RESUMO
After transplantation self-management is essential for graft survival and optimal quality of life. To address the need for home-based support in self-management, we implemented the "SelfCare after Renal Transplantation" (SeCReT) box, containing home-monitoring equipment combined with a smartphone application that was linked to the electronic patient records. This study investigated the uptake and continuation, protocol adherence, and subjective evaluation of this home-monitoring program. All "de novo" kidney recipients who received the SeCReT-box in the study period (Aug 2021-Dec 2022) were eligible for inclusion. Protocol adherence was defined as ≥75%. Subjective evaluation was assessed with a 5-item questionnaire. Of the 297 recipients transplanted, 178 participants (60%) were included in the analysis. Protocol adherence was 83%, 73%, 66%, and 57% respectively at 5, 10, 20, and 40 weeks of the protocol. With regard to continuation, 135 participants were still in the program at the end of the study period (75% retention rate). Regarding subjective evaluations, 82% evaluated the program positively, and 52% reported lower care needs due to home-monitoring. Results are positive among those who entered and continued the program. Qualitative research is needed on barriers to entering the program and facilitators of use in order to promote optimal implementation.
Assuntos
Transplante de Rim , Autocuidado , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Qualidade de Vida , Idoso , Inquéritos e Questionários , Smartphone , Aplicativos Móveis , Sobrevivência de Enxerto , Cooperação do Paciente , Serviços de Assistência DomiciliarRESUMO
OBJECTIVES: To study the effect of mycophenolate mofetil (MMF) on various vaccination responses in kidney transplant recipients. METHODS: In a randomized controlled trial (EudraCT nr.: 2014-001372-66), low immunologically risk kidney transplant recipients were randomized to TAC/MMF or TAC-monotherapy (TACmono), six months post-transplantation. One year after transplantation, in a pre-specified sub-study, recipients were vaccinated against pneumococcus, tetanus and influenza. Blood was sampled before and 21 days after vaccination. Adequate vaccination responses were defined by international criteria. A post-hoc analysis was conducted on SARS-CoV-2 vaccination responses within the same cohort. RESULTS: Seventy-one recipients received pneumococcal and tetanus vaccines (TAC/MMF: n = 37, TACmono: n = 34), with 29 also vaccinated against influenza. When vaccinated, recipients were 60 (54-66) years old, with median eGFR of 54 (44-67) ml/min, tacrolimus trough levels 6.1 (5.4-7.0) ug/L in both groups and TAC/MMF daily MMF dose of 1000 (500-2000) mg. Adequate vaccination responses were: pneumococcal (TAC/MMF 43%, TACmono 74%, p = 0.016), tetanus (TAC/MMF 35%, TACmono 82%, p < 0.0001) and influenza (TAC/MMF 20%, TACmono 71%, p = 0.0092). Only 7% of TAC/MMF responded adequately to all three compared to 36% of TACmono (p = 0.080). Additionally, 40% of TAC/MMF responded inadequately to all three, whereas all TACmono patients responded adequately to at least one vaccination (p = 0.041). Lower SARS-CoV-2 vaccination antibody responses correlated with lower pneumococcal antibody vaccination responses (correlation coefficient: 0.41, p = 0.040). CONCLUSIONS: MMF on top of tacrolimus severely hampers antibody responses to a broad range of vaccinations.
Assuntos
Influenza Humana , Transplante de Rim , Tétano , Humanos , Pessoa de Meia-Idade , Idoso , Ácido Micofenólico/uso terapêutico , Tacrolimo/uso terapêutico , Imunossupressores/uso terapêutico , Influenza Humana/tratamento farmacológico , Formação de Anticorpos , Vacinas contra COVID-19 , Tétano/prevenção & controle , Tétano/tratamento farmacológicoRESUMO
[This corrects the article DOI: 10.3389/fimmu.2023.1122409.].
