predict Graft Function and Donor Functional Gain.

Transplant Proc 2020 Apr 9;52(3):712-721. Epub 2020 Mar 9.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

Background: The 2 main objectives regarding living kidney transplant are to provide optimal graft function and to ensure the safety of donation. Our study hypothesized that the glomerular filtration rate of a single kidney (skGFR), when transplanted, might predict graft function and that the skGFR of the remaining kidney could predict donor functional gain.

Methods: A prospective monocentric study was conducted at Grenoble-Alpes University Hospital. Twenty couples of donors and recipients were included. Dimercaptosuccinic acid renal scintigraphy and Cr-ethylene-diamine tetra-acetic acid clearance were evaluated predonation to calculate skGFR. All patients had renal function according to Cr-ethylene-diamine tetra-acetic acid clearance at 1 year post transplant to assess graft function and donor functional gain. All donors had normal renal function predonation.

Results: At 1 year post transplant, median glomerular filtration rate of the graft was 50 mL/min/1.73 m (range, 46-56 mL/min/1.73 m) and donor median glomerular filtration rate was 59 mL/min/1.73 m (range, 55-74 mL/min/1.73 m). Median functional gain was 20 mL/min/1.73 m (range, 12-22 mL/min/1.73 m). No statistical correlation was found between skGFR of the transplanted kidney and graft function at 1 year (R = 0.096, P = .7). For the donor, functional gain was not associated with predonation skGFR of the remaining kidney (R = 0.17, P = .5). A statistical difference was found between donor functional gain (18 [SD, 10] mL/min) and recipient gain (delta between skGFR before and after transplant, 7 [SD, 16] mL/min; P = .02).

Conclusion: Predonation skGFR of the transplanted kidney had no influence on renal allograft function at 1 year post transplant. Similarly, there was no association between measured skGFR of the remaining kidney and donor functional gain at 1 year.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.026DOI Listing
April 2020

Where do we stand in 2020 regarding induction therapy after kidney transplantation?

Transpl Int 2020 Aug;33(8):858-862

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

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http://dx.doi.org/10.1111/tri.13604DOI Listing
August 2020

Transplantation of Marginal Organs: Immunological Aspects and Therapeutic Perspectives in Kidney Transplantation.

Front Immunol 2019 31;10:3142. Epub 2020 Jan 31.

Service de Néphrologie, Hémodialyse, Aphéréses et Transplantation Rénale, Centre Hospitalier Universitaire (CHU) de Grenoble-Alpes, Grenoble, France.

Recent data from the World Population Prospects projects that, by 2050, nearly all regions in the world will have a quarter or more of the population aged 60 and above. Chronic kidney disease (CKD) has a high global prevalence (~13%) worldwide, and the prevalence of chronic kidney disease and end-stage kidney disease increase with age. Kidney transplantation remains the best therapeutic option for end-stage kidney disease, offering a survival benefit in comparison with dialysis maintenance for most patients. This review focuses on immunological aspects of kidney transplantation in older patients and marginal donors, i.e., 60 years or older deceased kidney donors or 50-59 years old deceased kidney donors with comorbidities. Clinical outcomes of kidney recipients in terms of renal and patient survival are more than acceptable even for patients over 70. In this population, the first cause of graft loss is death with a functional graft. However, the inherent issues of these transplantations are the acceptance or refusal of frail kidney from an old donor and the increased immunogenicity of these organs in balance with potential frail and immunosenescent recipients. Finally, the immunosuppressive regimen itself is a challenge for the future of the transplant, to prevent adverse effects such as nephrotoxicity and higher risk of infections or cancer in a population already at risk. Belatacept may have a good place in the immunosuppressive strategy to improve efficacy and the safety posttransplantation.
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http://dx.doi.org/10.3389/fimmu.2019.03142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005052PMC
November 2020

Late Conversion From Calcineurin Inhibitors to Belatacept in Kidney-Transplant Recipients Has a Significant Beneficial Impact on Glycemic Parameters.

