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1.
J Hypertens ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32618887

RESUMO

AIMS: Myocardial fibrosis is a relevant component of hypertensive heart disease (HHD). Novel cardiovascular magnetic resonance (CMR) imaging techniques have shown potential in quantification of diffuse cardiac fibrosis, with T1 mapping, and estimating preclinical cardiac dysfunction, with strain analysis. Molecular biomarkers of fibrosis have been related with clinical outcomes and histologically proven myocardial fibrosis. The relationship between these CMR-imaging techniques and circulating biomarkers is not fully understood. METHODS AND RESULTS: CMR was performed on a 3T scanner in 36 individuals with HHD. Extracellular volume fraction (ECV) and the partition coefficient were assessed using the T1 mapping technique shMOLLI. Longitudinal, circumferential and radial strain was assessed using CMR-Feature Tracking. Molecular biomarkers of collagen synthesis (PICP and PIIINP) and collagen degradation (CITP and MMP-1) were measured in blood using commercial kits. Correlation models showed a significant relationship of T1 mapping measures with left atrial diameter, LV mass, LV posterior wall thickness, LV end-diastolic volume and longitudinal strain. In fully adjusted regression models, ECV was associated with left atrial diameter (ß=0.75, P = 0.005) and longitudinal strain (ß = 0.43, P = 0.030); the partition coefficient was associated with LV posterior wall thickness (ß = 0.53, P = 0.046). Strain measures were associated with cardiac geometry, and longitudinal strain was marginally associated with CITP. CONCLUSION: In individuals with HHD, CMR-derived measures of myocardial fibrosis and function are related and might be useful tools for the identification and characterization of preclinical cardiac dysfunction and diffuse myocardial fibrosis. Molecular biomarkers of fibrosis were marginally associated with myocardial strain, but not with the extension of CMR-measured cardiac fibrosis.

2.
Transpl Int ; 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32491249

RESUMO

Kidney paired donation (KPD) is a valuable tool to overcome immunological barriers in living donor transplantation. While small national registries encounter difficulties in finding compatible matches, multi-national KPD may be a useful strategy to facilitate transplantation. The Czech (Prague) and Austrian (Vienna) KPD programs, both initiated in 2011, were merged in 2015. A bi-national algorithm allowed for ABO- and low-level HLA antibody-incompatible exchanges, including the option of altruistic donor-initiated domino chains. Between 2011 and 2019, 222 recipients and their incompatible donors were registered. Of those, 95.7% (Prague) and 67.9% (Vienna) entered into KPD registries, and 81 patients received a transplant (95% 3-year graft survival). Inclusion of ABO-incompatible pairs in the Czech program contributed to higher KPD transplant rates (42.6% vs. 23.6% in Austria). After 2015 (11 bi-national match runs), the median pool size increased to 18 pairs, yielding 33 transplants (8 via cross-border exchanges). While matching rates doubled in Austria (from 9.1% to 18.8%), rates decreased in the Czech program, partly due to implementation of more stringent HLA antibody thresholds. Our results demonstrate the feasibility of merging small national KPD programs to increase pool sizes and may encourage the implementation of multi-national registries to expand the full potential of KPD.

4.
Transplantation ; 104(4): 708-714, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32224812

RESUMO

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence. The strengths of recommendations are provided in the full report. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

5.
Transplantation ; 104(4S1 Suppl 1): S11-S103, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32301874

RESUMO

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

6.
J Am Soc Nephrol ; 31(4): 701-715, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32034106

RESUMO

BACKGROUND: Gdf15 encodes a TGF-ß superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI. METHODS: We used genome editing to generate a Gdf15 nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization and genetic modification of Gdf15-expressing cells. We extensively mapped Gdf15 expression in the normal kidney and following bilateral ischemia-reperfusion injury, and quantified and compared renal responses to ischemia-reperfusion injury in the presence and absence of GDF15. In addition, we analyzed single nucleotide polymorphism association data for GDF15 for associations with patient kidney transplant outcomes. RESULTS: Gdf15 is normally expressed within aquaporin 1-positive cells of the S3 segment of the proximal tubule, aquaporin 1-negative cells of the thin descending limb of the loop of Henle, and principal cells of the collecting system. Gdf15 is rapidly upregulated within a few hours of bilateral ischemia-reperfusion injury at these sites and new sites of proximal tubule injury. Deficiency of Gdf15 exacerbated acute tubular injury and enhanced inflammatory responses. Analysis of clinical transplantation data linked low circulating levels of GDF15 to an increased incidence of biopsy-proven acute rejection. CONCLUSIONS: Gdf15 contributes to an early acting, renoprotective injury response, modifying immune cell actions. The data support further investigation in clinical model systems of the potential benefit from GDF15 administration in situations in which some level of tubular injury is inevitable, such as following a kidney transplant.

