RESUMO
Audiograms are sharply tuned to a frequency close to the second harmonic of the pulse. The tuning, which is much sharper than previously reported for any vertebrate receptor, provides a mechanism whereby the bat can effectively perceive echoes even during periods of pulse-echo overlap.
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BACKGROUND: Despite the ever-lengthening renal transplant waiting lists, without more donors, living donors serve as a treatment option for patients on dialysis. In the past, patients of advanced age were not considered to be candidates for living donor renal transplantation. Therefore, this study sought to analyze whether older age affects the outcome of living donor renal transplantation. METHODS: A total of 527 primary living donor renal transplantations were performed between January 1, 1995 and January 1, 2006. The subjects were divided into 2 subgroups based on patient age at the time of transplantation. The elder group included all recipients at least 60 years vs the control group of younger patients. RESULTS: Significant differences were observed in readmission rate (elder group, 44%; young group, 31.33%; P = .031) and patient survival rate (P < .001). No significant difference was noted in graft survival rate (P = .201), acute rejection rate (elder group, 10.6%; young group, 13.3%; P = .7), serum creatinine level, or length of stay (elder group, 8.51 days; young group, 6.31 days; P = .083). CONCLUSIONS: Our results confirm that elder patients may benefit from living donor renal transplantation.
Assuntos
Transplante de Rim/fisiologia , Doadores Vivos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Seguimentos , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Activation of the transcription factor nuclear factor-kappaB (NFkappaB) is impaired in T cells from patients with renal cell carcinomas (RCCs). In circulating T cells from a subset of patients with RCCs, the suppression of NFkappaB binding activity is downstream from the stimulus-induced degradation of the cytoplasmic factor IkappaBalpha. Tumor-derived soluble products from cultured RCC explants inhibit NFkappaB activity in T cells from healthy volunteers, despite a normal level of stimulus-induced IkappaBalpha degradation in these cells. The inhibitory agent has several features characteristic of a ganglioside, including sensitivity to neuraminidase but not protease treatment; hydrophobicity; and molecular weight less than 3 kDa. Indeed, we detected gangliosides in supernatants from RCC explants and not from adjacent normal kidney tissue. Gangliosides prepared from RCC supernatants, as well as the purified bovine gangliosides G(m1) and G(d1a), suppressed NFkappaB binding activity in T cells and reduced expression of the cytokines IL-2 and IFN-gamma. Taken together, our findings suggest that tumor-derived gangliosides may blunt antitumor immune responses in patients with RCCs.
Assuntos
Carcinoma de Células Renais/imunologia , Gangliosídeos/farmacologia , Proteínas I-kappa B , Imunossupressores/farmacologia , Neoplasias Renais/imunologia , NF-kappa B/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Humanos , Interferon gama/biossíntese , Interleucina-2/biossíntese , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Linfócitos T/metabolismoRESUMO
The antitumor effect of immuno- and chemotherapeutic agents is executed through stimulation of apoptotic programs in susceptible cells. Apoptosis induced in tumor cells requires activation of members of the caspase family of proteases. Deficient expression or activation of caspases may account in part for the failure of many current anticancer therapies. However, recent studies suggest that cell death can proceed in the absence of caspases. We investigated the susceptibility of human renal cell carcinoma (RCC) lines to two distinct modes of cell death, apoptosis and necrosis. RCC lines displayed almost complete resistance to apoptosis in response to the intracellular zinc chelator, N,N,N'N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), which instead induced dramatic accumulation of nonapoptotic necrotic cells. Conversely, TPEN was a potent inducer of apoptosis in caspase-competent normal kidney cells (NK-72) and Jurkat T lymphocytes. Resistance to apoptosis in RCC lines correlated with almost complete loss of caspase-3 expression and variable down-regulation of caspase-7, caspase-8, and caspase-10. These data may explain the resistance of RCC to drugs inducing apoptosis and have important consequences for further attempts to manipulate tumor cell death.
