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Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. Nucleated erythroid cells had high expression of ACKR1, which facilitated their direct contact with hematopoietic stem cells. The absence of erythroid ACKR1 altered mouse hematopoiesis including stem and progenitor cells, which ultimately gave rise to phenotypically distinct neutrophils that readily left the circulation, causing neutropenia. Individuals with a Duffy-negative phenotype developed a distinct profile of neutrophil effector molecules that closely reflected the one observed in the ACKR1-deficient mice. Thus, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of ACKR1 in the erythroid lineage, findings with major implications for the selection advantages that have resulted in the paramount fixation of the ACKR1 rs2814778(G) polymorphism in Africa.
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Sistema del Grupo Sanguíneo Duffy , Eritroblastos , Hematopoyesis , Células Madre Hematopoyéticas , Neutropenia , Neutrófilos , Receptores de Superficie Celular , Animales , Humanos , Ratones , Población Negra/genética , Médula Ósea/patología , Células de la Médula Ósea/metabolismo , Proliferación Celular , Sistema del Grupo Sanguíneo Duffy/genética , Sistema del Grupo Sanguíneo Duffy/metabolismo , Eritroblastos/metabolismo , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Hematopoyesis/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Microscopía Confocal , Neutropenia/genética , Neutrófilos/citología , Neutrófilos/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismoRESUMEN
Afferent lymph-borne dendritic cells essentially rely on the chemokine receptor CCR7 for their transition from the subcapsular lymph node sinus into the parenchyma, a migratory step driven by putative gradients of CCR7 ligands. We found that lymph node fringes indeed contained physiological gradients of the chemokine CCL21, which depended on the expression of CCRL1, the atypical receptor for the CCR7 ligands CCL19 and CCL21. Lymphatic endothelial cells lining the ceiling of the subcapsular sinus, but not those lining the floor, expressed CCRL1, which scavenged chemokines from the sinus lumen. This created chemokine gradients across the sinus floor and enabled the emigration of dendritic cells. In vitro live imaging revealed that spatially confined expression of CCRL1 was necessary and sufficient for the creation of functional chemokine gradients.
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Quimiocina CCL21/fisiología , Ganglios Linfáticos/inmunología , Receptores CCR/fisiología , Animales , Movimiento Celular , Células Dendríticas/fisiología , Ratones , Ratones Endogámicos C57BLRESUMEN
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP, receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the two cohorts (3 and 4 days; P = 0.31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B co-infection, an ovarian teratoma with associated anti-platelet antibodies, and multiple platelet transfusion before the correct diagnosis may have impeded immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians.
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Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.
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Diabetes Mellitus , Trasplante de Riñón , Trasplante de Órganos , Humanos , Consenso , Trasplante de Riñón/efectos adversos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Trasplante de Órganos/efectos adversos , Glucosa , Factores de Riesgo , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiologíaRESUMEN
AIM: The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. MATERIALS AND METHODS: Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). RESULTS: Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. CONCLUSIONS: eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.
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Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.
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Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Factores de Transcripción Forkhead , Subunidad alfa del Receptor de Interleucina-2 , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Femenino , Masculino , Linfocitos T CD8-positivos/inmunología , Persona de Mediana Edad , Factores de Transcripción Forkhead/metabolismo , Adulto , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Anciano , Complejo CD3/metabolismo , Citomegalovirus/inmunología , Factores de Riesgo , Receptores de Trasplantes , Supervivencia de Injerto/inmunologíaRESUMEN
BACKGROUND: Hyperkalemia is a common complication in cardiorenal patients treated with agents interfering with renal potassium (K+) excretion. It frequently leads to discontinuation of potentially life-saving medication, which has increased the importance of K+ monitoring. Non-invasive means to detect hyperkalemia are currently unavailable, but would be of potential use for therapy guidance. The aim of the present study was to assess the analytical performance of genetically encoded potassium-ion indicators (GEPIIs) in measuring salivary [K+] ([K+]Saliva) and to determine whether changes of [K+]Saliva depict those of [K+]Plasma. METHODS: We conducted this proof-of-concept study: saliva samples from 20 healthy volunteers as well as plasma and saliva from 29 patients on hemodialysis (HD) before and after three consecutive HD treatments were collected. We compared [K+]Saliva as assessed by the gold standard ion-selective electrode (ISE) with GEPII measurements. RESULTS: The Bland-Altmann analysis showed a strong agreement (bias 0.71; 95% limits of agreement from -2.79 to 4.40) between GEPII and ISE. Before treatment, patients on HD showed significantly higher [K+]Saliva compared with healthy controls [median 37.7 (30.85; 48.46) vs 23.8 (21.63; 25.23) mmol/L; P < .05]. [K+]Plasma in HD patients decreased significantly after dialysis. This was paralleled by a significant decrease in [K+]Saliva, and both parameters increased until the subsequent HD session. Despite similar kinetics, we found weak or no correlation between [K+]Plasma and [K+]Saliva. CONCLUSION: GEPIIs have shown an excellent performance in determining [K+]Saliva. [K+]Plasma and [K+]Saliva exhibited similar kinetics. To determine whether saliva could be a suitable sample type to monitor [K+]Plasma, further testing in future studies are required.
