RESUMO
BACKGROUND: Outcomes of patients with end-stage renal disease are mainly affected by their comorbidities. Detailed data evaluating the impact of pre-transplant comorbidities on long-term outcome after kidney transplantation are largely missing. METHODS: In a long-term retrospective analysis, we investigated 839 deceased donor kidney transplant recipients (KTRs) who received transplants between 1999 and 2014. The prevalence and impact of the most relevant comorbidities were studied in detail. RESULTS: At the time of transplantation, 25% of KTRs had coronary artery disease (CAD), 16% had diabetes mellitus (DM), 11% had peripheral arterial disease (PAD), 8% had chronic heart failure (CHF), and 7% had cerebrovascular disease (CVD). KTRs with pre-existing CAD, DM, PAD, and CHF showed a significantly inferior patient survival. Multivariate analysis adjusting for all relevant factors and comorbidities confirmed CAD as most hazardous independent risk factor for premature death (hazard ratio [HR] 1.70; P = .002). A multivariate analysis revealed CHF and PAD as independent risk factors for death censored graft loss (HR 2.20; P = .003 and HR 1.80; P = .013). Diabetes was independently and significantly associated with T-cell- (HR 1.46; P = .020) and antibody-mediated rejections (HR 2.27; P = .030). CONCLUSIONS: Detailed quantification of the impact of pre-transplant comorbidities may facilitate the evaluation of transplant candidates, guide post-transplant follow-up, and may help to further refine prediction algorithms and allocation systems.
Assuntos
Comorbidade , Falência Renal Crônica , Transplante de Rim/mortalidade , Transplantados , Adulto , Idoso , Diabetes Mellitus/epidemiologia , Feminino , Sobrevivência de Enxerto , Insuficiência Cardíaca/epidemiologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doença Arterial Periférica/epidemiologia , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Rituximab is frequently used in solid organ transplantation off-label, especially in patients with renal allografts. Few data are available on the safety aspects of solid organ transplant recipients receiving rituximab. There is a knowledge gap on long-term follow-up data, in particular on infectious complications. PATIENTS AND METHODS: A retrospective observational registry study (German Registry on Autoimmune Diseases) comprising a total of 681 patients was conducted. The data of 63 adult kidney transplant recipients who received rituximab between 2006 and 2013 were used in this analysis. RESULTS: Median follow-up was 42 (1-109) months. At least 1 severe infection occurred in 57% of patients. The median time between the first rituximab infusion and the first infection was 4 (1-48) months. Of the overall 88 infections, 74 were severe bacterial infections, 5 were severe viral infections, 3 were severe fungal infections, 2 were combined severe bacterial and fungal infections, and 4 were combined severe viral, fungal and bacterial infections. Seven patients died during the observational period, 2 of them due to infectious complications. In the observational period, 1 case of squamous cell carcinoma but no other malignancies were observed. CONCLUSION: Consistent with previous data, a high incidence of infections was observed after rituximab treatment in kidney transplant recipients. Most infections occurred within 6 months after rituximab initiation. With more than 3 years of follow-up, we were able to document a low incidence of secondary malignancies after rituximab with only 1 case in our cohort.
Assuntos
Fatores Imunológicos/efeitos adversos , Infecções/epidemiologia , Transplante de Rim/efeitos adversos , Neoplasias/epidemiologia , Rituximab/efeitos adversos , Adulto , Idoso , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Infecções/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neoplasias/induzido quimicamente , Sistema de Registros , Estudos RetrospectivosRESUMO
Recurrence of hepatitis C virus (HCV)-associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct-acting antiviral agents (DAAs) allow a highly effective and interferon-free treatment option for chronic HCV-infected patients. Data on the therapeutic safety and efficacy in HCV-infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63-year-old female HCV-positive renal transplant patient with biopsy-proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti-HCV-directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy-associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis-dependent renal transplant failure after treatment of recurrent HCV-associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs.
