RESUMO
BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.
Assuntos
Encefalopatias/etiologia , COVID-19/complicações , Síndrome da Liberação de Citocina/etiologia , Corticosteroides/uso terapêutico , Idoso , Barreira Hematoencefálica/fisiopatologia , Encéfalo/diagnóstico por imagem , Encefalopatias/fisiopatologia , Edema Encefálico/etiologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/fisiopatologia , Feminino , Humanos , Imunoglobulinas/uso terapêutico , AVC Isquêmico/diagnóstico , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVES: New biomarkers reflecting the degree of immunosuppression in transplant recipients are needed to provide an optimal personalized balance between rejection and infection risks. METHODS: For this purpose, we investigated TTV viremia dynamics in 66 kidney transplant recipients followed up for two years after transplantation, in relation to BK virus infection and graft rejection. RESULTS: After transplantation, TTV viremia rose by ≥2 log10 copies/mL from baseline to month 3, then declined by ≥1 log10 copies/mL thereafter. Higher TTV viremia was associated with recipients of a deceased donor, a lower count of CD8+ T cells and a higher BKV viremia. Importantly, TTV loads were significantly lower in KTR who would later display graft rejection; indeed, patients with TTV viremia lower than 3.4 log10 copies/mL at transplantation or lower than 4.2 log10 copies/mL at month 1 had a higher risk of developing graft rejection in the two following years (hazard ratio (HR) at D0 = 7.30, pâ¯=â¯0.0007 and HR at M1 = 6.16, pâ¯=â¯0.001). CONCLUSIONS: TTV viremia measurement at early times post transplantation predicts graft rejection and would represent a useful tool to improve kidney transplant monitoring.
Assuntos
Infecções por Vírus de DNA/diagnóstico , Rejeição de Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Torque teno virus/isolamento & purificação , Viremia/diagnóstico , Adolescente , Adulto , Idoso , Vírus BK/isolamento & purificação , Biomarcadores/sangue , Regras de Decisão Clínica , Infecções por Vírus de DNA/virologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/virologia , Estudos Prospectivos , Viremia/virologia , Adulto JovemRESUMO
The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.
Assuntos
Rejeição de Enxerto/etiologia , Isoanticorpos/sangue , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Tacrolimo/farmacologia , Doadores de Tecidos , Transplantados , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/sangue , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/farmacologia , Isoanticorpos/imunologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.
Assuntos
Marcadores Genéticos , Rejeição de Enxerto/genética , Ensaios de Triagem em Larga Escala/métodos , Transplante de Rim/efeitos adversos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Tacrolimo/administração & dosagem , Estudos de Coortes , Testes Genéticos , Genótipo , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Humanos , Imunossupressores/administração & dosagem , TransplantadosRESUMO
BACKGROUND: Delayed graft function (DGF) is an early postoperative complication of kidney transplantation (KT) predisposing to acute rejection and lower graft survival. Intraoperative arterial hypotension and hypovolemia are associated with DGF. Central venous pressure (CVP) is used to estimate volemia but its reliability has been criticized. Pleth variability index (PVI) is a hemodynamic parameter predicting fluid responsiveness. The aim of this study was to examine the relationship between intraoperative PVI and CVP values and the occurrence of DGF. METHODS: This was a prospective, noninterventional, observational, single-center study. All consecutive patients with KT from deceased donors were included. Recipients received standard, CVP, and PVI monitoring. Intraoperative hemodynamic parameters were recorded from recipients at 5 time points during KT. RESULTS: Forty patients were enrolled. There was a poor correlation between PVI and CVP values (r2 = 0.003; P = .44). Immediate graft function and DGF patients had similar hemodynamic values during KT, with the exception of PVI values, which were significantly higher in the DGF group. In particular, a PVI >9% before unclamping of the renal artery was the only predictive parameter of DGF in our multivariate analysis (P = .02). CONCLUSIONS: This study suggests that PVI values >9% during KT are associated with the occurrence of DGF.
