Successful renal transplantation in a patient with atypical hemolytic uremic syndrome carrying mutations in both Factor I and MCP (CD46)

7 páginas, 4 figuras, 2 tablas -- PAGS nros. 1477-1483Kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) carrying mutations in the soluble complement regulators factor H (CFH) or factor I (CFI) is associated with elevated risk of disease recurrence and almost certain graft loss. In contrast, recurrence is unusual in patients with mutations in the membrane-associated complement regulator membrane cofactor protein (MCP) (CD46). Therefore, a panel of experts recently recommended the combined liver–kidney transplantation to minimize aHUS recurrence in patients with mutations in CFH or CFI. There was, however, very limited information regarding transplantation in patients carrying mutations in both soluble and membrane-associated complement regulators to support a recommendation. Here, we report the case of an aHUS patient with a heterozygous mutation in both CFI and MCP who received an isolated kidney transplant expressing normal MCP levels. Critically, the patient suffered from a severe antibody-mediated rejection that was successfully treated with plasmapheresis and IvIgG. Most important, despite the complement activation in the allograft, there was no evidence of thrombotic microangiopathy, suggesting that the normal MCP levels in the grafted kidney were sufficient to prevent the aHUS recurrence. Our results suggest that isolated kidney transplantation may be a good first option for care in aHUS patients carrying CFI/MCP combined heterozygous mutationsFunding sources: Red de Investigación Renal (REDinREN, ISCIII 06/0016), Ministerio de Ciencia e Innovación (SAF2008-00226), Ministerio de Ciencia e Innovación (SAF2006-02948), CIBERER (INTRA/08/738.2) and the Fundacion Renal Iñigo Alvarez de ToledoPeer reviewe

Fósiles inteligentes: aplicaciones educativas de los modelos tridimensionales de los lagartos gigantes de Canarias

Desde el Área de Paleontología de la Universidad de La Laguna se está llevando a cabo la creación de una colección de modelos digitales de fósiles para su uso en educación y divulgación. Se ha demostrado que el empleo de modelos digitales son muy eficaces a la hora de hacer participe al público general de los resultados obtenidos en las investigaciones científicas. Apoyandose en la experiencia obte- nida en un trabajo previo en el que se crearon contenidos multimedia a partir de materiales fósiles de invertebrados, el Área de Paleontología ha iniciado un nuevo proyecto con materiales actuales y fósiles de lagartos gigantes endémicos de la Islas Canarias pertenecientes al género Gallotia. Dicho proyecto consta de dos fases, una primera en la que se obtendrá información científica y una segunda en la que se adaptaran los resultados para la generración de contenidos multi- media para el público general. Como primeros resultados del proyecto se han realizado con éxito las microtómografías, modelizaciones e impresiones de los especímenes en estudio y se ha iniciado con el estudio y obtención de información paleobiológica que será empleada en ambas fases.The Paleontology Area of La Laguna University has been developing a collection of digital models of fossils in order to use them in education and divulgation. It has been shown that the use of digital models are effective in getting closer the general public to the results obtained in scientific research. Based on the experience gained in previous work where multimedia contents were created from fossil invertebrate materials, the Paleontology Area has started a new project with present and fossils remains of endemic giant lizards from the Canary Islands belonging to the Ga- llotia genus. The project consists of two stages: firstly, scientific information will be obtained and secondly in which the results will be adapted to generate multimedia contents. The first results of the project were microtomographies, modeling and impressions of specimens under study. This stage has been successfully carried out. Moreover, the study and acquisition of paleobiological information that will be used in both phases has begun

Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions

Clinical Relevance of Corticosteroid Withdrawal on Graft Histological Lesions in Low-Immunological-Risk Kidney Transplant Patients

The impact of corticosteroid withdrawal on medium-term graft histological changes in kidney transplant (KT) recipients under standard immunosuppression is uncertain. As part of an open-label, multicenter, prospective, phase IV, 24-month clinical trial (ClinicalTrials.gov, NCT02284464) in low-immunological-risk KT recipients, 105 patients were randomized, after a protocol-biopsy at 3 months, to corticosteroid continuation (CSC, n = 52) or corticosteroid withdrawal (CSW, n = 53). Both groups received tacrolimus and MMF and had another protocol-biopsy at 24 months. The acute rejection rate, including subclinical inflammation (SCI), was comparable between groups (21.2 vs. 24.5%). No patients developed dnDSA. Inflammatory and chronicity scores increased from 3 to 24 months in patients with, at baseline, no inflammation (NI) or SCI, regardless of treatment. CSW patients with SCI at 3 months had a significantly increased chronicity score at 24 months. HbA1c levels were lower in CSW patients (6.4 +/- 1.2 vs. 5.7 +/- 0.6%; p = 0.013) at 24 months, as was systolic blood pressure (134.2 +/- 14.9 vs. 125.7 +/- 15.3 mmHg; p = 0.016). Allograft function was comparable between groups and no patients died or lost their graft. An increase in chronicity scores at 2-years post-transplantation was observed in low-immunological-risk KT recipients with initial NI or SCI, but CSW may accelerate chronicity changes, especially in patients with early SCI. This strategy did, however, improve the cardiovascular profiles of patients

