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1.
J Am Soc Nephrol ; 33(11): 2026-2039, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36316096

RESUMO

BACKGROUND: No validated system currently exists to realistically characterize the chronic pathology of kidney transplants that represents the dynamic disease process and spectrum of disease severity. We sought to develop and validate a tool to describe chronicity and severity of renal allograft disease and integrate it with the evaluation of disease activity. METHODS: The training cohort included 3549 kidney transplant biopsies from an observational cohort of 937 recipients. We reweighted the chronic histologic lesions according to their time-dependent association with graft failure, and performed consensus k-means clustering analysis. Total chronicity was calculated as the sum of the weighted chronic lesion scores, scaled to the unit interval. RESULTS: We identified four chronic clusters associated with graft outcome, based on the proportion of ambiguous clustering. The two clusters with the worst survival outcome were determined by interstitial fibrosis and tubular atrophy (IFTA) and by transplant glomerulopathy. The chronic clusters partially overlapped with the existing Banff IFTA classification (adjusted Rand index, 0.35) and were distributed independently of the acute lesions. Total chronicity strongly associated with graft failure (hazard ratio [HR], 8.33; 95% confidence interval [CI], 5.94 to 10.88; P<0.001), independent of the total activity scores (HR, 5.01; 95% CI, 2.83 to 7.00; P<0.001). These results were validated on an external cohort of 4031 biopsies from 2054 kidney transplant recipients. CONCLUSIONS: The evaluation of total chronicity provides information on kidney transplant pathology that complements the estimation of disease activity from acute lesion scores. Use of the data-driven algorithm used in this study, called RejectClass, may provide a holistic and quantitative assessment of kidney transplant injury phenotypes and severity.


Assuntos
Nefropatias , Transplante de Rim , Humanos , Transplante de Rim/métodos , Sobrevivência de Enxerto , Rejeição de Enxerto/patologia , Rim/patologia , Biópsia , Nefropatias/patologia , Proteínas do Sistema Complemento , Aloenxertos/patologia , Fenótipo
2.
BMC Nephrol ; 22(1): 416, 2021 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-34923958

RESUMO

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).


Assuntos
Seleção do Doador , Histocompatibilidade , Transplante de Rim , Seleção de Pacientes , Adolescente , Criança , Humanos , Medição de Risco , Resultado do Tratamento
3.
J Am Soc Nephrol ; 32(2): 397-409, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33323474

RESUMO

BACKGROUND: Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown. METHODS: This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival. RESULTS: In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years. CONCLUSIONS: In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed.


Assuntos
Aloenxertos/patologia , Sobrevivência de Enxerto , Transplante de Rim , Rim/patologia , Obtenção de Tecidos e Órgãos/organização & administração , Adulto , Idoso , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Tempo , Estados Unidos
4.
EBioMedicine ; 46: 463-472, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31378695

RESUMO

BACKGROUND: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available. METHODS: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases. The discovery and derivation phases of the study (N = 117 and N = 183 respectively) followed a case-control design and included whole genome transcriptomics and targeted mRNA expression analysis to construct and lock a multigene model. The primary end point was the diagnostic accuracy of the locked multigene assay for antibody-mediated rejection in a third validation cohort of serially collected blood samples (N = 387). This trial is registered with ClinicalTrials.gov, number NCT02832661. FINDINGS: We identified and locked an 8-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from the discovery and derivation phases for discrimination between cases with (N = 49) and without (N = 134) antibody-mediated rejection. In the validation cohort, this 8-gene assay discriminated between cases with (N = 41) and without antibody-mediated rejection (N = 346) with good diagnostic accuracy (ROC AUC 79·9%; 95% CI 72·6 to 87·2, p < 0·0001). The diagnostic accuracy of the 8-gene assay was retained both at time of stable graft function and of graft dysfunction, within the first year and also later after transplantation. The 8-gene assay is correlated with microvascular inflammation and transplant glomerulopathy, but not with the histological lesions of T-cell mediated rejection. INTERPRETATION: We identified and validated a novel 8-gene expression assay that can be used for non-invasive diagnosis of antibody-mediated rejection. FUNDING: The Seventh Framework Programme (FP7) of the European Commission.


Assuntos
Anticorpos/imunologia , Biomarcadores , Ácidos Nucleicos Livres , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , RNA Mensageiro/genética , Adulto , Feminino , Rejeição de Enxerto/sangue , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , RNA Mensageiro/sangue , Curva ROC , Reprodutibilidade dos Testes , Transplante Homólogo
5.
Transplantation ; 103(7): 1514-1522, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30247314

RESUMO

BACKGROUND: Considerable differences exist among the living donor Kidney Exchange Programmes (KEPs) that are in use and being built in Europe, contributing to a variation in the number of living donor transplants (Newsletter Transplant; International figures on donation and transplantation 2016). Efforts of European KEPs to exchange (best) practices and share approaches to address challenges have, however, been limited. METHODS: Experts from 23 European countries, collaborating on the European Network for Collaboration on Kidney Exchange Programmes Cooperation on Science and Technology Action, developed a questionnaire to collect detailed information on the functioning of all existing KEPs in Europe, as well as their opportunities and challenges. Following a comparative analysis, results were synthesized and interpreted by the same experts. RESULTS: The practices, opportunities and challenges reported by 17 European countries reveal that some of the 10 operating programs are mature, whereas others are in earlier stages of development. Over 1300 transplants were performed through existing KEPs up to the end of 2016, providing approximately 8% of their countries' living kidney donations in 2015. All countries report challenges to either initiating KEPs or increasing volumes. Some challenges are shared, whereas others differ because of differences in context (eg, country size, effectiveness of deceased donor program) and ethical and legal considerations (eg, regarding living donation as such, nonrelated donors, and altruistic donation). Transnational initiatives have started in Central Europe, Scandinavia, and Southern Europe. CONCLUSIONS: Exchange of best practices and shared advancement of national programs to address existing challenges, aided by transnational exchanges, may substantially improve access to the most (cost) effective treatment for the increasing number of patients suffering from kidney disease.


