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

Regulatory T-cell Number in Peripheral Blood at 1 Year Posttransplant as Predictor of Long-term Kidney Graft Survival

Background: Regulatory T (Treg) cells play a role in limiting kidney transplant rejection and can potentially promote long-term transplant tolerance. There are no large prospective studies demonstrating the utility of peripheral blood Treg cells as biomarkers for long-term graft outcome in kidney transplantation. The aim of our study was to analyze the influence of the absolute number of peripheral blood Treg cells after transplantation on long-term death-censored graft survival. Methods: We monitored the absolute numbers of Treg cells by flow cytometry in nonfrozen samples of peripheral blood in 133 kidney transplant recipients, who were prospectively followed up to 2 years after transplantation. Death-censored graft survival was determined retrospectively in January 2017. Results: The mean time of clinical follow-up was 7.4 ± 2.9 years and 24.1% patients suffered death-censored graft loss (DCGL). Patients with high Treg cells 1 year after transplantation and above the median value (14.57 cells/mm3), showed better death-censored graft survival (5-year survival, 92.5% vs 81.4%, Log-rank P = .030). One-year Treg cells showed a receiver operating characteristic - area under curve of 63.1% (95% confidence interval, 52.9-73.2%, P = 0.026) for predicting DCGL. After multivariate Cox regression analysis, an increased number of peripheral blood Treg cells was a protective factor for DCGL (hazard ratio, 0.961, 95% confidence interval, 0.924-0.998, P = 0.041), irrespectively of 1-year proteinuria and renal function. Conclusions: Peripheral blood absolute numbers of Treg cells 1 year after kidney transplantation predict a better long-term graft outcome and may be used as prognostic biomarkers

Urinary C-X-C Motif Chemokine 10 Is Related to Acute Graft Lesions Secondary to T Cell- and Antibody-Mediated Damage

Background: Non-invasive biomarkers of graft rejection are needed to optimize the management and outcomes of kidney transplant recipients. Urinary excretion of IFN-g-related chemokine CXCL10 is clearly associated with clinical and subclinical T cell-mediated graft inflammation, but its relationship with antibody-mediated damage has not been fully addressed. Further, the variables influencing levels of urinary CXCL10 excretion are unknown. Material/Methods: A total of 151 kidney graft biopsies (92 surveillance and 59 indication biopsies) and 151 matched urine samples obtained before biopsy were prospectively analyzed. T cell-mediated rejection (TCMR) and antibody-mediated rejection (AbMR) were defined according to the 2017 Banff classification criteria. Urinary CXCL10 levels were measured by ELISA and corrected by urinary creatinine. Results: Banff scores ?t?, ?i?, ?g?, and ?ptc? were significantly related to urinary CXCL10 levels. Multivariate analysis showed that ?t? (b=0.107, P=0.001) and ?ptc? (b=0.093, P=0.002) were significantly associated with urinary CXCL10. Donor specific antibodies (DSAs) were related to the high excretion of urinary CXCL10 at 1 year after transplantation (odds ratio [OR] 17.817, P=0.003). Urinary CXCL10 showed good discrimination ability for AbMR (AUC-ROC 0.760, P=0.001). The third tertile of urinary CXCL10 remained significantly associated with AbMR (OR 4.577, 95% confidence interval 1.799?11.646, P=0.001) after multivariate regression analysis. Conclusions: DSA was the only variable clearly related to high urinary CXCL10 levels. Urinary CXCL10 is a good non-invasive candidate biomarker of AbMR and TCMR, supplying information independent of renal function and other variables normally used to monitor kidney transplant

Measurement of galactosyl-deficient IgA1 by the monoclonal antibody KM55 contributes to predicting patients with IgA nephropathy with high risk of long-term progression

