Role of mTOR inhibitors in renal transplantation: long-term risk / benefit analysis of conversion to mTOR inhibitors

RESUMEN: Los resultados del trasplante renal a corto plazo han mejorado mucho sin haberse reflejado en los resultados a largo plazo, perdiéndose los injertos por disfunción crónica del injerto (DCI) y por muerte del paciente por enfermedades cardiovasculares y neoplasias. Los fármacos i-mTOR ofrecen ventajas teóricas que podrían mejorar los resultados del trasplante renal a largo plazo, disminuyendo la DCI, mejorando el perfil cardiovascular y disminuyendo la aparición de algunas infecciones víricas y neoplasias. El manejo clínico de i-mTOR es complicado por lo que es importante seleccionar los pacientes que se pudieran beneficiar de la conversión a i-mTOR. Realizamos un estudio de cohortes observacional con 637 pacientes trasplantados renales convertidos de ICN a i-mTOR entre 1999 y 2015, con causas de conversión protocolizadas y un seguimiento superior a 6 años. Los trasplantes renales que más se benefician de la conversión a i-mTOR en términos de mejoría de función renal (FR) son aquéllos que presentan un CKD-EPI>45mL/min/1,73m² y ausencia de proteinuria o proteinuria ligera ( 45mL/min/1,73m² and no proteinuria or mild proteinuria (<500 mg / day) at the time of conversion. The evolution of the pre-conversion RF also influences the improvement of RF post-conversion. Patients converted for tumor or cardiovascular disease improve RF more frequently. In the other hand, baseline RF and proteinuria correlate with long-term graft survival, as baseline hypercholesterolemia and drug suspension due to adverse events. Diabetes as the cause of chronic renal disease, tumor or severe cardiovascular disease as causes of conversion, retransplantations, patient's age at conversion and baseline proteinuria are further correlated with patient's survival

COVID-19-related collapse of transplantation systems: A heterogeneous recovery?

The coronavirus disease‐2019 (COVID‐19) pandemic has pushed healthcare systems to the limit worldwide. Hospital resources have been compromised, especially in intensive care units (ICUs). Regarding that, some nephrologists have alerted about the potential shortages of our ability to deliver kidney replacement therapy to all patients who need it (1). Simultaneously, two reports have highlighted the collapse of organ transplantation figures in several countries such as France (91%), the US (51%) and Spain (87%), mainly due to a reduction in the number of transplants from deceased donors

High Pretransplant BAFF Levels and B-cell Subset Polarized towards a Memory Phenotype as Predictive Biomarkers for Antibody-Mediated Rejection

Antibody-mediated rejection (AbMR) is one of the leading causes of graft loss in kidney transplantation and B cells play an important role in the development of it. A B-cell activating factor (BAFF) is a cytokine involved in B cell ontogeny. Here, we analyzed whether B cell maturation and the e ect of B cell soluble factors, such as BAFF could be involved in AbMR. Serum BAFF levels and B and T cell subpopulations were analyzed 109 kidney transplant patients before transplantation and at 6 and 12 months after kidney transplantation. Pretransplant serum BAFF levels as well as memory B cell subpopulations were significantly higher in those patients who su ered clinical AbMR during the first 12 months after kidney transplantation. Similar results were observed in the prospective analysis of patients with subclinical antibody-mediated rejection detected in the surveillance biopsy performed at 12 months after kidney transplantation. A multivariate analysis confirmed the independent role of BAFF in the development of AbMR, irrespective of other classical variables. Pretransplant serum BAFF levels could be an important non-invasive biomarker for the prediction of the development of AbMR and posttransplant increased serum BAFF levels contribute to AbMR

Urinary CXCL10 specifically relates to HLA-DQ eplet mismatch load in kidney transplant recipients

Background: Urinary CXCL10 (uCXCL10) is associated with graft inflammation and graft survival, but the factors related to its excretion are not well known. HLA molecular matching at epitope level allow estimating the "dissimilarity" between donor and recipient HLA more precisely, being better related to further transplant outcomes. The relationship between uCXCL10 and HLA molecular mismatch has not been previously explored. Methods: HLA class I and class II typing of some 65 recipients and their donors was retrospectively performed by high resolution sequence-specific-primer (Life Technologies, Brown Deer, WI). The HLA-Matchmaker 3.1 software was used to assess eplet matching. Urine samples collected on the day of the 1-year surveillance biopsy were available of these 65 patients. uCXCL10 was measured using a commercial enzyme-linked immunoassay kit. Results: 1-year uCXCL10 was independently associated with HLA-DQB1 eplet mismatch load (b 0.300, 95%CI 0.010-0.058, p = 0.006). Kidney transplant recipients with a HLA-DQB1 eplet mismatch load >3 showed higher values of uCXCL10 at 1-year (p = 0.018) than those with 3 with subclinical AbMR had significantly higher levels of the logarithm of 1-year uCXCL10 (No AbMR 0.88, IQR 0.37; AbMR 1.38, IQR 0.34, p = 0.002) than those without AbMR. Conclusions: uCXCL10 specifically relates to HLA-DQ eplet mismatch load. This relationship can partly explain the previously reported association between uCXCL10 excretion and graft inflammation. An adequate evaluation of any potential non-invasive biomarker, such as uCXCL10, must take into account the HLA molecular mismatch.This research was funded by grants for Fondo de Investigaciones Sanitarias-ISCIII (PI14/00378, PI16/01585, PI20/01710), RedinRen (RD16/0009/0027), and Instituto de Investigación Marqués de Valdecilla (IDIVAL, TRANSVAL18/01)

Manejo de la inmunosupresión en pacientes trasplantados de riñón con COVID19. Estudio multicéntrico nacional derivado del registro COVID de la Sociedad Española de Nefrología

Introduction: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated.Objectives: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis.Material and methods: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis.Results: renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years. The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased. Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7 +/- 0.8, 2.1 +/- 1.2 and 1.8 +/- 1 mg/dl respectively (p < 0.001). 56.9% of the patients (N = 350) were monitored for anti-HLA antibodies. 94% (N = 329) had no anti-HLA changes, while 6% (N = 21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N = 9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant.Conclusions: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis

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Donor-derived cell-free DNA at 1 month after kidney transplantation relates to HLA class II eplet mismatch load

Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage.Funding: This work was supported by the Instituto de Salud Carlos III through grant PI20/01710, co-funded by the European Regional Development Fund, “A way to make Europe”

Torque teno virus load predicts opportunistic Infections after kidney transplantation but Is not associated with maintenance immunosuppression exposure

Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905, p = 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957, p = 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.Funding: This research was funded by grants for Fondo de Investigaciones Sanitarias-ISCIII (PI20/01710) and RICORS (ISCIII RD21/0005/0010, “Financiado por la Unión Europea—NextGenerationEU,” Mecanismo para la Recuperación y la Resiliencia [MRR]). Acknowledgments: The authors are indebted to Consuelo Agüeros (Nephrology Research Laboratory, Hospital Marqués de Valdecilla-IDIVAL) for technician suppor

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Basta/Prou es el resultado de El desafío por la erradicación de la violencia contra las mujeres que el Instituto Universitario de Estudios Feministas y de Género Purificación Escribano de la Universitat Jaume I lanzó en los Diez días contra la violencia de género 2012