Transplant Direct 2020 Jan 24;6(1):e517. Epub 2019 Dec 24.

Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, Grenoble, France.

Background: Calcineurin inhibitors (CNIs) and steroids are strongly associated with new-onset diabetes after transplantation, worsening of pre-existing diabetes, and cardiovascular events. We assessed the benefit of conversion from CNI-based to belatacept-based immunosuppression in diabetic kidney-transplant (KT) recipients on glucose control and cardiovascular risk factors.

Methods: In this retrospective, noncontrolled single-study conducted between May 2016 and October 26, 2018, we recruited KT recipients converted from CNIs to belatacept at least 6 months after KT. The primary endpoint was the evolution of hemoglobin A1c (HbA1c) between baseline and after 6 months of treatment. Secondary endpoints included modifications to antidiabetic drugs, other cardiovascular risk factors, and renal function.

Results: One hundred and three KT recipients were included. Of these, 26 (25%) had type 2 diabetes. The patients were either receiving oral antidiabetic drugs (n = 21; 75%) or insulin therapy (n = 14; 54%). Overall HbA1c decreased significantly from 6.2 ± 1 to 5.8 ± 1%, < 0.001. In diabetic patients, HbA1c decreased from 7.2 ± 1 to 6.5 ± 1%, = 0.001. HbA1c significantly decreased in the subgroup of patients with new-onset diabetes after transplantation and whether diabetes was controlled at inclusion or not (ie, HA1c ≤7% or >7%). Moreover, no diabetic patient increased the number of oral antidiabetic drugs and the dose of basal insulin was not statistically different from baseline to 6 months (16 international unit at baseline and 16 international unit at 6 mo, 1). One patient had to start treatment by insulin pump. During follow-up, the renal function, body mass index, and hemoglobin level of all 103 patients remained stable, 2 patients presented acute cellular rejection, and no patient suffered from graft loss.

Conclusions: A late switch from CNI to belatacept was a valuable therapeutic option for diabetic kidney recipients and substantially improved glycemic parameters.
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http://dx.doi.org/10.1097/TXD.0000000000000964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964931PMC
January 2020

Recurrence of FSGS after Kidney Transplantation in Adults.

Clin J Am Soc Nephrol 2020 02 23;15(2):247-256. Epub 2020 Jan 23.

Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;

Background And Objectives: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients.

Design, Setting, Participants, & Measurements: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors.

Results: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival.

Conclusions: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.
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http://dx.doi.org/10.2215/CJN.08970719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015092PMC
February 2020

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

Blood Purif 2020 7;49(3):322-333. Epub 2020 Jan 7.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

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.
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http://dx.doi.org/10.1159/000504244DOI Listing
January 2020

Early Prediction of Graft Outcomes After Kidney Transplantation From Donors After Circulatory Death: Biomarkers and Transplantation Characteristics.

Transplant Proc 2019 Dec 13;51(10):3234-3243. Epub 2019 Nov 13.

Nephrology Hemodialysis Apheresis, and Kidney Transplantation, Grenoble University Hospital, La Tronche, France.

Background: This study aimed to identify transplantation characteristics and biomarkers that predict outcomes for kidney transplant (KT) patients from donors after circulatory death (DCDs).

Methods: Consecutive patients receiving a KT from a DCD in our center between 2014 and 2016 were included; the reference population was recipients with a living donor KT. The urinary tubular injury biomarker-to-creatinine ratio and serum lactate dehydrogenase (LDH) were measured at post-transplant days 1 and 3. The primary outcome was the occurrence of delayed graft function (DGF). Descriptive and receiver operating characteristic analyses were performed.