Assuntos
Carcinoma de Células Renais/patologia , Caspases/metabolismo , Neoplasias Renais/patologia , Apoptose , Carcinoma de Células Renais/enzimologia , Caspases/deficiência , Inibidores da Colinesterase/farmacologia , Etilenodiaminas/farmacologia , Humanos , Células Jurkat , Neoplasias Renais/enzimologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Necrose , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Células Tumorais CultivadasRESUMO
The limited success of IFN-alpha therapy for clinical treatment of transitional cell carcinoma (TCC) has prompted us to investigate the responsiveness of TCC lines to IFN-alpha. The response to IFN-alpha in terms of 561 gene induction, an IFN-stimulated response element-containing IFN-alpha/beta-inducible gene, and IFN-stimulated gene factor 3 (ISGF3) formation was normal in primary human urothelial cells. We tested the antiproliferative effects of IFN-alpha in three TCC lines as a measure of IFN-alpha responsiveness, and variable patterns of growth inhibition were observed in three TCC lines. More than 90% growth inhibition was noted in TCCSUP cells, whereas only 40% and 10% inhibition by IFN-alpha was observed in 5637 and HT1197 cells, respectively. IFN-alpha treatment formed extremely low levels of ISGF3 in electrophoretic mobility shift assays in these later two relatively insensitive cells. In addition, expression of the 561 gene was significantly reduced in these two TCC lines by Northern blots. We have further identified a low expression level of Tyk2 in HT1197 cells compared with two other TCCs. This suggests that an extremely low ISGF3 level after IFN-alpha treatment may be due to low Tyk2 expression or other unidentified defects. In 5637 cells, p48 protein expression was undetectable. This undetectable p48 expression is not due to a deletion in the coding region because the correct size protein is detected following IFN-gamma treatment. Consequently, the ISGF3 complex formation and 561 gene induction were restored by IFN-gamma pretreatment plus IFN-alpha treatment. Introduction of p48 expressing plasmid into 5637 cells was sufficient to form the ISGF3 complex by IFN-alpha treatment, suggesting the defect lies in the expression of p48 protein in 5637 cells. Detailed mechanistic understanding of the action of IFNs in bladder cancer cell lines may explain the abrogated therapeutic response of IFN-alpha in the clinical treatment of TCCs.
Assuntos
Carcinoma de Células de Transição/metabolismo , Proteínas de Ligação a DNA/biossíntese , Interferon-alfa/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Carcinoma de Células de Transição/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Fator Gênico 3 Estimulado por Interferon , Fator Gênico 3 Estimulado por Interferon, Subunidade gama , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Interferon gama/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fatores de Transcrição/genética , Ativação Transcricional , Transfecção , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/genéticaRESUMO
PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.
Assuntos
Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/terapia , Interleucina-2/administração & dosagem , Neoplasias Renais/secundário , Neoplasias Renais/terapia , Linfócitos do Interstício Tumoral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Método Duplo-Cego , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Proteínas Recombinantes , Análise de SobrevidaRESUMO
Fifty patients, 65 years of age or older, with renovascular disease were evaluated and treated between 1979 and 1981. Twenty-one patients were treated medically, 21 surgically and 8 with percutaneous transluminal angioplasty of the renal arteries. The age, sex, target organ involvement, initial blood pressure and serum creatinine were similar among the three groups. Sixty-six percent of the medical group demonstrated lower blood pressure. Ninety percent of the surgical group demonstrated a cure or improved blood pressure, and 43% of the patients with percutaneous transluminal angioplasty had improved blood pressure. Renal function deteriorated in 50% of the medical group, 19% of the surgical group and 25% of patients in the percutaneous transluminal angioplasty group. There was one operative death in the surgical group and one death related to percutaneous transluminal angioplasty. The data demonstrate that old age itself is not a contraindication to surgery. If hypertension is resistant to medical therapy, if the patient experiences undesirable side effects from the medications or if renal function is jeopardized, surgical therapy should be considered. More experience with percutaneous transluminal angioplasty is necessary to determine its precise role in managing atherosclerotic renal vascular disease in the elderly.