RESUMO
Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
Assuntos
Hipersensibilidade , Transplante de Rim , Humanos , Mastócitos , Citocinas/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
Vesicle-based medicines hold great promise for therapy development but essential knowledge on the bio-distribution and longevity of vesicles after administration is lacking. We generated vesicles from the membranes of human mesenchymal stromal cells (MSC) and we demonstrated earlier that these so-called membrane particles (MP) mediate immunomodulatory and regenerative responses in target cells. In the present study we examined the bio-distribution and longevity of MP after intravenous administration in mice. While most vesicle tracking methods are based on imaging techniques, which require labeling of vesicles and can only detect dense accumulations of vesicles, we used proteomics analysis to detect the presence of MP-derived proteins in multiple organs and tissues. MP proteins were mainly present in plasma and leukocytes at 1 h after injection, indicating that MP - in contrast to whole MSC - do not accumulate in the lungs upon first passage but remain in circulation. After 24 h, MP proteins were still present in plasma but were most abundant in the liver. RNA sequencing of livers demonstrated that MP impact liver function and in particular induce metabolic pathways. These data provide a clear view of the bio-distribution and longevity of MP, which is likely extrapolatable to other types of vesicles, and demonstrate that MP circulate for up to 24 h and may be a tool for targeting the liver.
Assuntos
Vesículas Extracelulares , Células-Tronco Mesenquimais , Animais , Vesículas Extracelulares/metabolismo , Humanos , Imunomodulação , Fígado , Células-Tronco Mesenquimais/metabolismo , CamundongosRESUMO
BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.
Assuntos
Vacinas contra COVID-19 , Transplante de Rim , Diálise Renal , Insuficiência Renal Crônica/terapia , Vacinas contra COVID-19/administração & dosagem , Estudos de Coortes , Humanos , Países Baixos , Estudos Observacionais como Assunto , Estudos Prospectivos , Fatores de TempoRESUMO
Background: The impact of donor-specific antibodies (DSA) in (highly-) immunized living donor kidney transplant recipients is reported differentially in various patient cohorts. Methods: We have performed a retrospective analysis of all consecutive HLA-incompatible living donor kidney transplant recipients in our center between 2010-2019. Recipients who underwent plasmafiltration for a positive CDC-crossmatch were excluded. For each DSA+ recipient (DSA+), one immunized recipient without DSA (pPRA+) and two non-immunized recipients (pPRA-) were included. Patient and graft survival were analyzed and a subgroup analysis of DSA+ recipients was performed. Results: For 63 DSA+ recipients, 63 PRA+ and 126 PRA- recipients were included. 26 (41%) had class I, 24 (38%) class II and 13 (21%) combined HLA class I and II DSA. Death-censored graft survival was inferior in DSA+ recipients compared to pPRA+ (HR 2.38 [95% CI 1.00-5.70]) as well as to pPRA- (HR 3.91 [1.86-8.22]). In multivariate analysis, DSA remained of negative influence on death-censored graft survival. Flowcytometric crossmatch, MFI value, HLA class and origin of DSA were not of significant impact. Conclusion: In our cohort of (highly-) immunized recipients, pretransplant DSA led to inferior death-censored graft survival. There were no "safe" DSA characteristics since only DSA per se impacted death-censored graft survival.
Assuntos
Transplante de Rim , Doadores Vivos , Humanos , Estudos Retrospectivos , Transplante de Rim/efeitos adversos , Antígenos HLA , AnticorposRESUMO
The rapid emergence of the COVID-19 pandemic is unprecedented and poses an unparalleled obstacle in the sixty-five year history of organ transplantation. Worldwide, the delivery of transplant care is severely challenged by matters concerning - but not limited to - organ procurement, risk of SARS-CoV-2 transmission, screening strategies of donors and recipients, decisions to postpone or proceed with transplantation, the attributable risk of immunosuppression for COVID-19 and entrenched health care resources and capacity. The transplant community is faced with choosing a lesser of two evils: initiating immunosuppression and potentially accepting detrimental outcome when transplant recipients develop COVID-19 versus postponing transplantation and accepting associated waitlist mortality. Notably, prioritization of health care services for COVID-19 care raises concerns about allocation of resources to deliver care for transplant patients who might otherwise have excellent 1-year and 10-year survival rates. Children and young adults with end-stage organ disease in particular seem more disadvantaged by withholding transplantation because of capacity issues than from medical consequences of SARS-CoV-2. This report details the nationwide response of the Dutch transplant community to these issues and the immediate consequences for transplant activity. Worrisome, there was a significant decrease in organ donation numbers affecting all organ transplant services. In addition, there was a detrimental effect on transplantation numbers in children with end-organ failure. Ongoing efforts focus on mitigation of not only primary but also secondary harm of the pandemic and to find right definitions and momentum to restore the transplant programs.
Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Transplante de Órgãos/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Adolescente , Betacoronavirus/isolamento & purificação , COVID-19 , Criança , Pré-Escolar , Humanos , Países Baixos , Pandemias , SARS-CoV-2 , Obtenção de Tecidos e Órgãos , TransplantadosRESUMO
B cells have various functions, besides being plasma cell precursors. We determined the presence of intragraft B cells at time of acute rejection (AR) and looked for correlates of B cell involvement in peripheral blood. Renal biopsies at time of AR or stable graft function were analysed for the presence of B cells and B cell-related gene expression, as well as C4d staining. Peripheral blood B cell subset distribution was analysed at various time-points in patients with AR and controls, alongside serum human leucocyte antigen (HLA) antibodies. AR was accompanied by intragraft CD20+ B cells, as well as elevated CD20 (MS4A1) and CD19 gene expression compared to controls. B cell infiltrates were proportional to T cells, and accompanied by the chemokine pair C-X-C motif chemokine ligand 13 (CXCL13)-C-X-C motif chemokine receptor 5 (CXCR5) and B cell activating factor (BAFF). Peripheral blood memory B cells were decreased and naive B cells increased at AR, in contrast to controls. While 22% of patients with AR and 5% of controls showed de-novo donor-specific antibodies (DSA), all biopsies were C4d-negative. These results suggest a role for B cells in AR by infiltrating the graft alongside T cells. We hypothesize that the shift in peripheral blood B cell composition is related to the graft infiltration at time of AR.
Assuntos
Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Rim , Rim/patologia , Subpopulações de Linfócitos/imunologia , Linfócitos T/imunologia , Doença Aguda , Adulto , Idoso , Antígenos CD20/metabolismo , Circulação Sanguínea , Movimento Celular , Quimiocina CXCL13/metabolismo , Feminino , Humanos , Memória Imunológica , Isoanticorpos/sangue , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a small vessel disease caused by C-terminal truncating TREX1 mutations. The disease is typically characterized by vascular retinopathy and focal and global brain dysfunction. Systemic manifestations have also been reported but not yet systematically investigated. METHODS: In a cross-sectional study, we compared the clinical characteristics of 33 TREX1 mutation carriers (MC+) from three Dutch RVCL-S families with those of 37 family members without TREX1 mutation (MC-). All participants were investigated using personal interviews, questionnaires, physical, neurological and neuropsychological examinations, blood and urine tests, and brain MRI. RESULTS: In MC+, vascular retinopathy and Raynaud's phenomenon were the earliest symptoms presenting from age 20 onwards. Kidney disease became manifest from around age 35, followed by liver disease, anaemia, markers of inflammation and, in some MC+, migraine and subclinical hypothyroidism, all from age 40. Cerebral deficits usually started mildly around age 50, associated with white matter and intracerebral mass lesions, and becoming severe around age 60-65. CONCLUSIONS: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is a rare, but likely underdiagnosed, systemic small vessel disease typically starting with vascular retinopathy, followed by multiple internal organ disease, progressive brain dysfunction, and ultimately premature death.
Assuntos
Leucoencefalopatias , Doença de Raynaud , Vasculite Retiniana , Vasculite Sistêmica , Adulto , Idade de Início , Exodesoxirribonucleases/genética , Feminino , Humanos , Nefropatias/diagnóstico , Nefropatias/etiologia , Leucoencefalopatias/congênito , Leucoencefalopatias/epidemiologia , Leucoencefalopatias/fisiopatologia , Leucoencefalopatias/psicologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Testes Neuropsicológicos , Fosfoproteínas/genética , Doença de Raynaud/diagnóstico , Doença de Raynaud/etiologia , Vasculite Retiniana/diagnóstico , Vasculite Retiniana/etiologia , Vasculite Sistêmica/diagnóstico , Vasculite Sistêmica/epidemiologia , Vasculite Sistêmica/etiologia , Substância Branca/diagnóstico por imagemRESUMO
AIMS: Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of dosing, as the optimal immunosuppressive dose in calcineurin-free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment-limiting toxicity. METHODS: We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens. RESULTS: We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75-1 mg twice daily (BID) results in subtherapeutic trough levels (<6 µg l-1 ) and that a higher starting dose of 2.25-3 mg BID is required. CONCLUSION: For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Everolimo/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Everolimo/efeitos adversos , Everolimo/farmacocinética , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/imunologia , Prednisolona/administração & dosagem , Prednisolona/farmacocinética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética , Transplante Homólogo/efeitos adversos , Resultado do TratamentoRESUMO
In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.