Assuntos
Injúria Renal Aguda/cirurgia , Antivirais/uso terapêutico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Rejeição de Enxerto/tratamento farmacológico , Hepacivirus/patogenicidade , Hepatite C/complicações , Transplante de Rim/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranoproliferativa/etiologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Imunossupressores/uso terapêutico , Testes de Função Renal , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Recidiva , Fatores de RiscoAssuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Terapia Genética/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neoplasias Pancreáticas/terapia , Adenocarcinoma/genética , Protocolos Clínicos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Neoplasias Pancreáticas/genética , Seleção de Pacientes , VacinaçãoRESUMO
Paclitaxel is active in metastatic breast cancer. Combination studies have demonstrated complex interactions between paclitaxel and other cytotoxic agents, including sequence-dependent cytotoxic, toxicological, and pharmacological effects. The principal objectives of this study were to determine the maximum tolerated doses of paclitaxel (3-h infusion) and cyclophosphamide (1-h infusion) administered every 3 weeks with granulocyte colony-stimulating factor (Filgrastim) and to determine if the sequence-dependent toxicological effects that have previously been observed with this combination when paclitaxel was administered over 24 h were evident when paclitaxel was administered over 3 h. Fifteen women with metastatic breast cancer were treated. Starting doses were 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, with granulocyte colony-stimulating factor (5 micrograms/kg/day) given s.c. beginning 24 h after chemotherapy. Doses of both drugs were escalated in cohorts of at least four patients. The sequence of drug administration was alternated with each consecutive patient and with each subsequent course of therapy in each individual patient, enabling the evaluation of sequence-dependent toxicological and pharmacological effects. Severe myelosuppression was the principal dose-limiting toxicity for this regimen, precluding dose escalation above 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, the maximum tolerated dose for this combination on this schedule. As has been previously demonstrated with this combination, when paclitaxel is administered over 24 h, the hematopoietic toxicity was sequence dependent. Paired analysis of toxicity data using each patient as her own control indicated more severe hematological toxicity in courses in which paclitaxel was administered first. There was no evidence of sequence-dependent effects on the pharmacokinetics of these drugs that might account for this phenomenon. The impact of drug sequencing on toxicity should be considered in the further development of combination therapy containing alkylating agents and paclitaxel, when the latter is administered over 3 h.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doenças Hematológicas/induzido quimicamente , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinéticaRESUMO
Therapy with anti-TNF antibody is reported to be effective in preventing morbidity and mortality in baboons given lethal infusions of Escherichia coli. Treated animals survived, and organ histopathology was absent when antibody was administered early after lethal infusions of E. coli. The present study explored the relationship between antibody dosage, pathophysiology, and survivability from shock. When antibody dose was decreased lungs, kidneys, adrenals, spleen, and liver were injured as shown by increased vascular congestion, hemorrhage, edema, and necrosis of tissues. Survival was also affected. All animals treated with 15 mg/kg antibody survived as reported earlier; less than 60% survived with 7.5 mg/kg; 9% survived with 5.0 mg/kg, and all died with 1.5 mg/kg. Serum concentrations of interleukin-6 (IL-6) increased markedly as dose of antibody decreased. The increases in concentrations of IL-6 were associated with increases in morbidity and mortality following E. coli administration.
Assuntos
Imunoterapia , Choque Séptico/terapia , Fator de Necrose Tumoral alfa/imunologia , Glândulas Suprarrenais/patologia , Animais , Anticorpos Monoclonais/administração & dosagem , Relação Dose-Resposta Imunológica , Infecções por Escherichia coli , Interleucina-6/metabolismo , Rim/patologia , Fígado/patologia , Pulmão/patologia , Papio , Choque Séptico/mortalidade , Choque Séptico/patologia , Baço/patologia , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We have evaluated a recently developed bioassay based on porcine kidney (PK(15)) cells for the detection of tumor necrosis factor-alpha (TNF-alpha) from eight different species. This test could also be used to measure human TNF-beta with similar sensitivity when compared to the widely used L929 bioassay.
Assuntos
Anticorpos Monoclonais , Fator de Necrose Tumoral alfa/análise , Animais , Bovinos , Cães , Estudos de Avaliação como Assunto , Cabras , Cavalos , Humanos , Cinética , Camundongos , Testes de Neutralização , Sensibilidade e Especificidade , Ovinos , Especificidade da Espécie , Suínos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21-77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (< 65 or > 65 years) versus dose delivered [< the maximum tolerated dose (MTD) vs > or = the MTD] or toxicity (< grade 3 vs > or = grade 3). Of 344 patients, 81 (23.5%) were > 65 years old, 34 (9.9%) were > or = 70 years old, and 5 (1.5%) were > or = 75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged > or = 75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.
Assuntos
Envelhecimento/metabolismo , Antineoplásicos/farmacocinética , Drogas em Investigação/farmacocinética , Adulto , Idoso , Ensaios Clínicos Fase I como Assunto , Humanos , Pessoa de Meia-IdadeRESUMO
Escherichia coli and Staphylococcus aureus are the most common pathogens encountered in septic shock. This is a descriptive study in which the pathophysiologic response to infusions of LD100 concentrations of E. coli and S. aureus are staged and compared. Equivalent concentrations of both organisms were infused over a 2 hr period into antibiotic-treated and untreated animals with the following results: 1) The apparent clearance of E. coli was less than that of S. aureus over the 2-hr infusion period, but far greater during the next 8 hr in both antibiotic-treated and untreated animals. Thus the clearance of E. coli fits a one-compartment (intravascular), and that of S. aureus fits a two-compartment (intra- and extravascular) model. 2) The intensity of the cardiovascular, temperature, and metabolic response to E. coli was greater, whereas that of the disseminated intravascular coagulant (DIC) response to S. aureus was greater. We conclude, therefore, that the response to E. coli consists of four stages with no invasion and colonization of tissues, whereas the response to S. aureus consists of two stages with invasion and colonization of tissues.