Key Factors for Optimal Care Models for Heart Failure: An Integrative and Multidisciplinary Approach

[Resumen] Introducción y objetivos. La insuficiencia cardiaca (IC) supone un reto para los sistemas sanitarios que se puede responder a través del desarrollo de modelos integrales de atención. Un grupo multidisciplinar de expertos reflexionó sobre los factores clave para avanzar en el desarrollo de este tipo de modelos, planteando una hoja de ruta dirigida a todos los agentes (administraciones, gestores y profesionales sanitarios). Métodos. Se conformó un panel Delphi multidisciplinar integrado por un comité asesor de 15 expertos y un panel adicional de 31 expertos. A través de una revisión bibliográfica sistemática y entrevistas individuales semiestructuradas se realizó un diagnóstico e identificación de retos y áreas de mejora a lo largo del proceso asistencial. El panel Delphi consensuó y priorizó los factores clave con la metodología Delphi Rand/UCLA, valorando su adecuación y necesidad. Resultados. Tras 2 rondas de valoración Delphi se consensuó una propuesta de 7 retos y 75 factores clave para el desarrollo de modelos integrados para la IC. Los 25 factores clave considerados altamente prioritarios se relacionan con la necesidad de una mayor coordinación y planificación a nivel de gestión sanitaria, el abordaje integral durante la hospitalización y la implantación de medidas de continuidad y coordinación asistencial, garantizando que se cubren las necesidades específicas de diferentes perfiles de pacientes. Conclusiones. La propuesta y priorización de acciones para avanzar en modelos de atención integral a la IC debe surgir de reflexiones multidisciplinares y multinivel que incluyan la visión de los pacientes y cuidadores.[Abstract] Introduction and objectives. Heart failure (HF) is a challenge for health systems that can be responded through the development of comprehensive care models. A multidisciplinary group of experts reflected on the key factors that could facilitate the development of this type of models, proposing a roadmap aimed at all agents (politicians, managers, administrators, and health professional). Methods. A multidisciplinary Delphi panel was formed, made up of an advisory committee of 15 experts and an additional panel of 31 experts. After a systematic bibliographic review and semi-structured individual interviews, a diagnosis and identification of challenges and areas for improvement were made throughout the healthcare process. The Delphi panel agreed and prioritized the key factors applying Delphi Rand/UCLA methodology, assessing their appropriateness and need. Results. After 2 rounds of Delphi assessment, a proposal of 7 challenges and 75 key factors was agreed upon for the development of integrated models for HF. The 25 key factors considered high priority are related to the need for greater coordination and planning at the health management level, the comprehensive approach during hospitalization and the implementation of measures of continuity and care coordination, ensuring that the specific needs of different patient profiles. Conclusions. The proposal and prioritization of actions to advance in models of comprehensive care for HF must arise from multidisciplinary and multilevel reflections that include the vision of patients and caregivers.El proyecto MAIC ha sido financiado por Boehringer Ingelheim Españ

Recovery of dialysis patients with COVID-19 : health outcomes 3 months after diagnosis in ERACODA

Background. Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. Methods. We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. Results. In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. Conclusions. Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis

Macrophage overexpressing NGAL ameliorated kidney fibrosis in the UUO mice model

[Background/Aims] Alternatively activated macrophages (AAM) have regenerative and anti-inflammatory characteristics. Here, we sought to evaluate whether AAM cell therapy reduces renal inflammation and fibrosis in the unilateral ureteral obstruction (UUO) mice model.[Methods] We stabilized macrophages by adenoviral vector NGAL (Neutrophil gelatinase-associated lipocalin-2) and infused them into UUO mice. To ascertain whether macrophages were capable of reaching the obstructed kidney, macrophages were stained and detected by in vivo cell tracking.[Results] We demonstrated that some infused macrophages reached the obstructed kidney and that infusion of macrophages overexpressing NGAL was associated with reduced kidney interstitial fibrosis and inflammation. This therapeutic effect was mainly associated with the phenotype and function preservation of the transferred macrophages isolated from the obstructed kidney[Conclusions] Macrophage plasticity is a major hurdle for achieving macrophage therapy success in chronic nephropathies and could be overcome by transferring lipocalin-2.This research was supported by Spanish Government Instituto de Salud Carlos III (ISCIII) grant PI12/01427, PI15/00638 and PI12/00720 Confunded by FEDER funds/European Regional Development Fund (ERDF)-a way to Build Europe-//, AMGEN grant under the auspices of The Red de Investigación Renal (European Regional Development Funds ISCIII Red Temática de Investigación Cooperativa en Salud Red de Investigación Renal; RD16/0009/0003) and SENEFRO (awarded to AS). SAF 2015-67770 (awarded to GH). AS is supported by Miguel Servet contracting system (CP08/00138).Peer reviewe