Assuntos
Everolimo/uso terapêutico , Fibrose/tratamento farmacológico , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Prednisolona/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Feminino , Fibrose/etiologia , Rejeição de Enxerto/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , DesmameRESUMO
Across the world, the proportions of senior citizens (i.e. those ≥65years) increase rapidly and are predicted to constitute over 25% of the general population by 2050. In 2012 already 48% of the population with end stage renal disease (ESRD) was aged 65years or older. Transplantation is considered the preferred treatment option for ESRD offering survival advantage over long-term dialysis in the majority of patients. Indeed, acceptable outcomes have been documented for selected patients over the age of 70years or even cases over 80years. The reality of organ scarcity and prolonged waiting times for a deceased donor kidney transplantation, however, indicate that at best 50% of the selected elderly may have realistic expectations to receive a timely transplant offer. By choice or medical selection, access to transplantation also decreases with increasing age. In order to expedite the chance for elderly to receive a kidney transplant dedicated allocation systems have been developed. These allocation systems, like the Eurotransplant Senior Program (ESP), support preferential local allocation of kidneys from older donors to older patients in order to match recipient and graft life while disregarding histocompatibility for HLA antigens. The consequence has been more acute rejection episodes and an increase in immunosuppressive load. In the elderly, the most common cause of graft loss is death with functioning graft and death from infectious diseases is one of the dominant causes. The Eurotransplant Senior DR-compatible Program (ESDP) was designed to further improve the perspective of successful transplantation in the elderly in terms of life and quality of life by re-introducing matching criteria for HLA-DR in the old-for-old algorithm.
Assuntos
Teste de Histocompatibilidade/estatística & dados numéricos , Falência Renal Crônica/cirurgia , Transplante de Rim/estatística & dados numéricos , Idoso , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Acessibilidade aos Serviços de Saúde , Humanos , Imunossupressores/imunologia , Incidência , Falência Renal Crônica/epidemiologia , Transplante de Rim/mortalidade , Seleção de Pacientes , Qualidade de Vida , Sistema de Registros , Fatores de Risco , Obtenção de Tecidos e Órgãos , Listas de EsperaRESUMO
Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Transplante de Rim , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Ensaios Clínicos como Assunto , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunomodulação , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/imunologia , Transplante Homólogo , Resultado do TratamentoRESUMO
Because microvascular disease is one of the most important drivers of diabetic complications, early monitoring of microvascular integrity may be of clinical value. By assessing profiles of circulating microRNAs (miRNAs), known regulators of microvascular pathophysiology, in healthy controls and diabetic nephropathy (DN) patients before and after simultaneous pancreas-kidney transplantation (SPK), we aimed to identify differentially expressed miRNAs that associate with microvascular impairment. Following a pilot study, we selected 13 candidate miRNAs and determined their circulating levels in DN (n = 21), SPK-patients (n = 37), healthy controls (n = 19), type 1 diabetes mellitus patients (n = 15) and DN patients with a kidney transplant (n = 15). For validation of selected miRNAs, 14 DN patients were studied longitudinally up to 12 months after SPK. We demonstrated a direct association of miR-25, -27a, -126, -130b, -132, -152, -181a, -223, -320, -326, -340, -574-3p and -660 with DN. Of those, miR-25, -27a, -130b, -132, -152, -320, -326, -340, -574-3p and -660 normalized after SPK. Importantly, circulating levels of some of these miRNAs tightly associate with microvascular impairment as they relate to aberrant capillary tortuosity, angiopoietin-2/angiopoietin-1 ratios, circulating levels of soluble-thrombomodulin and insulin-like growth factor. Taken together, circulating miRNA profiles associate with DN and systemic microvascular damage, and might serve to identify individuals at risk of experiencing microvascular complications, as well as give insight into underlying pathologies.