Results: Forty-one patients were included in the analysis: 15 (36.59%) DCD KTs (9 of which suffered from DGF) and 26 (63.41%) living donor KTs. For the primary endpoint, neutrophil gelatinase-associated lipocalin, N-acetyl-beta-D-glucosaminidase, urinary tubular injury biomarker-to-creatinine ratio, and LDH areas under the curve were 1 and 0.96 (95% confidence interval: 0.84-1.0), 1 and 0.92 (95% confidence interval: 0.73-1.0), respectively. Among the transplant characteristics, only the 30-minute resistive index on the perfusion machine was significantly higher in DCD KTs with DGF vs those without DGF (0.26 mm Hg/mL/min [0.20; 0.32] vs 0.14 mm Hg/mL/min [0.12; 0.16], P = .05). Median 3-month creatinine clearance among DGF DCD KTs was 49 mL/min/1.73 m [IQR: 42; 65] and 65 mL/min/1.73 m [IQR: 62; 66] among DCD KTs without DGF (P = .22).

Conclusion: In the DCD KT population, clinical and biological markers were identified that provided predictive tools for DGF. Thus, systematic measurement of these biomarkers, particularly LDH, could improve the management of kidney graft recipients' immunosuppressive therapy.
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http://dx.doi.org/10.1016/j.transproceed.2019.09.009DOI Listing
December 2019

Apheresis Therapy for Steroid-Resistant Idiopathic Nephrotic Syndrome: Report on a Case Series.

Case Rep Nephrol 2019 9;2019:7304786. Epub 2019 Oct 9.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

Idiopathic nephrotic syndrome (INS) represents 15%-30% of adulthood glomerulopathies. Corticosteroids have been the main treatment for decades and are effective in 70% of minimal-change disease patients and ~30% of focal segmental glomerulosclerosis patients. Multidrug-resistant (steroids, calcineurin-inhibitors, cyclophosphamide, mycophenolate-mofetil, rituximab) idiopathic nephrotic syndrome is a major therapeutic challenge in nephrology. Apheresis (double-filtration plasmapheresis or semi specific immunoadsorption) could act by eliminating the circulating factor (apolipoproteinA1b, solubleCD40L, suPAR) increasing glomerular permeability seen in INS. The aim of the study was to report the outcome of three patients with multidrug-resistant INS treated successfully with apheresis.
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http://dx.doi.org/10.1155/2019/7304786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803719PMC
October 2019

[How to implement a complete apheresis program within a hemodialysis unit].

Nephrol Ther 2019 Nov 1;15(6):439-447. Epub 2019 Oct 1.

Service de Néphrologie Hémodialyse Aphérèses et Transplantation rénale, CHU de Grenoble-Alpes, CS 10217, 38043 Grenoble cedex 09, France.

Many apheresis techniques can be performed in a blood-bank facility or a hemodialysis (HD) facility. However, it makes sense to perform apheresis in a hemodialysis facility as apheresis involves extra-corporeal circuits and because HD can be performed at the same time as apheresis (tandem procedure). Apheresis techniques comprise therapeutic plasma exchange, double-filtration plasmapheresis, and its derivative (rheopheresis and LDL-apheresis), and immunoadsorption (specific and semi-specific). We have setup an apheresis platform in our hospital that fulfills health recommendations. This process has involved financial investment and significant human resources, and has enabled us to network with different specialties (neurology, hematology, vascular medicine). We have setup protocols according to the type of pathology to be treated by apheresis, and to monitor clinical and biological data for each apheresis session. The main side effects of apheresis are a fall in blood pressure when a session is initiated, an increase in fluid overload, hypocalcemia, and the loss of some essential plasmatic factors. However, these side-effects are easily identified and can be properly managed in real time. Within two-years, we have performed 1845 apheresis sessions (134 patients). Of these, 66 received apheresis before and/or after kidney transplantation for ABO and/or HLA incompatibility (desensitization), for humoral rejection, or in the setting of relapsing focal-segmental glomerulosclerosis. Our patients' outcomes have been similar to those reported in the literature. The other 68 patients had various conditions. Because our program is now well-established, we are currently forming a specialist center to train physicians and nurses in the various apheresis techniques/procedures.
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http://dx.doi.org/10.1016/j.nephro.2019.01.005DOI Listing
November 2019

Immunosuppression and Graft Rejection in Living-related HLA-identical Renal Transplantation: The RADOVFULL Study.