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Hiperpotasemia , Potasio , Humanos , Diálisis Renal , Riñón , Plasma/químicaRESUMEN
Health-related quality of life (HRQOL) improves after kidney transplantation (KT) but declines over time. Studies on the effect of early postoperative basal insulin therapy on HRQOL after KT, especially KTRs at high risk of developing post-transplant diabetes mellitus (PTDM) are missing. Data from a randomized controlled trial on 148 non-diabetic KTRs were analyzed. HRQOL using the KDQOL-SF™ was compared in KTRs who either received early postoperative basal insulin therapy or standard-of-care and in KTRs at risk of developing PTDM. Determinants of HRQOL outcomes were investigated using multivariable linear regression analysis. In total, 148 patients completed the KDQOL-SF at baseline. Standard-of-care or early basal insulin therapy after KT did not influence HRQOL. Overall, KT improved the mental (MCS) and physical component summary (PCS) scores at 6-month after KT, which remained stable during further follow-up visits. However, patients at high-risk for PTDM had significantly greater impairment in the PCS score (baseline, 24 months) without differences in MCS scores. In the multivariable regression analysis, allograft function and hemoglobin levels were associated with decreased MCS and PCS scores, respectively. A limitation of the study is the fact that only around 50% of the ITP-NODAT study patients participated in the HRQOL evaluation. Still, our data clearly show that early basal insulin therapy does not affect HRQOL after KT but is negatively influenced by classical clinical factors and PTDM-risk at 24 months after KT. The latter might be influenced by older age.
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Diabetes Mellitus , Insulinas , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Calidad de Vida , Trasplante Homólogo , Modelos Lineales , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
Increasing the information depth of single kidney biopsies can improve diagnostic precision, personalized medicine and accelerate basic kidney research. Until now, information on mRNA abundance and morphologic analysis has been obtained from different samples, missing out on the spatial context and single-cell correlation of findings. Herein, we present scoMorphoFISH, a modular toolbox to obtain spatial single-cell single-mRNA expression data from routinely generated kidney biopsies. Deep learning was used to virtually dissect tissue sections in tissue compartments and cell types to which single-cell expression data were assigned. Furthermore, we show correlative and spatial single-cell expression quantification with super-resolved podocyte foot process morphometry. In contrast to bulk analysis methods, this approach will help to identify local transcription changes even in less frequent kidney cell types on a spatial single-cell level with single-mRNA resolution. Using this method, we demonstrate that ACE2 can be locally upregulated in podocytes upon injury. In a patient suffering from COVID-19-associated collapsing FSGS, ACE2 expression levels were correlated with intracellular SARS-CoV-2 abundance. As this method performs well with standard formalin-fixed paraffin-embedded samples and we provide pretrained deep learning networks embedded in a comprehensive image analysis workflow, this method can be applied immediately in a variety of settings.