Assuntos
Nefropatias Diabéticas/sangue , Transplante de Rim , MicroRNAs/sangue , Transplante de Pâncreas , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Simultaneous pancreas-kidney transplantation (SPK) is an advanced treatment option for type 1 diabetes mellitus (DM) patients with microvascular disease including nephropathy. Sidestreamdarkfield (SDF) imaging has emerged as a noninvasive tool to visualize the human microcirculation. This study assessed the effect of SPK in diabetic nephropathy (DN) patients on microvascular alterations using SDF and correlated this with markers for endothelial dysfunction. Microvascular morphology was visualized using SDF of the oral mucosa in DN (n = 26) and SPK patients (n = 38), healthy controls (n = 20), DM1 patients (n = 15, DM ≥ 40 mL/min) and DN patients with a kidney transplant (KTx, n = 15). Furthermore, 21 DN patients were studied longitudinally up to 12 months after SPK. Circulating levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and soluble thrombomodulin (sTM) were measured using ELISA. Capillary tortuosity in the DN (1.83 ± 0.42) and DM ≥ 40 mL/min (1.55 ± 0.1) group was increased and showed reversal after SPK (1.31 ± 0.3, p < 0.001), but not after KTx (1.64 ± 0.1). sTM levels were increased in DN patients and reduced in SPK and KTx recipients (p < 0.05), while the Ang-2/Ang-1 ratio was normalized after SPK and not after KTx alone (from 0.16 ± 0.04 to 0.08 ± 0.02, p < 0.05). Interestingly, in the longitudinal study, reversal of capillary tortuosity and decrease in Ang-2/Ang-1 ratio and sTM was observed within 12 months after SPK. SPK is effective in reversing the systemic microvascular structural abnormalities in DN patients in the first year after transplantation.
Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Transplante de Rim , Microcirculação , Transplante de Pâncreas , Adulto , Estudos Transversais , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/cirurgia , Feminino , Seguimentos , Humanos , Rim/fisiopatologia , Rim/cirurgia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Mycophenolate mofetil (MMF) has recently been established as a potent drug in maintenance treatment for lupus nephritis. However, there is no consensus on the optimal dosing regimen because of a high inter-individual variability of mycophenolic acid (MPA), the active metabolite of MMF. This retrospective study aimed to investigate the effect of an individualized dosing regimen through concentration-controlled treatment on MPA exposure and renal outcome in patients with lupus nephritis. METHODS: Sixteen patients with lupus nephritis and treatment with low-dose intravenous cyclophosphamide followed by MMF were included. MPA area under the plasma concentration-time curve from 0 to 12 hours (MPA-AUC(0-12)) was assessed within a month after MMF initiation. After determination of MPA-AUC(0-12), MMF doses were titrated to achieve a target MPA-AUC(0-12) of 60-90 mg*h/l. After on average six months, MPA-AUC(0-12) measures were repeated to assess the effect of dose adjustment. RESULTS: One month after introducing MMF, MPA-AUC(0-12) was low and showed a high inter-individual variability. Dose adjustment with a target MPA-AUC(0-12) of 60-90 mg*h/l resulted in individualized MMF dosing, significantly higher MPA-AUC(0-12) levels, and a non-significant reduction in variability of MPA-AUC(0-12). Adverse effects were reported by 37.5% of patients, which resulted in a switch to azathioprine in two patients. There was no significant relationship between the occurrence of adverse effects and MPA-AUC(0-12). At 12 months of follow-up 87.5% of patients had achieved either partial (18.7%) or complete (68.8%) remission. CONCLUSION: Concentration-controlled dose adjustments with a target MPA-AUC(0-12) of 60-90 mg*h/l was associated with optimized MPA exposure and an excellent renal outcome at 12 months of follow-up in a small sample of SLE patients with lupus nephritis.
Assuntos
Imunossupressores/administração & dosagem , Nefrite Lúpica/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Ácido Micofenólico/administração & dosagem , Estudos Retrospectivos , Adulto JovemRESUMO
Donor brain death has profound effects on post-transplantation graft function and survival. We hypothesized that changes initiated in the donor influence the graft's response to ischemia and reperfusion. In this study, human brain dead donor kidney grafts were compared to living and cardiac dead donor kidney grafts. Pretransplant biopsies of brain dead donor kidneys contained notably more infiltrating T lymphocytes and macrophages. To assess whether the different donor conditions result in a different response to reperfusion, local cytokine release from the reperfused kidney was studied by measurement of paired arterial and renal venous blood samples. Reperfusion of kidneys from brain dead donors was associated with the instantaneous release of inflammatory cytokines, such as G-CSF, IL-6, IL-9, IL-16 and MCP-1. In contrast, kidneys from living and cardiac dead donors showed a more modest cytokine response with release of IL-6 and small amounts of MCP-1. In conclusion, this study shows that donor brain death initiates an inflammatory state of the graft with T lymphocyte and macrophage infiltration and massive inflammatory cytokine release upon reperfusion. These observations suggest that brain dead donors require a novel approach for donor pretreatment aimed at preventing this inflammatory response to increase graft survival.