Assuntos
Benchmarking/organização & administração , Comportamento Cooperativo , Prestação Integrada de Cuidados de Saúde/organização & administração , Disparidades em Assistência à Saúde/organização & administração , Cooperação Internacional , Transplante de Rim , Doadores Vivos , Obtenção de Tecidos e Órgãos/organização & administração , Europa (Continente) , Humanos , Formulação de Políticas , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde
7.
Nephrol Dial Transplant ; 31(9): 1515-22, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26908765

RESUMO

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.


Assuntos
Seleção do Doador/normas , Rejeição de Enxerto/epidemiologia , Transplante de Rim/mortalidade , Alocação de Recursos/normas , Obtenção de Tecidos e Órgãos/normas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Reoperação , Inquéritos e Questionários , Listas de Espera , Adulto Jovem
8.
Nephrol Dial Transplant ; 23(6): 2033-42, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18174264

RESUMO

BACKGROUND: Post-transplant diabetes mellitus (PTDM) has serious consequences for renal allograft survival, cardiovascular risk and patient survival. METHODS: The predictive value of a fasting plasma glucose (FPG) level and oral glucose tolerance test (OGTT) on the fifth day post-transplantation were prospectively evaluated in 359 de novo renal allograft recipients. PTDM was defined as the uninterrupted need for glucose-lowering medication for at least 3 months. RESULTS: Sixty-four patients (17.8%) developed PTDM (follow-up 42.8 +/- 16.9 months). Recipient age, body mass index (BMI), biopsy-proven acute rejection (BPAR), early graft function and proteinuria, tacrolimus-based therapy, cumulative corticosteroid dose and thiazide diuretics were associated with PTDM (univariate analysis). Multivariate logistic regression analysis identified age [OR (odds ratio): 1.05 (95% confidence interval: 1.019-1.083)], BMI [OR: 1.09 (1.013-1.189)], proteinuria on Day 5 [OR: 1.51 (1.043-2.210)] and BPAR [OR: 2.74 (1.345-5.604)] as independent risk factors for PTDM while a normal OGTT on Day 5 post-transplantation was associated with a strongly reduced risk for PTDM [OR: 0.03 (0.008-0.166)]. A similar risk reduction was conferred by a normal FPG on Day 5 [OR: 0.06 (0.012-0.338)]. OGTT had the best sensitivity (93.4%) and specificity (71.9%) with a high negative predictive value (97.6%). CONCLUSION: The Day 5 OGTT is an independent predictor of PTDM that can be used for identifying recipients at reduced risk for PTDM, taking into account the impact of independent clinical risk factors like age, BMI and BPAR (treatment). This information can help clinicians in directing therapeutic management of modifiable risk factors for PTDM after renal transplantation.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus/diagnóstico , Hiperglicemia/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Diabetes Mellitus/tratamento farmacológico , Diagnóstico Precoce , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Teste de Tolerância a Glucose , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/diagnóstico , Transplante de Rim/métodos , Modelos Logísticos , Masculino , Análise Multivariada , Cuidados Pós-Operatórios/métodos , Valor Preditivo dos Testes , Probabilidade , Estudos Prospectivos , Medição de Risco , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Fatores de Tempo , Transplante Homólogo
9.
Drug Saf ; 28(2): 153-81, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15691225

RESUMO

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.


Assuntos
Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Transplante de Rim , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Animais , Rejeição de Enxerto/prevenção & controle , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco
10.
Nephrol Dial Transplant ; 19(2): 433-8, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14736970

RESUMO

BACKGROUND: Chronic haemodialysis patients are at increased risk for developing tuberculosis (TB). Appropriate screening methods to detect latent Mycobacterium tuberculosis infection are required. The aim of this prospective multi-centre study was to evaluate the tuberculin skin test (TST) as a screening method for detection of M.tuberculosis infection in haemodialysis patients. METHODS: A total of 224 patients in two haemodialysis centres were prospectively tested, using 2 units of tuberculin PPD RT23. Up to three booster injections were given with a 7 day interval to patients not responding to the previous test. The results were compared with clinical and radiological data. RESULTS: The cumulative prevalence of a positive TST was 14.7% for the first test, 27.8% for the second test and 32.6% for the fourth test. There was no influence of age, gender, haemodialysis centre, dialysis efficiency, nutritional state, levels of zinc, vitamin D therapy, primary renal disease, (previous or active) immunosuppressive therapy or response to hepatitis B vaccination. There was a significant, but weak, correlation between TST positivity and a history of positive TST or TB. Chest radiography and positive TST were not correlated, yet a positive chest X-ray increased the detection of patients with latent M.tuberculosis infection up to 47.8%. CONCLUSIONS: In haemodialysis patients, a positive response of >30% to repeated TST was obtained. Two consecutive TSTs were sufficient to recruit most of the booster reactions. Since only a weak correlation was found with anamnestic data, regular TST evaluation in combination with a chest X-ray, is a useful tool to detect infection with M.tuberculosis in haemodialysis patients.


Assuntos
Falência Renal Crônica/terapia , Teste Tuberculínico , Tuberculose Pulmonar/diagnóstico , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Bélgica/epidemiologia , Comorbidade , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Incidência , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Análise Multivariada , Probabilidade , Estudos Prospectivos , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Reprodutibilidade dos Testes , Medição de Risco , Distribuição por Sexo , Estatísticas não Paramétricas , Tuberculose Pulmonar/epidemiologia
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