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COVID-19 , Aprendizaje Profundo , Enzima Convertidora de Angiotensina 2 , COVID-19/genética , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , SARS-CoV-2RESUMEN
Posttransplant diabetes mellitus (PTDM) and prediabetes (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]) are associated with cardiovascular events. We assessed the diagnostic performance of fasting plasma glucose (FPG) and HbA1c as alternatives to oral glucose tolerance test (OGTT)-derived 2-hour plasma glucose (2hPG) using sensitivity and specificity in 263 kidney transplant recipients (KTRs) from a clinical trial. Between visits at 6, 12, and 24 months after transplantation, 28%-31% of patients switched glycemic category (normal glucose tolerance [NGT], IGT/IFG, PTDM). Correlations of FPG and HbA1c against 2hPG were lower at 6 months (r = 0.59 [FPG against 2hPG]; r = 0.45 [HbA1c against 2hPG]) vs. 24 months (r = 0.73 [FPG against 2hPG]; r = 0.74 [HbA1c against 2hPG]). Up to 69% of 2hPG-defined PTDM cases were missed by conventional HbA1c and FPG thresholds. For prediabetes, concordance of FPG and HbA1c with 2hPG ranged from 6%-9%. In conclusion, in our well-defined randomized trial cohort, one-third of KTRs switched glycemic category over 2 years and although the correlations of FPG and HbA1c with 2hPG improved with time, their diagnostic concordance was poor for PTDM and, especially, prediabetes. Considering posttransplant metabolic instability, FPG's and HbA1c 's diagnostic performance, the OGTT remains indispensable to diagnose PTDM and prediabetes after kidney transplantation.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Trasplante de Riñón , Estado Prediabético , Humanos , Estado Prediabético/diagnóstico , Estado Prediabético/etiología , Glucemia/metabolismo , Trasplante de Riñón/efectos adversos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/etiología , Glucosa , Hemoglobina Glucada/análisis , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiologíaRESUMEN
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is caused by severe ADAMTS-13 deficiency. Immune-mediated TTP develops due to autoantibodies against ADAMTS-13, whereas congenital TTP is caused by mutations in the ADAMTS13 gene. Diagnostic possibilities and treatment options in TTP have emerged in recent years, which prompted the International Society on Thrombosis and Haemostasis (ISTH) to publish clinical practice guidelines for the diagnosis and treatment of TTP in 2020. In this article, the European Renal Best Practice Working Group endorsed the ISTH guidelines and emphasizes a number of considerations, including the importance of rapid ADAMTS-13 activity testing, the use of rituximab and anti-von Willebrand factor therapies such as caplacizumab, that enhance the clinical applicability of the guidelines in Europe.
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Púrpura Trombocitopénica Trombótica , Trombosis , Proteína ADAMTS13 , Hemostasis , Humanos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/etiología , Púrpura Trombocitopénica Trombótica/terapia , Trombosis/diagnóstico , Trombosis/etiología , Trombosis/terapia , Factor de von WillebrandRESUMEN
BACKGROUND: Post-transplantation diabetes mellitus (PTDM) might be preventable. METHODS: This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test-derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant. RESULTS: In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24. CONCLUSIONS: At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM-a significant reduction after adjustment for baseline differences-suggesting the intervention merits further study.Clinical Trial registration number: NCT03507829.
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Diabetes Mellitus/prevención & control , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina Isófana/uso terapéutico , Trasplante de Riñón/efectos adversos , Adulto , Anciano , Glucemia/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/etiología , Femenino , Hemoglobina Glucada/metabolismo , Adhesión a Directriz , Humanos , Hiperglucemia/sangre , Hiperglucemia/etiología , Hipoglucemia/inducido químicamente , Insulina Lispro/uso terapéutico , Insulina Isófana/efectos adversos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios , Periodo Posoperatorio , Factores de Riesgo , Factores Sexuales , Nivel de Atención , Factores de TiempoRESUMEN
Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential COVID-19 biomarkers in end-stage kidney disease (CKD G5), we analyzed the plasma metabolites in different COVID-19 stages in patients with or without HD. We recruited 18 and 9 asymptomatic and mild, 11 and 11 moderate, 2 and 13 severely affected, and 10 and 6 uninfected HD and non-HD patients, respectively. Plasma samples were taken at the time of diagnosis and/or upon admission to the hospital and analyzed by targeted metabolomics and cytokine/chemokine profiling. Targeted metabolomics confirmed stage-dependent alterations of the metabolome in non-HD patients with COVID-19, which were less pronounced in HD patients. Elevated kynurenine levels and lipid dysregulation, shown by an increase in circulating free fatty acids and a decrease in lysophospholipids, could distinguish patients with moderate COVID-19 from non-infected individuals in both groups. Kynurenine and lipid alterations were also associated with ICAM-1 and IL-15 levels in HD and non-HD patients. Our findings support the kynurenine pathway and plasma lipids as universal biomarkers of moderate and severe COVID-19 independent of kidney function.