Assuntos
Morte Encefálica/fisiopatologia , Inflamação/etiologia , Transplante de Rim/métodos , Rim/fisiopatologia , Adulto , Idoso , Quimiocina CCL2/metabolismo , Feminino , Sobrevivência de Enxerto , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Inflamação/patologia , Interleucina-16/metabolismo , Interleucina-6/metabolismo , Interleucina-9/metabolismo , Rim/imunologia , Transplante de Rim/efeitos adversos , Macrófagos/citologia , Masculino , Pessoa de Meia-Idade , Reperfusão , Linfócitos T/imunologiaRESUMO
BACKGROUND: Chemokines play an essential role in regulating the infiltration of leukocytes into allografts in experimental models. Little is known of their expression or function after human cardiac transplantation. METHODS AND RESULTS: We analyzed 169 sequential human endomyocardial biopsies by immunocytochemistry for infiltration by CD3(+) T cells and the expression of the chemokine receptors CCR1, CCR3, CCR5, and CXCR3. In both cross-sectional and longitudinal analyses, the expression of each of the chemokine receptors correlated with the degree of CD3(+) T-cell infiltration. In particular, the expression of CXCR3 was temporally and spatially associated with CD3(+) T-cell infiltrates and correlated with the histopathological diagnosis of acute rejection (OR, 11.73 and 4.05, respectively; P<0.001). Of 7 patients followed up longitudinally for 1 year, 4 with consecutive biopsies developed intimal thickening by intravascular ultrasound. In these patients, there was a trend for persistent expression of CD3- and CXCR3-expressing infiltrates in the later part of the first posttransplant year. The chemokines eotaxin, IP-10, lymphotactin, MCP-1, Mig, RANTES, and SDF-1 were examined in an additional 35 biopsies by RT-PCR. Eotaxin, lymphotactin, MCP-1, Mig, and SDF-1 were present in both normal and rejecting biopsies. However, the CXCR3 ligand IP-10, which was rarely expressed in normal biopsies, was markedly induced in acute rejection (OR, 19.43; P=0.01). CONCLUSIONS: The presence of CXCR3(+) T cells and the CXCR3 ligand IP-10 within endomyocardial biopsies is strongly associated with acute rejection. The CXCR3-IP-10 interaction warrants consideration as a therapeutic target in the management of cardiac allograft recipients.
Assuntos
Quimiocinas CXC/biossíntese , Rejeição de Enxerto/metabolismo , Transplante de Coração , Receptores de Quimiocinas/biossíntese , Transcrição Gênica , Adulto , Biópsia , Complexo CD3/análise , Quimiocina CXCL10 , Quimiocinas/biossíntese , Quimiocinas/genética , Quimiocinas CXC/genética , Estudos Transversais , Feminino , Rejeição de Enxerto/genética , Rejeição de Enxerto/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , RNA Mensageiro/biossíntese , Receptores CXCR3 , Receptores de Quimiocinas/genética , Linfócitos T/imunologiaRESUMO
This study addresses a mechanism by which lymphocytes may promote vascular endothelial growth factor (VEGF) expression and angiogenesis in immune inflammation. Resting human umbilical endothelial cells (HUVECs) were found to express low levels of VEGF messenger RNA (mRNA) by reverse transcription polymerase chain reaction and ribonuclease protection assay with little or no change in expression following activation by cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1, interferon gamma, or IL-4. In contrast, treatment of HUVECs and monocytes with soluble CD40 ligand (sCD40L) resulted in a marked dose-dependent induction of VEGF mRNA (approximately 4-fold), which peaked between 1 and 5 hours post-stimulation. Transient transfection of HUVECs was performed with a luciferase reporter construct under the control of the human VEGF promoter. Treatment of transfected HUVECs with sCD40L was found to enhance luciferase activity (approximately 4-fold) compared with controls, similar to the relative fold induction in mRNA expression in parallel cultures. Thus, CD40-dependent VEGF expression was a result of transcriptional control mechanisms. Treatment of HUVECs with sCD40L was also found to function in vitro to promote growth and proliferation in a VEGF-dependent manner, and CD40-dependent HUVEC growth was comparable to that found following treatment with recombinant human VEGF. Furthermore, subcutaneous injection of sCD40L in severe combined immunodeficient and nude mice induced VEGF expression and marked angiogenesis in vivo. Taken together, these findings are consistent with a function for CD40L-CD40 interactions in VEGF-induced angiogenesis and define a mechanistic link between the immune response and angiogenesis. (Blood. 2000;96:3801-3808)