Assuntos
Função Retardada do Enxerto/etiologia , Transplante de Rim/efeitos adversos , Monitorização Intraoperatória/estatística & dados numéricos , Adulto , Pressão Venosa Central/fisiologia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Monitorização Fisiológica/métodos , Monitorização Fisiológica/estatística & dados numéricos , Pletismografia/métodos , Pletismografia/estatística & dados numéricos , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
BACKGROUND: Cryptosporidium spp. is a ubiquitous parasite affecting humans as well as domestic and wild vertebrates, causing diarrhea in both immunocompetent and immunocompromised hosts worldwide. Its transmission occurs primarily by the fecal-oral route. In humans, C. parvum and C. hominis are the most prevalent species, whereas immunocompetent and immunocompromised individuals can also be infected by other zoonotic species. Renal transplant patients are prone to develop cryptosporidiosis, which can induce severe and life-threatening diarrhea. CASE PRESENTATION: We report here a series of nearly concomitant cases of acute symptomatic cryptosporidiosis in three renal transplant patients attending the Strasbourg University Hospital Nephrology Unit. The clinical presentation was persistent diarrhea and acute renal failure. The diagnosis was confirmed by microscopic stool examination using a modified Ziehl-Neelsen staining method and species identification by molecular tools. All patients were treated with nitazoxanide and recovered from diarrhea after 14 days of therapy. CONCLUSION: Genotypic species identification was not consistent with an epidemic context, thus underlining the need for genotyping to monitor at risk patients.
Assuntos
Infecção Hospitalar/parasitologia , Criptosporidiose/transmissão , Cryptosporidium/patogenicidade , Transplante de Rim , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/parasitologia , Adulto , Animais , Coccidiostáticos/uso terapêutico , Criptosporidiose/complicações , Criptosporidiose/tratamento farmacológico , Cryptosporidium/genética , Diarreia/etiologia , Diarreia/parasitologia , Fezes/parasitologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Nitrocompostos , Tiazóis/uso terapêuticoRESUMO
Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.
Assuntos
Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/tratamento farmacológico , Falência Renal Crônica/genética , Transplante de Rim/efeitos adversos , Farmacogenética , Tacrolimo/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Genótipo , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Tacrolimo/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND: End-stage renal disease (ESRD) is associated with premature aging of the T-cell system. Nevertheless, the clinical significance of pre-transplant ESRD-related immune senescence is unknown. METHODS: We studied whether immune risk phenotype (IRP), a typical feature of immune senescence, may affect post-transplant infectious complications. A total of 486 patients were prospectively studied during the first year post transplant. IRP was defined as positive cytomegalovirus serology with at least 1 of the following criteria: CD4/CD8 ratio <1 and/or CD8 T-cell count >90th percentile. RESULTS: We found that 47 patients (9.7%) had pre-transplant IRP. IRP+ patients did not differ from IRP- patients for any clinical characteristics, but exhibited more pronounced immune senescence. Both opportunistic infections (43% vs. 6%, P < 0.001) and severe bacterial infection (SBI) (40% vs. 25%, P = 0.028) were more frequent in IRP(+) patients. In multivariate analysis, IRP was predictive of both opportunistic infection (hazard ratio [HR] 2.97 [95% confidence interval {CI} 1.53-5.76], P = 0.001), and SBI (HR 2.33 [95% CI 1.34-3.92], P = 0.008). Acute rejection rates were numerically much lower in IRP+ patients. A total of 418 patients (86%) had biological evaluation 1 year post transplant. Among 41 IRP+ patients, 35 (85%) remained IRP+ 1 year post transplant. CONCLUSION: Pre-transplant IRP is associated with an increased risk of post-transplant infection.
Assuntos
Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/imunologia , Falência Renal Crônica/imunologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/imunologia , Adulto , Idoso , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Feminino , Rejeição de Enxerto/imunologia , Humanos , Rim/cirurgia , Rim/virologia , Falência Renal Crônica/virologia , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas , Fatores de Risco , Linfócitos T/imunologia , TransplantadosRESUMO
Persistent ATG-induced CD4(+) T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR -62 patients receiving ATG and 35 receiving anti-CD25 mAb (α-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34(+) hematopoietic progenitor cells (CD34(+) HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased one-year posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57(+) /CD28(-) T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4(+) T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.
Assuntos
Soro Antilinfocitário/imunologia , Transplante de Rim , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.
Assuntos
Ciclosporina/administração & dosagem , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Everolimo/administração & dosagem , Transplante de Rim , Rim/patologia , Insuficiência Renal/cirurgia , Adolescente , Adulto , Idoso , Biópsia , Inibidores de Calcineurina/administração & dosagem , Progressão da Doença , Feminino , Fibrose , Sobrevivência de Enxerto , Humanos , Terapia de Imunossupressão , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.
Assuntos
Alelos , Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Rim , Tacrolimo/farmacocinética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8-31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1-25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6-36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.