Assuntos
Infecções por Escherichia coli/fisiopatologia , Infecções Estafilocócicas/fisiopatologia , Animais , Ceftriaxona/uso terapêutico , Modelos Animais de Doenças , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/etiologia , Gentamicinas/uso terapêutico , Hemodinâmica , Hemostasia , Rim/patologia , Pulmão/microbiologia , Pulmão/patologia , Papio , Choque Séptico/etiologia , Choque Séptico/fisiopatologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/etiologiaRESUMO
Monoclonal antibody against human tumor necrosis factor alpha (TNF MAb) prevents death induced by intravenous gram-negative bacteria or lipopolysaccharide (LPS) in primates. Although these studies have demonstrated that TNF plays a prominent role in the development of lethal septic shock, exploration of dose-response relationships and possible mechanisms of protection have been limited. We addressed these questions in a series of experiments conducted in E. coli-challenged pigs. First, we determined that TNF MAb neutralized the cytotoxic activity found in septic pig plasma and in culture media from pig monocytes incubated with LPS. Second, we demonstrated that pretreatment with TNF MAb promotes survival, in a dose-dependent fashion, in an otherwise lethal E. coli bacteremic pig model. The results of the survival study highly correlate (r = 0.96, P < 0.01) the presence of TNF in the circulation with mortality. In an additional series of physiologic monitoring experiments designed to delineate possible mechanisms of protection, the authors demonstrate that TNF MAb pretreatment abrogates the prolonged leukopenia, thrombocytopenia, and microvascular leakiness resulting from intravenous bacterial challenge and maintains arterial blood pressure while diminishing pulmonary edema. These findings may provide a mechanism whereby neutralization of TNF systemically affords protection against the lethal sequelae of bacteremia.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/fisiologia , Suínos/microbiologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Relação Dose-Resposta a Droga , Infecções por Escherichia coli/mortalidade , Feminino , Hematócrito , Interleucina-6/sangue , Leucopenia/prevenção & controle , Lipopolissacarídeos/farmacologia , Masculino , Monócitos/efeitos dos fármacos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/imunologia , Trombocitopenia/prevenção & controle , Fator de Necrose Tumoral alfa/análiseRESUMO
A successful experimental treatment for gram-positive sepsis to our knowledge has not been achieved. The objectives of this study were to develop a nonhuman primate model of lethal gram-positive sepsis employing the micro-organism Staphylococcus aureus and to determine the efficacy of treatment using monoclonal antibody (MAb) to tumor necrosis factor alpha (TNF). The antibody was administered intravenously, 15 mg/kg, 30 minutes after the beginning of a 2-hour infusion of S. aureus, 4 x 10(10) colony forming units/kilogram. The baboons infused with S. aureus demonstrated the release of the cytokines TNF and interleukin-6 (IL-6), but endotoxin was not observed in the plasma at any time. Treatment with antibody to TNF abolished the rise in serum TNF levels and reduced the increased levels of IL-6. Treatment with MAb to TNF prevented multiple organ failure and achieved permanent (> 7 day) survival of all baboons.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Choque Séptico/terapia , Infecções Estafilocócicas/complicações , Fator de Necrose Tumoral alfa/imunologia , Animais , Coagulação Sanguínea , Contagem de Colônia Microbiana , Interleucina-6/sangue , Papio , Choque Séptico/imunologia , Choque Séptico/mortalidade , Choque Séptico/fisiopatologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação , Fator de Necrose Tumoral alfa/análiseRESUMO
Tumor necrosis factor alpha (TNF) has been described as a primary mediator of the pathophysiology associated with bacterial sepsis/endotoxemia. We tested the efficacy and possible mechanisms of protection of a monoclonal antibody against TNF (TNF Mab) in a low mortality (29%), endotoxemic baboon model. A number of parameters were monitored at days 0, 1, 2 and 5-7 after challenge with 2 mg E. coli endotoxin/kg. TNF Mab pretreatment (15 mg/kg) prevented the increase in detectable serum TNF and the early perturbations in cardiovascular function which occurred in the control group. Early metabolic dysfunction was delayed in the TNF MAb group and was attenuated thereafter. Dysfunction of the kidney, liver, and coagulation systems and the increased IL-6 levels were significantly attenuated in the TNF MAb group; neutrophil activation was not affected by TNF MAb. No deaths occurred in the TNF MAb group. These results support the hypothesis that TNF plays a central role in the pathophysiology of endotoxic shock.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Choque Séptico/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Aspartato Aminotransferases/análise , Coagulação Sanguínea/efeitos dos fármacos , Glicemia/análise , Modelos Animais de Doenças , Escherichia coli , Feminino , Hemodinâmica , Interleucina-6/análise , Lactatos/sangue , Masculino , Papio , Choque Séptico/mortalidade , Choque Séptico/prevenção & controle , Fator de Necrose Tumoral alfa/análiseRESUMO
