RESUMO
Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.
Assuntos
Rejeição de Enxerto/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Proteínas Associadas aos Microtúbulos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Supressoras de Tumor/genética , Doença Aguda , Adulto , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/genética , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.
Assuntos
Rejeição de Enxerto/induzido quimicamente , Imunossupressores/efeitos adversos , Transplante de Rim , Ácido Micofenólico/efeitos adversos , Adulto , Fatores Etários , Idoso , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Pessoa de Meia-Idade , Modelos Biológicos , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Curva ROCRESUMO
De novo tumors in renal allografts are rare and their prevalence is underestimated. We therefore analyzed renal cell carcinomas arising in renal allografts through a retrospective French renal transplant cohort. We performed a retrospective, multicentric survey by sending questionnaires to all French kidney transplantation centers. All graft tumors diagnosed after transplantation were considered as de novo tumors. Thirty-two centers participated in this study. Seventy-nine tumors were identified among 41 806 recipients (Incidence 0.19%). Patients were 54 men and 25 women with a mean age of 47 years old at the time of diagnosis. Mean tumor size was 27.8 mm. Seventy-four (93.6%), 53 (67%) and 44 tumors (55.6%) were organ confined (T1-2), low grade (G1-2) and papillary carcinomas, respectively. Four patients died of renal cell carcinomas (5%). The mean time lapse between transplantation and RCC diagnosis was 131.7 months. Thirty-five patients underwent conservative surgery by partial nephrectomy (n = 35, 44.3%) or radiofrequency (n = 5; 6.3%). The estimated 5 years cancer specific survival rate was 94%. Most of these tumors were small and incidental. Most tumors were papillary carcinoma, low stage and low grade carcinomas. Conservative treatment has been preferred each time it was feasible in order to avoid a return to dialysis.
Assuntos
Carcinoma Papilar/etiologia , Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Transplante de Rim/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/epidemiologia , Carcinoma Papilar/mortalidade , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/mortalidade , Feminino , França/epidemiologia , Humanos , Incidência , Neoplasias Renais/epidemiologia , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Bordetella holmesii is a gram-negative rod that was initially identified in 1995. It causes bacteremia, pneumonia, and endocarditis mostly in patients with anatomical or functional asplenia. We report here, to the best of our knowledge, the first case of B. holmesii bacteremia in a renal transplant recipient following rituximab therapy for recurrence of membranoproliferative glomerulonephritis.
Assuntos
Infecções por Bordetella/microbiologia , Bordetella/classificação , Transplante de Rim/efeitos adversos , Adulto , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Infecções por Bordetella/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Masculino , RituximabRESUMO
Calcineurin inhibitors improve acute rejection rates and short-term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5-year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL- or CsA-based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent-to-treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on-treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.
Assuntos
Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Sirolimo/administração & dosagem , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent-to-treat population (ITT): 62.6 mL/min/1.73 m(2) versus 57.1 mL/min/1.73 m(2) (p = 0.013) and in the on-treatment population (OT): 67.5 mL/min/1.73 m(2) versus 57.4 mL/min/1.73 m(2) (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new-onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.
Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Transplante de Rim , Sirolimo/uso terapêutico , Adulto , Ciclosporina/efeitos adversos , Ciclosporina/farmacologia , Feminino , Sobrevivência de Enxerto , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Taxa de SobrevidaRESUMO
Cyclosporin A (CsA) is a substrate for cytochrome P450 3A and the efflux transporter P-glycoprotein (P-gp; ABCB1), both abundantly expressed in the kidney. In a long-term follow-up of a cohort of patients who had received kidney transplants between the years 1990 and 2005, we retrospectively investigated the effect of CYP3A4, CYP3A5, and ABCB1 polymorphisms in kidney graft donors on recipients' renal function and risk of subsequent graft loss. DNA samples from 227 donors and clinical data from the 259 respective recipients were analyzed. Graft loss was significantly associated with the presence of the ABCB1 variant haplotype 1236T/2677T/3435T in the donor (1236T/2677T/3435T vs. other haplotypes: hazard ratio = 9.346; 95% confidence interval (CI) (2.278-38.461); P = 0.0019) and with previous episodes of acute organ rejection (hazard ratio = 3.077; 95% CI (1.213-7.812); P = 0.0178). The variant haplotype was also associated with a greater decrease in renal function (homozygotes for TTT -3.047 mlxmin(-1)/year; heterozygotes for TTT -4.435 mlxmin(-1)/year; others -2.186 mlxmin(-1)/year; P = 0.0240). The study showed that the presence of ABCB1 polymorphisms in donors influences long-term graft outcome adversely with decrease in renal function and graft loss in transplant recipients receiving CsA.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Ciclosporina/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/genética , Imunossupressores/uso terapêutico , Transplante de Rim/fisiologia , Rim/fisiologia , Polimorfismo Genético/genética , Polimorfismo Genético/fisiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Idoso , Análise de Variância , Estudos de Coortes , Citocromo P-450 CYP3A/genética , Feminino , Seguimentos , Genótipo , Haplótipos , Humanos , Estimativa de Kaplan-Meier , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos/estatística & dados numéricos , Adulto JovemRESUMO
Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.