Backgroundandobjective:About25%ofpatientswithIgAnephropathy(IgAN)progresstostage5chronickidneydisease(CKD)afteryearsofevolution.Varioustoolshavebeendevelopedinrecentyearsdesignedtopredictwhichofthepatientswillhadpooreroutcomes.Thevalueofcirculatinggalactosyl-deficientIgA1(Gd-IgA1)hasbeenrelatedtoaworseevolutionofIgANinseveralstudies.TherearealsosomepublicationsthatrelatehigherAPRILvalueswithaworseevolution.Recently,anewmethodhasbeendevelopedthatallowsmeasuringthevalueofcirculatingGd-IgA1inasimplerwaythanthosepreviouslyavailable.TheobjectiveofthisstudyistoanalyzetheinfluenceofcirculatingGd-IgA1,measuredbythismethod,ontheprogressionofIgAN.Materialsandmethods:Forty-ninepatientswithadiagnosisofIgANdemonstratedbyrenalbiopsywereselectedinourcenter,withouthavingreceivedpriorimmunosuppressivetreat-ment,forwhomfrozenserumwasavailable.Themedianfollow-upwas4years.Gd-IgA1wasmeasuredbylectin-independentELISAwiththemonoclonalantibodyKM55(IgA1kitCat.No.30111694.IBLInt.,Hamburg,Germany).Likewise,APRILlevelswerealsomeasuredinthesepatients.Results:19(38.8%)patientsreachedstage5CKD.ThefourthquartileofcirculatingGd-IgA1wasrelatedtoahighercumulativeriskofreachingstage5CKDintheKaplan?Meieranalysis(riskatthe5thyear39.4%vs.24.3%,logrankp=0.019).TheGd-IgA1valuewasrelatedto anincreasedriskofCKDstage5(HR1.147,95%CI1.035?1.270,p=0.009),regardlessofglomerularfiltrationrate,proteinuria,thepercentageofsclerosedglomeruliandthevalueofsegmentalsclerosis.WedidnotfindsignificantdifferencesintheAPRILvalues.Conclusions:ThevalueofcirculatingGd-IgA1measuredbythemonoclonalantibodyKM55isrelatedtoaworseevolutionofpatientswithIgANindependentlyofothervariables,soitcouldbeincludedinthestudyofpatientstoimprovethepredictionoftheriskofdiseaseprogression

Healthcare workers hospitalized due to COVID-19 have no higher risk of death than general population. Data from the Spanish SEMI-COVID-19 Registry

Aim To determine whether healthcare workers (HCW) hospitalized in Spain due to COVID-19 have a worse prognosis than non-healthcare workers (NHCW). Methods Observational cohort study based on the SEMI-COVID-19 Registry, a nationwide registry that collects sociodemographic, clinical, laboratory, and treatment data on patients hospitalised with COVID-19 in Spain. Patients aged 20-65 years were selected. A multivariate logistic regression model was performed to identify factors associated with mortality. Results As of 22 May 2020, 4393 patients were included, of whom 419 (9.5%) were HCW. Median (interquartile range) age of HCW was 52 (15) years and 62.4% were women. Prevalence of comorbidities and severe radiological findings upon admission were less frequent in HCW. There were no difference in need of respiratory support and admission to intensive care unit, but occurrence of sepsis and in-hospital mortality was lower in HCW (1.7% vs. 3.9%; p = 0.024 and 0.7% vs. 4.8%; p<0.001 respectively). Age, male sex and comorbidity, were independently associated with higher in-hospital mortality and healthcare working with lower mortality (OR 0.211, 95%CI 0.067-0.667, p = 0.008). 30-days survival was higher in HCW (0.968 vs. 0.851 p<0.001). Conclusions Hospitalized COVID-19 HCW had fewer comorbidities and a better prognosis than NHCW. Our results suggest that professional exposure to COVID-19 in HCW does not carry more clinical severity nor mortality

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Estudio de los efectos de los inhibidores de mTOR en el transplante renal

RESUMEN: Los resultados del trasplante renal a largo plazo están limitados por la pérdida a largo plazo del injerto y la muerte con injerto funcionante. Los inmunosupresores tienen gran importancia por su efecto sobre el injerto (control de la respuesta inmunológica y nefrotoxicidad) y sobre los factores de riesgo cardiovascular y el desarrollo de neoplasias. Los nuevos inmunosupresores apuntan a un mejor perfil en este sentido para reducir estos dos tipos de complicaciones y prolongar la supervivencia del injerto y del paciente, siendo los fármacos del grupo mTOR los más prometedores en este sentido. La presente tesis doctoral analiza los efectos de este grupo de fármacos inmunosupresores (Sirolimus y Everolimus) en pacientes trasplantados renales. Se analizan los efectos del uso de inhibidores de mTOR en pacientes trasplantados renales sobre el daño crónico del injerto en biopsias de protocolo, sobre la aparición de proteinuria como complicación de su uso en pacientes estables y sobre la formación de células T reguladoras circulantes en sangre periférica.ABSTRACT: Long-term results of kidney transplantation are limited by the chronic graft failure and the death of the patient with a functioning kidney. Immunosuppressive drugs have an important role due to its effects on the graft (control of immune response and nephrotoxicity) and on vascular risk factors and the development of neoplasms. New immunosuppressive drugs, specially mTOR inhibitors have a better profile and are able to reduce both types of complications, increasing graft and patient survival. The present doctoral thesis analyzes the effects of this group of immunosuppressive drugs (Sirolimus and Everolimus) in renal transplant recipients. The effects of mTOR inhibitors over chronic graft damage in protocol kidney biopsies, on the appearance of proteinuria as a complication of its use in stable patients and on the formation of circulating regulatory T-cells in renal transplant patients are analyzed