The addition of either cathepsin-G or leukocyte elastase to endotoxin-stimulated human peripheral blood monocytes decreased the immunoreactive tumor necrosis factor (TNF) detected in culture supernatants in a concentration-dependent manner. Both enzymes also induced a loss of supernatant cytolytic activity as determined on the WEHI-164 target cell line. Incubation of recombinant human TNF and lymphotoxin (LT) with either cathepsin-G or leukocyte elastase resulted in a loss of cytokine bioactivity. Examination of enzyme-treated recombinant cytokines by gel electrophoresis revealed that cathepsin-G cleaved LT into a 12.6-kDa fragment and leukocyte elastase fragmented LT into a 14.1-kDa product. On Western blots cathepsin-G and leukocyte elastase degraded TNF into 11- and 7.6-kDa fragments, respectively. Incubating leukocyte elastase with plasma elastase inhibitor alpha-1-antitrypsin prevented the loss of recombinant TNF bioactivity and blocked the degradation of this cytokine. This study suggests that two of the most abundant neutrophil proteases, cathepsin-G and leukocyte elastase, may be important regulators of TNF and LT bioactivity.
Assuntos
Catepsinas/farmacologia , Linfotoxina-alfa/metabolismo , Elastase Pancreática/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Western Blotting , Catepsina G , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Interleucina-1/metabolismo , Elastase de Leucócito , Neutrófilos/fisiologia , Proteínas Recombinantes/farmacologia , Serina Endopeptidases , alfa 1-Antitripsina/farmacologiaRESUMO
An anesthetized endotoxemic baboon model has been developed by infusing 2.0 mg E. coli endotoxin/kg i.v. over 1 hr (n = 7). Animals were monitored for 5-7 days with analyses of: cardiovascular, metabolic, and organ dysfunction; acid base, hemostatic, and hematological alterations; as well as tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels. Pathophysiologies detected at 2 hr included transient decreases in vascular resistance and blood pressure, a 157% increase in blood lactate, and a 90% decrease in circulating neutrophils. Organ dysfunction was not observed until 24 hr and, although thrombocytopenia was prevalent (-72% at 48 hr), disseminated intravascular coagulation (DIC) was not a major pathology. Hematocrit fell 21% by 24 hr and was -41% at 5-7 days. Serum TNF peaked at 90 min (7.8 +/- 0.2 ng/mL) and was undetectable after 3 hr. IL-6 also increased early, peaked at 3 hr (3872 +/- 846 U/mL) and was still detectable at 24 hr. A low mortality primate model of gram-negative sepsis has been developed that is characterized by early cardiovascular and metabolic dysfunction (2-6 hr), late organ dysfunction (24-48 hr), sub-clinical DIC, a prolonged anemia, and a 29% mortality between 48 and 72 hr.
Assuntos
Endotoxinas/sangue , Escherichia coli , Doenças Metabólicas/complicações , Equilíbrio Ácido-Base , Animais , Contagem de Células Sanguíneas , Temperatura Corporal , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/patologia , Infecções por Escherichia coli/fisiopatologia , Feminino , Gases/sangue , Hemodinâmica , Hemostasia , Interleucina-6/sangue , Masculino , Papio , Superóxidos/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/análiseRESUMO
Deep preauricular sulci were identified on abdominal radiographs in 29 of 190 (15%) adult females and in none of 110 adult males. To assess the value of the deep preauricular sulcus as an index of past pregnancy, we examined gravidity and parity records of 190 women, using standard films that included the sacroiliac region. Deep, radiographic preauricular grooves were identified in 4 of 41 (10%) nulliparous women and in 25 of 149 (17%) women with positive pregnancy histories. We also examined radiographs obtained before and after pregnancy in six primigravidas. No evidence of radiographic changes in the preauricular grooves was seen in any of the six women. We conclude that the presence of a deep, radiographic preauricular sulcus is not necessarily an indication of past pregnancy.