Transplantation 2020 06;104(6):1256-1262

Hôpital Tenon (Assistance Publique Hôpitaux de Paris), Urgences Néphrologiques et Transplantation Rénale, Paris, France.

Background: We aimed to describe the immunosuppressive regimens and graft rejection rates in living-related HLA-identical (LR HLAid) renal transplantation.

Methods: We performed a retrospective multicenter analysis of the French national database for LR HLAid renal transplantations performed between 2002 and 2012. Univariate and multivariate analysis were performed to determine risk factors for graft rejection in LR HLAid recipients.

Results: A total of 27 218 renal transplantations were performed, of whom 163 had a LR HLAid donor. About immunosuppressive treatment, <60% of the cohort had induction therapy with polyclonal or monoclonal antibodies, 28% did not receive calcineurin inhibitors, and 36% did not receive steroids in maintenance. Biopsy-proven acute rejection was diagnosed in 21 patients (12.9%). Rejection occurred on an average of 24 months after transplantation, in 28.5% of the cases after minimization of immunosuppression. Factors associated with rejection were age of recipient (OR, 0.91 [0.84-0.96]; P = 0.003), the body mass index of donors (odds ratio [OR], 1.22 [1.04-1.46]; P = 0.01), and minimization of immunosuppression (OR, 26.2 [5.48-166.6]; P < 0.001). Overall and graft survival rates were not statistically different according to rejection at 1, 5, and 10 years posttransplantation.

Conclusions: Minimization of immunosuppression should be done with caution in LR HLAid renal transplantations.
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http://dx.doi.org/10.1097/TP.0000000000002937DOI Listing
June 2020

Immunoadsorption in nephrotic syndrome: Where are we now and where are we going from here?

Atheroscler Suppl 2019 Dec 17;40:55-60. Epub 2019 Aug 17.

Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria.

Idiopathic nephrotic syndrome (INS) is characterized by three different entities, namely minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). While there is an increasing understanding of primary MN with the discovery of antibodies directed against phospholipase A2 receptor (PLA2R Ab) and thrombospondin type 1 domain-containing 7A, circulatory factors causative of inducing MCD and FSGS remain in part elusive. Extracorporeal treatment forms (mostly plasma exchange) have been reserved for patients with either a disease course refractory to commonly prescribed immunosuppressive drugs or to patients with recurrence after kidney transplantation. There is a paucity of data supporting the use of immunoadsorption (IAS) in the management of MCD and MN and evidence to perform LDL-apheresis in the former is limited to reports from Japan. Treatment with IAS in primary FSGS has shown mixed responses, possibly biased by including treatment-resistant cases in the absence of genetic testing. In those with recurrence of the disease following kidney transplantation, IAS has shown high remission rates with an acceptable safety profile. There is a need to compare IAS to plasma exchange (PLEX) in this indication and due to a higher amount of plasma processed during one session, IAS may have advantages over PLEX. Removal of PLA2R Ab by IAS is currently being tested in a phase II clinical trial. More clinical trials in a prospective and randomized fashion need to be designed to prove the concept that IAS may be a treatment option for INS. While PLEX is still the leading extracorporeal treatment form in these indications, this review aims to highlight the efficacy and safety of IAS in the management of INS.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2019.08.027DOI Listing
December 2019

The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival.

Transplantation 2020 06;104(6):1263-1271

Nephrology, Dialysis, Apheresis and Transplantation Department, Grenoble University Hospital, France.

Background: Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS).

Methods: We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate).

Results: Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041).

Conclusions: C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.
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http://dx.doi.org/10.1097/TP.0000000000002920DOI Listing
June 2020

An Atypical Case of Shiga Toxin Producing- Hemolytic and Uremic Syndrome (STEC-HUS) in a Lung Transplant Recipient.