RESUMO
Epstein-Barr virus (EBV) contributes to the pathogenesis of post-transplant lymphoproliferative disease (PTLD) in more than 70% of cases. EBV DNAemia surveillance has been reported to assist in the prevention and treatment of PTLD in hematopoietic stem-cell transplantation (HSCT) recipients. Derived from experience in HSCT and taking into account that PCR-based EBV monitoring techniques are currently available in most solid organ transplant (SOT) centres, there is a great interest in EBV surveillance and prevention of PTLD in SOT recipients. In the present document we have tried to address from a practical perspective different important topics regarding the prevention and management of EBV-related PTLD in SOT. To this end, available information on SOT was analysed and combined with potentially useful data from HSCT and expert observations. The document is therefore structured according to different specific questions, each of them culminating in a consensus opinion of the panel of European experts, grading the answers according to internationally recognized levels of evidence. The addressed issues were grouped under the following topics. (i) Timing and epidemiological data of PTLD. Prophylaxis guided by clinical risk factors of early and late PTLD in SOT. (ii) Relationship of EBV DNAemia load monitoring and the development of PTLD in solid organ transplant recipients. (iii) Monitoring of EBV DNAemia after SOT. Which population should be monitored? What is the optimal timing of the monitoring? (iv) Management of SOT recipients with persistent and/or increasing EBV DNAemia.
Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Transtornos Linfoproliferativos/epidemiologia , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/prevenção & controle , Transplante de Órgãos , Transplantados , Monitoramento Epidemiológico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/prevenção & controle , Infecções por Vírus Epstein-Barr/terapia , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/prevenção & controle , Transtornos Linfoproliferativos/terapia , Programas de Rastreamento/métodos , Técnicas de Diagnóstico Molecular , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/terapiaRESUMO
The risk of fractures after kidney transplantation is high. Hyperparathyroidism frequently persists after successful kidney transplantation and contributes to bone loss, but its impact on fracture has not been demonstrated. This longitudinal study was designed to evaluate hyperparathyroidism and its associations with mineral disorders and fractures in the 5 posttransplant years. We retrospectively analyzed 143 consecutive patients who underwent kidney transplantation between August 2004 and April 2006. The biochemical parameters were determined at transplantation and at 3, 12 and 60 months posttransplantation, and fractures were recorded. The median intact parathyroid hormone (PTH) level was 334 ng/L (interquartile 151-642) at the time of transplantation and 123 ng/L (interquartile 75-224) at 3 months. Thirty fractures occurred in 22 patients. The receiver operating characteristic (ROC) curve analysis for PTH at 3 months (area under the ROC curve = 0.711, p = 0.002) showed that a good threshold for predicting fractures was 130 ng/L (sensitivity = 81%, specificity = 57%). In a multivariable analysis, independent risk factors for fracture were PTH >130 ng/L at 3 months (adjusted hazard ratio [AHR] = 7.5, 95% CI 2.18-25.50), and pretransplant osteopenia (AHR = 2.7, 95% CI 1.07-7.26). In summary, this study demonstrates for the first time that persistent hyperparathyroidism is an independent risk factor for fractures after kidney transplantation.
Assuntos
Calcificação Fisiológica , Fraturas Ósseas/etiologia , Hiperparatireoidismo/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Hormônio Paratireóideo/sangue , Complicações Pós-Operatórias , Adulto , Idoso , Feminino , Seguimentos , Fraturas Ósseas/sangue , Fraturas Ósseas/diagnóstico , Taxa de Filtração Glomerular , Humanos , Hiperparatireoidismo/sangue , Hiperparatireoidismo/diagnóstico , Testes de Função Renal , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/antagonistas & inibidores , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Microangiopatias Trombóticas/prevenção & controle , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Terapia Combinada , Feminino , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/terapia , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Troca Plasmática , Contagem de Plaquetas , Qualidade de Vida , Adulto JovemRESUMO
Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.
Assuntos
Biomarcadores/análise , Proteínas do Sistema Complemento/genética , Testes Genéticos , Rejeição de Enxerto/genética , Sobrevivência de Enxerto/genética , Síndrome Hemolítico-Urêmica/terapia , Transplante de Rim , Adolescente , Adulto , Idoso , Síndrome Hemolítico-Urêmica Atípica , Biomarcadores/metabolismo , Complemento C3/genética , Fator B do Complemento/genética , Fator H do Complemento/genética , Feminino , Fibrinogênio/genética , Síndrome Hemolítico-Urêmica/genética , Humanos , Masculino , Proteína Cofatora de Membrana/genética , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
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
A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.