RESUMO
Belatacept, a CTLA4-Ig, was designed to prevent rejection and graft loss in kidney transplant recipients. This immunotherapy showed a long-term clinical benefit mainly on renal function and better glycemic control but was also associated with a higher number of severe infectious diseases, particularly CMV disease, and lymphoproliferative disease. Therapeutic drug monitoring usually guides the benefit-risk assessment of long-term immunosuppression. In this study, an analytical method by LC-MS/MS was developed in 20 microL of plasma for the belatacept quantification. Intra- and inter-assay precision and accuracy were lower than 20% for the limit of quantification, and 15% for higher concentrations. The method was implemented in our lab and provided data about the inter-variability (N = 108) and intra-variability (N = 33) of belatacept concentrations in kidney transplant recipients with a stable renal function, after conversion from a CNI- to a belatacept-based regimen.
RESUMO
Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.
Assuntos
Transplante de Rim , Adulto , Humanos , Pré-Escolar , Transplante de Rim/métodos , Teste de Histocompatibilidade/métodos , Antígenos HLA , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Anticorpos , IsoanticorposRESUMO
The utility of zero-time kidney biopsies (KB) in deciding to accept expanded criteria donor (ECD) kidneys remains controversial. However, zero-time histology is one of the main causes for discarding kidneys in the United States. In a single-centre study, we examined the utility and impact on outcome of the use of frozen section zero-time KB among ECD. Ninety-two zero-time KB were analysed for accept/discard decision between 2005 and 2015 among ECD. 53% of kidneys were rejected after zero-time KB analysis; there was no difference in individual clinical and biological data between accepted/rejected groups. However, histology of rejected kidneys showed more sclerotic glomeruli (20% vs. 8%; P < 0.001), increased interstitial fibrosis (1.25 ± 0.12 vs. 0.47 ± 0.09; P < 0.0001), more arteriosclerosis (2.14 ± 0.17 vs. 1.71 ± 0.11; P = 0.0032) and arteriolar hyalinosis (2.15 ± 0.12 vs. 1.55 ± 0.11; P = 0.0006). Using propensity score matching, we generated a group of 42 kidney allograft recipients who received a transplant matched for donor zero-time histology and clinical characteristics with donors whose kidneys were rejected. Interestingly, their 1- and 5-year graft survival and function were similar to the global cohort of ECD recipients. In conclusion, when performed, zero-time KB was a decisive element for kidney discard decision. However, adverse zero-time histology was not associated with poorer graft survival and kidney function among ECD.
Assuntos
Transplante de Rim , Sobrevivência de Enxerto , Humanos , Rim , Nefrectomia , Estudos Retrospectivos , Doadores de Tecidos , Estados UnidosRESUMO
Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4-68.5]) were converted to belatacept (median of 11.5 months [2.5-37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R- CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p-y, respectively. CMV diseases under belatacept were atypical, with late-onset disease (24/40 patients [60%]), high CMV seropositivity (27/40, 67%), increased severe and tissue-invasive disease rates (gastrointestinal involvement in 32/40 [80%]) and life-threatening diseases (4/40 [10%]). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.
Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Abatacepte , Idoso , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Imunossupressores/efeitos adversos , Incidência , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , TransplantadosRESUMO
The urinary chemokines CXCL9 and CXCL10 are promising noninvasive diagnostic markers of acute rejection (AR) in kidney recipients, but their levels might be confounded by urinary tract infection (UTI) and BK virus (BKV) reactivation. Multiparametric model development and validation addressed these confounding factors in a training set of 391 samples, optimizing the diagnostic performance of urinary chemokines. CXCL9/creatinine increased in UTI and BKV viremia with or without nephropathy (BKVN) (no UTI/leukocyturia/UTI: -0.10/1.61/2.09, P = .0001 and no BKV/viremia/BKVN: -0.10/1.90/2.29, P < .001) as well as CXCL10/creatinine (1.17/2.09/1.98, P < .0001 and 1.13/2.21/2.51, P < .001, respectively). An optimized 8-parameter model (recipient age, sex, estimated glomerular filtration rate, donor specific antibodies, UTI, BKV blood viral load, CXCL9, and CXCL10) diagnosed AR with high accuracy (area under the curve [AUC]: 0.85, 95% confidence interval [CI]: 0.80-0.89) and remained highly accurate at the time of screening (AUC: 0.81, 95% CI: 0.48-1) or indication biopsies (AUC: 0.85, 95% CI: 0.81-0.90) and within the first year (AUC: 0.86, 95% CI: 0.80-0.91) or later (AUC: 0.90, 95% CI: 0.84-0.96), achieving AR diagnosis with an AUC of 0.85 and 0.92 (P < .0001) in 2 external validation cohorts. Decision curve analyses demonstrated the clinical utility of the model. Considering confounding factors rather than excluding them, we optimized a noninvasive multiparametric diagnostic model for AR of kidney allografts with unprecedented accuracy.
Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Aloenxertos , Quimiocina CXCL10 , Quimiocina CXCL9 , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/diagnósticoRESUMO
Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T0 ) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T0 at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV-associated nephropathy (P = 0.033) without impacting 5-year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor-specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium-term clinical outcome but increases the risk of developing dnDSAs.
Assuntos
Vírus BK , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/tratamento farmacológico , Adulto , Idoso , Esquema de Medicação , Feminino , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ácido Micofenólico/administração & dosagem , Infecções por Polyomavirus/diagnóstico , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Viremia/virologiaRESUMO
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrence after kidney transplantation. However, reports of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago. To further delineate its optimal use, we describe the largest series of kidney transplant recipients treated with prophylactic eculizumab. METHODS: Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab: 10 from day 0 and 2 at the time of recurrence (days 6 and 25). Clinical and histological features, complement assessment, and free eculizumab measurements were analyzed. The median follow-up was 24.6 months. RESULTS: Five patients had failed at least 1 previous renal transplant from aHUS. A genetic mutation was identified in 9 patients, anti-H antibodies were found in 2. No patient demonstrated biological recurrence of thrombotic microangiopathy under treatment. Three antibody-mediated rejections (AMRs) occurred without detectable C5 residual activity. AMR was associated with subclinical thrombotic microangiopathy in 2 patients. One patient lost his graft after several complications, including AMR. One patient experienced posttransplant C3 glomerulonephritis. The last median serum creatinine was 128.2 ± 40.8 µmol/L. CONCLUSIONS: These data confirm that eculizumab is highly effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesis.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/prevenção & controle , Falência Renal Crônica/cirurgia , Transplante de Rim , Adolescente , Adulto , Síndrome Hemolítico-Urêmica Atípica/complicações , Biópsia , Complemento C3/química , Complemento C5/química , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.
Assuntos
Quimiocina CXCL10/urina , Rejeição de Enxerto , Insuficiência Renal/diagnóstico , Insuficiência Renal/imunologia , Adulto , Anticorpos/sangue , Área Sob a Curva , Biomarcadores/urina , Biópsia , Quimiocina CXCL9/urina , Estudos de Coortes , Creatinina/urina , Feminino , Humanos , Inflamação , Interferon gama/metabolismo , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Insuficiência Renal/urina , Reprodutibilidade dos Testes , Transplante HomólogoRESUMO
Acute clinical antibody-mediated rejection is currently defined by (1), an acute renal failure occurring during the first months following transplantation, (2), at least a microcirculation inflammation (glomerulitis and peritubular capillaritis) on kidney biopsy and (3), the presence in peripheral blood of donor specific antibodies, mostly anti-human leukocyte antigen (HLA) antibodies. The prognosis of this rejection is scored using the severity of vascular lesions and the positivity of C4d on peritubular capillaries. Recently, a subclinical variety of antibody-mediated rejection was recognized as an entity because, as the clinical rejection, it leads to chronic antibody-mediated rejection, currently the most frequent cause of graft loss. The description of these various aspects of antibody-mediated rejection allowed a better understanding of its pathophyiology that may lead in a near future to a more specific treatment.
Assuntos
Rejeição de Enxerto/imunologia , Transplante de Rim , Doença Aguda , Antígenos CD20/imunologia , Complemento C4b/análise , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/patologia , Antígenos HLA/imunologia , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/sangue , Isoanticorpos/imunologia , Rim/irrigação sanguínea , Rim/patologia , Microcirculação , Fragmentos de Peptídeos/análise , Circulação RenalRESUMO
Paradoxical worsening of tuberculosis associated with immune reconstitution during antiretroviral therapy in patients with HIV infection is known as the immune reconstitution inflammatory syndrome (IRIS). Here, we report a case of paradoxical worsening of IFN-alpha induced tuberculosis in a patient experiencing reconstitution of pathogen-specific immune responses after discontinuing TNFα antagonist therapy. This case serves to alert clinicians that complications such as tuberculosis may worsen after TNFα antagonist discontinuation. This situation may paradoxically require readministration of the immunosuppressive drug in some patients.
Assuntos
Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Tuberculose Latente/diagnóstico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Idoso , Anticorpos Monoclonais Humanizados , Antituberculosos/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Humanos , Síndrome Inflamatória da Reconstituição Imune/imunologia , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Suspensão de TratamentoRESUMO
Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma characterized by a circulating monoclonal IgM. Renal involvement in classical cases of WM is rare, and the pathological hallmark finding in the renal biopsy specimen is a thrombotic microangiopathy. We report the case of a 69-year-old man with the diagnosis of WM for 3 months before he presented with acute renal failure (ARF). A renal biopsy performed suggested the diagnosis of acute tubular necrosis. The diagnosis of ARF related to IgM flare after Rituximab therapy was made.