Exploring macrophage cell therapy on Diabetic Kidney Disease

Alternatively activated macrophages (M2) have regenerative properties and shown promise as cell therapy in chronic kidney disease. However, M2 plasticity is one of the major hurdles to overcome. Our previous studies showed that genetically modified macrophages stabilized by neutrophil gelatinase-associated lipocalin (NGAL) were able to preserve their M2 phenotype. Nowadays, little is known about M2 macrophage effects in diabetic kidney disease (DKD). The aim of the study was to investigate the therapeutic effect of both bone marrow-derived M2 (BM-фM2) and ф-NGAL macrophages in the db/db mice. Seventeen-week-old mice with established DKD were divided into five treatment groups with their controls: D+BM-фM2; D+ф-BM; D+ф-NGAL; D+ф-RAW; D+SHAM and non-diabetic (ND) (db/- and C57bl/6J) animals. We infused 1 × 10 macrophages twice, at baseline and 2 weeks thereafter. BM-фM2 did not show any therapeutic effect whereas ф-NGAL significantly reduced albuminuria and renal fibrosis. The ф-NGAL therapy increased the anti-inflammatory IL-10 and reduced some pro-inflammatory cytokines, reduced the proportion of M1 glomerular macrophages and podocyte loss and was associated with a significant decrease of renal TGF-β1. Overall, our study provides evidence that ф-NGAL macrophage cell therapy has a therapeutic effect on DKD probably by modulation of the renal inflammatory response caused by the diabetic milieu.This work was supported by Spanish Government Instituto de Salud Carlos III (ISCIII) grant PI12/01427, PI15/00638 and PI12/ 00720, AMGEN grant under the auspices of The Red de Investigación Renal (European Regional Development Funds ISCIII Red Temática de Investigación Cooperativa en Salud Red de Investigación Renal; RD16/0009/0003) and SENEFRO (awarded to AS). SAF 2015‐ 67770 (awarded to GH). AS is supported by Miguel Servet Contracting System (CP08/00138)

Lipocalin-2 abrogates epithelial cell cycle arrest by PPARγ inhibition

Macrophage-epithelial cross-talk regulates cell cycle progression and represents an important factor in rescuing epithelial cells from cell cycle arrest in order to maintain a healthy epithelial phenotype. However, the underlying mechanisms are still not well defined. We provide evidence that macrophage-secreted lipocalin-2 (Lcn-2) plays a key role during this process. In a co-culture setup using cell cycle arrested NRK52e renal epithelial cells and primary bone marrow-derived macrophages, Lcn-2 restores proliferation through inhibition of peroxisome proliferator-activated receptor (PPAR)-γ. Lcn-2 overexpression in macrophages overcomes epithelial cell cycle arrest and enhances epithelial markers via megalin and the downstream activation of PI3K/Akt signalling pathway, whereas a knockdown of Lcn-2 in macrophages prevented this effect. Our results show that macrophage-secreting Lcn-2 is crucial in rescuing epithelial cells from cell cycle arrest and in promoting epithelial proliferation.Financial support of this study came from grants from Fondo de Investigación Sanitaria (FIS) PI1701411 (awarded to A.S.) and SAF2015-67770-R from Ministerio de Economia y Competitividad (awarded to G.H.). A.S. was supported by Miguel Servet II contracting system (CPII 14/00026) and M.J. was supported by a grant from Fritz Thyssen Stiftung (Az.10.12.2.156) and a young researcher grant from Goethe-University Frankfurt (Focus Line B).Peer reviewe

Mammalian target of rapamycin inhibitors combined with Calcineurin inhibitors as initial immunosuppression in renal transplantation: a meta-analysis

Background: The current standard of care immunosuppressive regimen in kidney transplantation (KT) includes a combination of mycophenolates (MMF/MPA) with a calcineurin inhibitor (CNI). Methods: We designed a systematic review including all randomized clinical trials (RCTs) assessing the outcomes in KT recipients receiving mTORi + CNI compared with regimens containing MMF/MPA or azathioprine with CNI. Results: A total of 24 studies with 7356 participants were included. The comparison between mTORi-CNI and MMF/MPA-CNI did not show differences in acute rejection, mortality, or graft loss rates. Better graft function was observed using MMF/MPA-CNI than using mTORi + CNI, but this difference was not evident when the mTORi was associated with reduced dose CNI in more recent studies with everolimus. Dyslipidemia, lymphoceles, and impaired wound healing were more frequent with mTORi-CNI and diarrhea and leukopenia were more frequent with MMF/MPA-CNI. Viral infections at any time and malignant neoplasia beyond 2 years were less frequent with mTORi-CNI. Rates of discontinuation because of adverse effects in the mTORi groups varied between 17% and 46% compared to 0%-26.6% in MMF/MPA groups. The current use of lower mTORi dosage has decreased the discontinuation rates. Conclusions: Efficacy is similar with mTORi + CNI and MMF/MPA-CNI. The safety profile is the predominant difference between the 2 regimens