8.
Transpl Int ; 33(7): 729-739, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31970822

RESUMO

Although separate prediction models for donors and recipients were previously published, we identified a need to predict outcomes of donor/recipient simultaneously, as they are clearly not independent of each other. We used characteristics from transplantations performed at the Oslo University Hospital from 1854 live donors and from 837 recipients of a live donor kidney transplant to derive Cox models for predicting donor mortality up to 20 years, and recipient death, and graft loss up to 10 years. The models were developed using the multivariable fractional polynomials algorithm optimizing Akaike's information criterion, and optimism-corrected performance was assessed. Age, year of donation, smoking status, cholesterol and creatinine were selected to predict donor mortality (C-statistic of 0.81). Linear predictors for donor mortality served as summary of donor prognosis in recipient models. Age, sex, year of transplantation, dialysis vintage, primary renal disease, cerebrovascular disease, peripheral vascular disease and HLA mismatch were selected to predict recipient mortality (C-statistic of 0.77). Age, dialysis vintage, linear predictor of donor mortality, HLA mismatch, peripheral vascular disease and heart disease were selected to predict graft loss (C-statistic of 0.66). Our prediction models inform decision-making at the time of transplant counselling and are implemented as online calculators.

9.
Transplant Rev (Orlando) ; 34(2): 100531, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31955920

RESUMO

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation (KT), but its use is complicated by a narrow therapeutic index and high inter- and intra-patient pharmacokinetic variability. There are three available oral formulations of tacrolimus: immediate-release tacrolimus (IR-Tac), extended-release tacrolimus (ER-Tac) and a MeltDose® (LCPT) formulation, the latter favoring a prolonged drug release and increased bioavailability. The time-concentration curves of these formulations are different. Compared with IR-Tac and ER-Tac, LCPT has a relatively flat pharmacokinetic profile with less fluctuation between trough and peak exposures, and a delayed peak concentration. This translates to a more stable delivery of tacrolimus and may alleviate the risk of underexposure and allograft rejection or overexposure and toxicity. The once-daily formulation of both ER-TAC and LCPT may also offer a potential advantage on patient adherence. Fast metabolizers of tacrolimus, the elderly, and human leukocyte antigen-sensitized patients are at risk of poorer outcomes after KT, possibly associated with a different exhibited pharmacokinetics of tacrolimus or different requirements in terms of exposure. Simple, practical strategies are needed to identify patients at risk of suboptimal KT outcomes and those who would benefit from a more proactively personalized approach to tacrolimus treatment. This review aims to increase awareness of the link between the pharmacokinetics of oral tacrolimus formulations and the clinical needs of patients after KT, particularly among those who have clinically significant pharmacokinetic variation of tacrolimus.

10.
Nephrol Dial Transplant ; 35(4): 547-549, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711222
11.
Curr Opin Organ Transplant ; 25(1): 66-73, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31815789

RESUMO

PURPOSE OF REVIEW: In this review, we summarize different allocation schemes around the world and identify ways to exchange organs between countries. RECENT FINDINGS: The primary goal of transplantation is prolongation of patient survival and an improved quality of life. Most allocation systems try to match the potential survival of the organ with the life expectancy of its recipient. Kidney transplantation enables cost reductions by the avoidance of dialysis for the healthcare system, which is sometimes the driving force for state interventions to enhance donor recruitmentThe major benefit from international exchange is the possibility to transplant highly sensitized patients or patients with rare HLA allele.In a broad international exchange system, there are three possibilities: exchange of surplus organs, exchange of organs to support patients with a potentially excessive waiting time because of HLA antibodies or rare alleles, and exchange of organs to make the best possible match between donor and recipient. SUMMARY: It is possible to shape a hierarchical allocation scheme, which could be applicable in the majority of populations despite different geographical and socioeconomic conditions: allocation to recipients with special requirements (high-urgency, highly sensitized); identification of a within the region/country; in case no suitable recipient can be identified, offer countrywide or between countries; for every organ transferred to another country, there must be an obligation to give one back.