Assuntos
Transplante de Rim/imunologia , Ácido Micofenólico/análogos & derivados , Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Área Sob a Curva , Basiliximab , Ciclosporina/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Segurança , Transplante HomólogoRESUMO
This study analyzed the initial presentation and revascularization outcomes of patients with radiation-induced renal artery stenosis, a rare complication of therapeutic irradiation. Of 11 patients with renal artery stenosis after irradiation, 7 patients fulfilled the following criteria: normotension before irradiation, radiation dose greater than 25 grays delivered to the renal arteries, associated perirenal radiation-induced lesions, and absence of arterial disease outside the radiation field. The median age at irradiation was 30 years, and the median local irradiation dose was 40 grays. The median time from irradiation to referral was 13 years. All patients were hypertensive at referral, with a median blood pressure (BP) of 171/102 mm Hg and median treatment score of two. The median glomerular filtration rate was 67 mL/min. Two patients had bilateral stenoses and 1 patient had stenosis affecting a single kidney. Stenoses were proximal in 6 patients and truncal in 1 patient, and all had the appearance of atherosclerotic stenosis. Percutaneous transluminal renal artery angioplasty (PTRA) was successful in 5 patients, but required multiple insufflations. PTRA failed in 1 patient, who subsequently underwent an aortorenal bypass. After a median follow-up of 36 months, 2 patients had died of noncardiovascular causes and 4 patients remained hypertensive, with a median BP of 136/85 mm Hg and median treatment score of two. No restenosis occurred, but aneurysms developed at the site of angioplasty in 1 patient. If hypertension occurs even decades after irradiation, a radiation-induced renal artery stenosis should be sought in patients who have undergone abdominal irradiation.
Assuntos
Lesões por Radiação/diagnóstico , Lesões por Radiação/terapia , Radioterapia Adjuvante/efeitos adversos , Obstrução da Artéria Renal/diagnóstico , Obstrução da Artéria Renal/terapia , Adulto , Angioplastia com Balão , Arteriopatias Oclusivas/etiologia , Obstrução Duodenal/etiologia , Evolução Fatal , Seguimentos , Doença de Hodgkin/terapia , Humanos , Hipertensão/etiologia , Neoplasias Renais/radioterapia , Neoplasias Renais/secundário , Neoplasias Renais/cirurgia , Linfoma/tratamento farmacológico , Linfoma/radioterapia , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Lesões por Radiação/etiologia , Obstrução da Artéria Renal/etiologia , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Retroperitoneais/radioterapia , Seminoma/radioterapia , Seminoma/secundário , Tumor de Wilms/radioterapia , Tumor de Wilms/cirurgiaRESUMO
Plasminogen activator inhibitor type 1 plays a prominent part in the regulation of extra and intra-vascular fibrinolysis through the inhibition of plasmin formation. In addition to its role in the resolution of blood clots, PAI-1 is involved in a variety of other biological processes including extracellular remodeling, cellular mobility, embryo implantation, development and tumoral proliferation. Moreover, PAI-1 is also implicated in various pathological processes such as thromboembolic diseases, atherosclerosis and fibrosis formation, particularly in the kidney and the lung. Inhibition of PAI-1 activity or of PAI-1 synthesis by specific antibodies, peptidic antagonists, antisens oligonucleotides or decoy oligonucleotides has been obtained in vitro but need to be evaluated in vivo. All these findings may have new therapeutical implications, explaining the importance of studies on PAI-1 production and regulation.