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COVID-19 , Quinurenina , Humanos , Triptófano , Diálisis Renal , LípidosRESUMEN
Co-stimulation is a prerequisite for pathogenic activity in T cell-mediated diseases and has been demonstrated to achieve tolerance in organ-specific autoimmunity as a therapeutic target. Here, we evaluated the involvement of the tumor necrosis factor family members CD30 and OX40 in immune-complex mediated kidney disease. In vitro stimulation and proliferation studies were performed with CD4+ cells from wild type and CD30/OX40 double knock-out (CD30OX40-/-) mice. In vivo studies were performed by induction of nephrotoxic serum nephritis in wild type, CD30OX40- /- , CD30-/-, OX40-/-, reconstituted Rag1-/- and C57Bl/6J mice treated with αCD30L αOX40L antibodies. CD30, OX40 and their ligands were upregulated on various leukocytes in nephrotoxic serum nephritis. CD30OX40-/- mice, but not CD30-/- or OX40-/- mice were protected from nephrotoxic serum nephritis. Similar protection was found in Rag1-/- mice injected with CD4+ T cells from CD30OX40-/- mice compared to Rag1-/- mice injected with CD4+ T cells from wild type mice. Furthermore, CD4+ T cells deficient in CD30OX40-/- displayed decreased expression of CCR6 in vivo. CD30OX40-/- cells were fully capable of differentiating into disease mediating T helper cell subsets, but showed significantly decreased levels of proliferation in vivo and in vitro compared to wild type cells. Blocking antibodies against CD30L and OX40L ameliorated nephrotoxic serum nephritis without affecting pan-effector or memory T cell populations. Thus, our results indicate disease promotion via CD30 and OX40 signaling due to facilitation of exaggerated T cell proliferation and migration of T helper 17 cells in nephrotoxic serum nephritis. Hence, co-stimulation blockade targeting the CD30 and OX40 signaling pathways may provide a novel therapeutic strategy in autoimmune kidney disease.
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Glomerulonefritis , Receptores OX40 , Animales , Linfocitos T CD4-Positivos , Glomerulonefritis/genética , Antígeno Ki-1 , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Necrosis Tumoral alfa , Factores de Necrosis TumoralRESUMEN
Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r-/- mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r-/- mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r-/- mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell-dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy.
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Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/farmacología , Liraglutida/farmacología , Activación de Linfocitos/inmunología , Nefritis/prevención & control , Linfocitos T/inmunología , Animales , Receptor del Péptido 1 Similar al Glucagón/fisiología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nefritis/inmunología , Nefritis/metabolismo , Nefritis/patología , Linfocitos T/efectos de los fármacosRESUMEN
Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Trasplante de Riñón , Humanos , Hipoglucemiantes/uso terapéutico , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Complicaciones Posoperatorias , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: There is only limited clinical data on the benefit of intense immunosuppression in patients with severe interstitial pneumonia associated with autoimmune features or new-onset connective tissue disease. CASE PRESENTATION: We here report a series of three consecutive patients suffering from severe interstitial lung disease necessitating endotracheal intubation and mechanical ventilation. The first two patients fulfilled many diagnostic criteria for new-onset antisynthetase syndrome, the third patient for systemic lupus erythematosus. We decided to implement aggressive immunosuppressive strategies in these critically-ill patients including therapeutic plasma exchange, immunoadsorption, cyclophosphamide and rituximab. All three patients improved from respiratory failure, were successfully weaned from the respirator, and eventually dismissed from hospital with ongoing immunosuppressive therapy. CONCLUSION: Patients suffering from severe connective tissue disease-associated interstitial lung disease and respiratory failure may benefit from an aggressive immunosuppressive regimen and extracorporeal blood purification with rapid reduction of circulating autoantibodies. The impressive clinical responses in this small case series warrant a controlled clinical trial.