12.
Transpl Int ; 33(1): 50-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31560143

RESUMO

Most research in transplant medicine includes statistical analysis of observed data. Too often authors solely rely on P-values derived by statistical tests to answer their research questions. A P-value smaller than 0.05 is typically used to declare "statistical significance" and hence, "proves" that, for example, an intervention has an effect on the outcome of interest. Especially in observational studies, such an approach is highly problematic and can lead to false conclusions. Instead, adequate estimates of the observed size of the effect, for example, expressed as the risk difference, the relative risk or the hazard ratio, should be reported. These effect size measures have to be accompanied with an estimate of their precision, like a 95% confidence interval. Such a duo of effect size measure and confidence interval can then be used to answer the important question of clinical relevance.

13.
Transpl Int ; 33(1): 5-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31650645

RESUMO

Recognition of non-self structures on donor cells represents the main immunological barrier in solid organ transplantation. The human leukocyte antigens (HLA) are considered the most important non-self (allo)antigens in transplantation. Long-term graft attrition is mainly caused by the formation of alloreactive antibodies that are directed against non-self structures (i.e., epitopes) on cell surface proteins. Recently published data provided evidence for a similar importance of non-HLA mismatches between donors and recipients in acute rejection as well as long-term kidney allograft survival. These data suggest a broader concept of immunological non-self that goes beyond HLA incompatibility and expands the current concept of polymorphic non-self epitopes on cell surface molecules from HLA to non-HLA targets. Amino acid substitutions caused by single nucleotide variants in protein-coding genes or complete loss of gene expression represent the basis for polymorphic residues in both HLA and non-HLA molecules. To better understand these novel insights in non-HLA alloimmunity, we will first review basic principles of the alloimmune response with a focus on the HLA epitope concept in donor-specific antibody formation before discussing key publications on non-HLA antibodies.

14.
Wien Klin Wochenschr ; 131(Suppl 6): 489-590, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31792659

RESUMO

Elevated blood pressure remains a major cause of cardiovascular disease, disability, and premature death in Austria, with suboptimal rates of detection, treatment and control also in recent years. Management of hypertension is a common challenge for physicians with different spezializations. In an attempt to standardize diagnostic and therapeutic strategies and, ultimately, to increase the rate of patients with controlled blood pressure and to decrease the burden of cardiovascular disease, 13 Austrian medical societies reviewed the evidence regarding prevention, detection, workup, treatment and consequences of high blood pressure in general and in various clinical scenarios. The result is presented as the first national consensus on blood pressure. The authors and societies involved are convinced that a joint national effort is needed to decrease hypertension-related morbidity and mortality in our country.


Assuntos
Anti-Hipertensivos , Doenças Cardiovasculares , Hipertensão , Anti-Hipertensivos/uso terapêutico , Áustria , Pressão Sanguínea , Doenças Cardiovasculares/prevenção & controle , Consenso , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico
15.
Kidney Int ; 96(6): 1381-1388, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31679767

RESUMO

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.

16.
Trials ; 20(1): 601, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651370

RESUMO

BACKGROUND: Fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney disease, and calcimimetic therapy reduces plasma concentrations of FGF23. It remains unknown whether treatment with the calcimimetic etelcalcetide (ETL) reduces LVH in patients on hemodialysis. METHODS/DESIGN: This single-blinded randomized trial of 12 months duration will test the effects of ETL compared with alfacalcidol on LVH and cardiac fibrosis in maintenance hemodialysis patients with secondary hyperparathyroidism. Both treatment regimens will be titrated to equally suppress secondary hyperparathyroidism while alfacalcidol treatment causes an increase and ETL a decrease in FGF23, respectively. Patients treated thrice weekly with hemodialysis for ≥ 3 months and ≤ 3 years with parathyroid hormone levels ≥ 300 pg/ml and LVH will be enrolled in the study. The primary study endpoint is change from baseline to 12 months in left ventricular mass index (LVMI; g/m2) measured by cardiac magnetic resonance imaging. Sample size calculations showed that 62 randomized patients will be necessary to detect a difference in LVMI of at least 20 g/m2 between the two groups at 12 months. Due to the strong association of volume overload and LVH, randomization will be stratified by residual kidney function, and regular body composition monitoring will be performed to control the volume status of patients. Study medication will be administered intravenously by the dialysis nurses after every hemodialysis session, thus omitting adherence issues. Secondary study endpoints are cardiac parameters measured by echocardiography, biomarker concentrations of bone metabolism (FGF23, vitamin D, parathyroid hormone, calcium, phosphate, s-Klotho), cardiac markers (pro-brain natriuretic peptide, pre- and postdialysis troponin T) and metabolites of the renin-angiotensin-aldosterone cascade (angiotensin I (Ang I), Ang II, Ang-(1-7), Ang-(1-5), Ang-(1-9), and aldosterone). DISCUSSION: The causal inference and pathophysiology of LVH regression by FGF23 reduction using calcimimetic treatment has not yet been shown. This intervention study has the potential to discover a new strategy for the treatment of cardiac hypertrophy and fibrosis in patients on maintenance hemodialysis. It might be speculated that successful treatment of cardiac morphology will also reduce the risk of cardiac death in this population. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2017-000222-35; ClinicalTrials.gov, NCT03182699 . Registered on.