Assuntos
Nefropatias/fisiopatologia , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Aldosterona/fisiologia , Fibrinólise/fisiologia , Fibrose , Humanos , Rim/patologia , Transplante de Rim , Inibidor 1 de Ativador de Plasminogênio/química , Sistema Renina-Angiotensina/fisiologia , Fator de Crescimento Transformador beta/fisiologiaRESUMO
Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. The progression of renal lesions to fibrosis involves several mechanisms, among which the inhibition of extracellular matrix (ECM) degradation appears to play an important role. Two interrelated proteolytic systems are involved in matrix degradation: the plasminogen activation system and the matrix metalloproteinase system. The plasminogen activator inhibitor type 1 (PAI-1), as the main inhibitor of plasminogen activation, regulates fibrinolysis and the plasmin-mediated matrix metalloproteinase activation. PAI-1 is also a component of the ECM, where it binds to vitronectin. PAI-1 is not expressed in the normal human kidney but is strongly induced in various forms of kidney diseases, leading to renal fibrosis and terminal renal failure. Thrombin, angiotensin II, and transforming growth factor-beta are potent in vitro and in vivo agonists in increasing PAI-1 synthesis. Several experimental and clinical studies support a role for PAI-1 in the renal fibrogenic process occurring in chronic glomerulonephritis, diabetic nephropathy, focal segmental glomerulosclerosis, and other fibrotic renal diseases. Experimental models of renal diseases in PAI-1-deficient animals are in progress, and preliminary results indicate a role for PAI-1 in renal fibrogenesis. Inhibition of PAI-1 activity or of PAI-1 synthesis by specific antibodies, peptidic antagonists, antisense oligonucleotides, or decoy oligonucleotides has been obtained in vitro, but needs to be evaluated in vivo for the prevention or the treatment of renal fibrosis.
Assuntos
Rim/patologia , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Animais , Ativação Enzimática/fisiologia , Fibrinólise/fisiologia , Fibrose/etiologia , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Metaloendopeptidases/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare complication in solid organ transplantation. It can be associated with severe hypertension. Several risk factors have been identified including immunosuppressive drugs such as cyclosporin A and, more recently, tacrolimus. METHODS: Here we report a case of tacrolimus-induced HUS in a 61-yr-old woman after liver transplantation. Hypertension, microangiopathic anemia and end-stage renal failure occurred 2 yr after liver transplantation. RESULTS: At admission, she had malignant hypertension with a severe hypertensive retinopathy, renal failure (creatininemia: 800 micromol/L) and microangiopathic anemia (Hb: 7.3 g/dL, a low platelet count and elevated lactate dehydrogenase). At renal biopsy, histologic findings were ischemic and sclerotic glomeruli with hyaline thrombi, severe mesangiolysis and interstitial fibrosis. CONCLUSION: Despite steroid treatment, antihypertensive agents and fresh frozen plasma therapy, end-stage renal failure was observed and chronic hemodialysis treatment was required.
Assuntos
Síndrome Hemolítico-Urêmica/induzido quimicamente , Imunossupressores/efeitos adversos , Falência Renal Crônica/induzido quimicamente , Transplante de Fígado , Tacrolimo/efeitos adversos , Feminino , Síndrome Hemolítico-Urêmica/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Falência Renal Crônica/patologia , Pessoa de Meia-IdadeRESUMO
Renal transplant vein thrombosis is an unusual event occurring in 0.3-3% of renal transplantations. Prognosis is uniformly poor with graft loss in nearly every case. We report here the first three cases of renal graft vein thrombosis successfully treated by percutaneous endoluminal thromboaspiration. After an initially uneventful course all recipients developed anuria and required hemodialysis. In two cases, an ultrasound examination suggested a diagnosis of venous thrombosis. Emergency arteriography and phlebography were performed, confirming the complete thrombosis of the graft veins. Thromboaspiration was carried out with full heparinization and led to renal function improvement in all cases. Grafts are still functioning 6 months after the procedure, with serum creatinine levels of 176 mumol/l, 120 mumol/l and 184 mumol/l, respectively. Thus, this procedure avoids surgical and anaesthetic risks and allows, if performed at an early stage, restoration of graft function. Great care must be taken to avoid vein wall damage, vascular suture line rupture, or pulmonary embolism.