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Autoanticuerpos/efectos de los fármacos , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Miositis/tratamiento farmacológico , Autoanticuerpos/sangre , Ciclofosfamida , Humanos , Enfermedades Pulmonares Intersticiales/inmunología , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Miositis/inmunología , Rituximab , Resultado del TratamientoRESUMEN
INTRODUCTION: Scleroderma renal crisis (SRC) is a rare but one of the most recognised complications of systemic sclerosis (SSc). Corticosteroid (CS) use has been considered as a major risk factor for SRC. Several studies reported the efficacy of rituximab (RTX) with an acceptable safety profile in SSc. However, data on the long-term effect of high-dose CS concomitant to RTX on kidney function are lacking. METHODS: We retrospectively analysed SSc patients (n = 35) treated with a lower dosage and short-interval RTX and concomitant high-dose CS at the Department of Internal Medicine at the Medical University of Graz between 2010 and 2019. The kidney function was assessed using the estimated glomerular filtration rate (eGFR) at every RTX admission. The annual decline of kidney function was evaluated by linear mixed model analysis. RESULTS: At the RTX initiation, one patient had a decreased kidney function indicated by eGFR < 60 mL/min/1.73 m2 (median: 96 mL/min/1.73 m2 ; interquartile range (IQR): 43-136). Patients received RTX and complementary high-dose CS for a median follow-up time of 3.4 years (range 0.6-9.5). A linear mixed model analysis with the patient as random effect and time from first RTX as fixed effect estimated an annual decline of 1.98 mL/min/1.73 m2 of the eGFR (95% confidence interval: [-2.24, -1.72]; P <.001). During the follow-up period, no patient experienced SRC or a significant drop in kidney function. CONCLUSIONS: A regular, high-dose CS given contemporary to RTX seems to be a safe option for kidney function in patients with SSc. Our findings provide additional knowledge in risk evaluation and planning of individualised therapies or designing clinical studies using RTX.
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Esclerodermia Sistémica , Corticoesteroides , Humanos , Riñón , Estudios Retrospectivos , Rituximab/efectos adversos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Microangiopathic hemolytic anemias and thrombocytopenias in pregnant or postpartum women constitute an interdisciplinary diagnostic and therapeutic challenge in the evaluation of thrombotic microangiopathies (TMA), where urgent care must be considered. CASE PRESENTATION: We here report the case of a 21-year-old Somali woman, who was delivered by emergency caesarean section at 35 weeks of gestational age with acute dyspnea, placental abruption and gross edema due to severe preeclampsia/HELLP syndrome. After delivery, she developed acute kidney failure and thrombotic microangiopathy as revealed by kidney biopsy. The lack of early response to plasma exchange prompted extensive laboratory workup. Ultimately, the patient completely recovered with negative fluid balance and control of severe hypertension. CONCLUSIONS: This case report emphasizes the importance to differentiate between primary TMA syndromes and microangiopathic hemolytic anemias due to systemic disorders. Delayed recovery from preeclampsia/HELLP syndrome and malignant hypertension can clinically mimic primary TMA syndromes in the postpartum period.
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Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Manejo de la Enfermedad , Atención Posnatal/métodos , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/terapia , Lesión Renal Aguda/complicaciones , Cesárea/efectos adversos , Cesárea/tendencias , Femenino , Humanos , Intercambio Plasmático/métodos , Intercambio Plasmático/tendencias , Embarazo , Adulto JovenRESUMEN
Prostaglandin E2 (PGE2) signaling is known to modulate inflammation and vascular resistance. Receptors of PGE2 [E-type prostanoid receptors (EP)] might be an attractive pharmacological target in immune-mediated diseases such as glomerulonephritis. We hypothesized that selective EP4 antagonism improves nephrotoxic serum nephritis (NTS) by its anti-inflammatory properties. Mice were subjected to NTS and treated with the EP4 antagonist ONO AE3-208 (10 mg·kg body wt-1·day-1] or vehicle starting from disease initiation. In one set of experiments, treatment was started 4 days after NTS induction. Tubular epithelial cells were evaluated in vitro under starving conditions. EP4 antagonist treatment significantly improved the NTS phenotype without affecting blood pressure levels. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. EP4 antagonism decreased tubular chemokine (C-X-C motif) ligand ( Cxcl) 1 and Cxcl-5 expression and thereby subsequently reduced interstitial neutrophil infiltration into the kidney. In vitro, tubular epithelial cells increasingly expressed Cxcl-5 mRNA and Cxcl-5 protein when treated with PGE2 or an EP4 agonist under starving conditions, which was blunted by EP4 antagonist treatment. Together, EP4 antagonism improves the NTS phenotype, probably by decreasing mainly Cxcl-5 production in tubular cells, thereby reducing renal neutrophil infiltration.