Assuntos
Calcimiméticos/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Hipertrofia Ventricular Esquerda/prevenção & controle , Peptídeos/uso terapêutico , Diálise Renal/efeitos adversos , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Áustria , Biomarcadores/sangue , Calcimiméticos/efeitos adversos , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Fibrose , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/etiologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Peptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Detecção de Cálcio/agonistas , Receptores de Detecção de Cálcio/metabolismo , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento
17.
BMC Nephrol ; 20(1): 346, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477052

RESUMO

BACKGROUND: Kidney transplantation is the optimal treatment in end stage renal disease but the allograft survival is still hampered by immune reactions against the allograft. This process is driven by the recognition of allogenic antigens presented to T-cells and their unique T-cell receptor (TCR) via the major histocompatibility complex (MHC), which triggers a complex immune response potentially leading to graft injury. Although the immune system and kidney transplantation have been studied extensively, the subtlety of alloreactive immune responses has impeded sensitive detection at an early stage. Next generation sequencing of the TCR enables us to monitor alloreactive T-cell populations and might thus allow the detection of early rejection events. METHODS/DESIGN: This is a prospective cohort study designed to sequentially evaluate the alloreactive T cell repertoire after kidney transplantation. The TCR repertoire of patients who developed biopsy confirmed acute T cell mediated rejection (TCMR) will be compared to patients without rejection. To track the alloreactive subsets we will perform a mixed lymphocyte reaction between kidney donor and recipient before transplantation and define the alloreactive TCR repertoire by next generation sequencing of the complementary determining region 3 (CDR3) of the T cell receptor beta chain. After initial clonotype assembly from sequencing reads, TCR repertoire diversity and clonal expansion of T cells of kidney transplant recipients in periphery and kidney biopsy will be analyzed for changes after transplantation, during, prior or after a rejection. The goal of this study is to describe changes of overall T cell repertoire diversity, clonality in kidney transplant recipients, define and track alloreactive T cells in the posttransplant course and decipher patterns of expanded alloreactive T cells in acute cellular rejection to find an alternative monitoring to invasive and delayed diagnostic procedures. DISCUSSION: Changes of the T cell repertoire and tracking of alloreactive T cell clones after combined bone marrow and kidney transplant has proven to be of potential use to monitor the donor directed alloresponse. The dynamics of the donor specific T cells in regular kidney transplant recipients in rejection still rests elusive and can give further insights in human alloresponse. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03422224 , registered February 5th 2018.

20.
Wien Klin Wochenschr ; 131(Suppl 1): 151-163, 2019 May.
Artigo em Alemão | MEDLINE | ID: mdl-30980144

RESUMO

Recent epidemiological investigations have shown that approximately 2-3% of all Austrians suffer from diabetes with renal involvement, i. e. 250,000 people in Austria are affected. The risk of occurrence and progression of this disease can be ameliorated by life style interventions as well as optimization of blood pressure, blood glucose levels and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society for Nephrology for the diagnostics and treatment strategies of diabetic kidney disease.


Assuntos
Nefropatias Diabéticas , Dietoterapia/normas , Terapia por Exercício/normas , Guias de Prática Clínica como Assunto , Áustria , Pressão Sanguínea , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/terapia , Humanos , Estilo de Vida , Comportamento de Redução do Risco , Resultado do Tratamento
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