Case Rep Transplant 2019 11;2019:9465040. Epub 2019 Apr 11.

Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France.

We herein describe the first case of thrombotic microangiopathy (TMA) which was related to Shiga toxin producing- Hemolytic and Uremic Syndrome (STEC-HUS) after lung transplantation. His maintenance immunosuppression relied on tacrolimus plus mycophenolic acid. TMA was treated with plasma exchanges (PE) (fresh frozen plasma substitution). After five days of PE, platelets count and lactate dehydrogenase level normalized, whereas hemoglobin continued to gradually decrease and no improvement in kidney function was observed. After seven PE sessions, all TMA biological signs resolved. However, kidney function did not improve, and the patient still required chronic dialysis.
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http://dx.doi.org/10.1155/2019/9465040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487164PMC
April 2019

Switching renal transplant recipients to belatacept therapy: results of a real-life gradual conversion protocol.

Transpl Immunol 2019 10 6;56:101207. Epub 2019 May 6.

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Conversion to belatacept immunosuppression is a therapeutic option for renal-transplant recipients with calcineurin inhibitors (CNI) toxicity, but it associates with high risk of acute rejection. Gradual conversion and serial immune monitoring with urinary chemokine CXCL9 may allow increasing safety of this maneuver. We converted kidney transplant recipients with signs of toxicity to CNI or other immunosuppressive drugs to belatacept over a 2-month period. We monitored renal function, metabolic profile, and circulating lymphocyte subsets. We also quantified urinary CXCL9 over a 12-month follow-up period. Between September 2016 and March 2017, 35 patients were successfully switched to belatacept immunosuppression at 3.3 (1.3-7.2) years after transplant. Two patients had a reversible rise in serum creatinine, associated with acute rejection in one case. Urinary CXCL9 increased before serum creatinine. After conversion, blood pressure and HbA1c significantly declined while eGFR and proteinuria remained stable. The percentage of circulating effector T cells and memory B cells significantly declined. Conversion from CNI to belatacept, in this setting, was feasible and safe, provided it was performed over a 2-month time-period. Monitoring urinary CXCL9 may further increase safety through earlier identification of patients at risk for acute rejection. The procedure associates with improved blood pressure, metabolic profile, and reduced circulating effector T and B cells.
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http://dx.doi.org/10.1016/j.trim.2019.04.002DOI Listing
October 2019

An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization.

Expert Opin Drug Saf 2019 04 1;18(4):285-294. Epub 2019 Apr 1.

a Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale , CHU Grenoble-Alpes , Grenoble , France.

Introduction: Tacrolimus-based immunosuppression remains the immunosuppressive drug of choice in kidney transplantation.

Areas Covered: Its safety profile is closely linked to its pharmacokinetic properties. A narrow therapeutic range allows to limit under- and over-immunosuppression consequences. Minimization of tacrolimus exposure, using appropriate companion drugs, leads to the best renal outcomes in the long term. Also, reducing tacrolimus exposure variability helps in reducing tacrolimus toxicity. The novel concept of tacrolimus concentration-to-dose ratio (C/D ratio) associates with renal outcomes as well and provides some new possible improvements on tacrolimus safety, possibly by identifying kidney transplant recipient subpopulations at higher risk of tacrolimus toxicity. Similarly, the incidence of new-onset diabetes after transplantation (NODAT), a major side-effect of tacrolimus, can also be reduced by optimizing tacrolimus exposure. In this review, the authors summarize the safety profile of tacrolimus when optimizing mean tacrolimus exposure, tacrolimus exposure variability and tacrolimus C/D ratio. The impact of these adjustments on nephrotoxicity and NODAT is reviewed. Using such prescription optimization, tacrolimus' safety profile is positive.

Expert Opinion: Tacrolimus-based immunosuppression remains a valid option for kidney transplant recipients, and might even improve by individualizing prescriptions, the next frontier in transplant immunosuppression.
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http://dx.doi.org/10.1080/14740338.2019.1599858DOI Listing
April 2019