Assuntos
Hipertensão Renovascular/terapia , Idoso , Angioplastia com Balão , Pressão Sanguínea , Creatina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão Renovascular/mortalidade , Hipertensão Renovascular/fisiopatologia , Hipertensão Renovascular/cirurgia , Rim/fisiopatologia , Masculino , NefrectomiaRESUMO
The antitumor effect of T cells is executed either through CD95 or Perforin (PFN)/Granzyme B (GrB) pathways. Induction of apoptosis by either mode requires activation of caspase family members. However, recent studies have suggested that cell death can proceed in the absence of caspase induction and apoptotic events. We investigated the contribution of CD95 and PFN/GrB-mediated cytotoxicity to apoptotic and necrotic mechanisms of cell death in human renal cell carcinoma. Although freshly isolated and cultured tumors expressed CD95 on their surface, they were resistant to CD95-mediated apoptosis. CD95 resistance coincided with decreased levels of FADD protein and diminished caspase-3-like activity. In contrast, we demonstrated that tumor cell death mediated by PFN/GrB can be achieved in the absence of functional caspase activity and is accompanied by a dramatic accumulation of nonapoptotic necrotic cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/patologia , Linfócitos T Citotóxicos/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Proteínas de Transporte/metabolismo , Caspase 8 , Caspase 9 , Caspases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ativação Enzimática/efeitos dos fármacos , Proteína Ligante Fas , Proteína de Domínio de Morte Associada a Fas , Granzimas , Humanos , Células Jurkat , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/farmacologia , Necrose , Perforina , Proteínas Citotóxicas Formadoras de Poros , Serina Endopeptidases/farmacologia , Células Tumorais Cultivadas , Receptor fas/imunologia , Receptor fas/metabolismoRESUMO
Antitumor immunity fails to adequately develop in many cancer patients, including those with renal cell carcinoma (RCC). A number of different mechanisms have been proposed to explain the immune dysfunction observed in cancer patient T cells. Here we show that T cells from RCC patients display increased sensitivity to apoptosis. Tumor-infiltrating lymphocytes (TILs) display the most profound sensitivity, because 10-15% of those cells are apoptotic when assessed by terminal deoxynucleotidyltransferase-mediated nick end labeling in situ, and the number of apoptotic TILs further increases after 24 h of culture. Peripheral blood T cells from RCC patients are not directly apoptotic, although T lymphocytes derived from 40% of those individuals undergo activation-induced cell death (AICD) upon in vitro stimulation with phorbol myristate acetate and ionomycin. This is in contrast to T cells from normal individuals, which are resistant to AICD. TILs and peripheral blood T cells from RCC patients also exhibit impaired activation of the transcription factor, nuclear factor (NF)-kappaB. Additional findings presented here indicate that the heightened sensitivity of patient T cells to apoptosis may be tumor induced, because supernatants from RCC explants sensitize, and in some instances directly induce, normal T cells to apoptosis. These same supernatants also inhibit NF-kappaB activation. RCC-derived gangliosides may represent one soluble tumor product capable of sensitizing T cells to apoptosis. Pretreatment with neuraminidase, but not proteinase K, abrogated the suppressive effects of tumor supernatants on both NF-kappaB activation and apoptosis. Additionally, gangliosides isolated from tumor supernatants not only inhibited NF-kappaB activation but also sensitized T cells to AICD. These findings demonstrate that tumor-derived soluble products, including gangliosides, may contribute to the immune dysfunction of T cells by altering their sensitivity to apoptosis.
Assuntos
Apoptose , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , NF-kappa B/fisiologia , Núcleo Celular/metabolismo , Fragmentação do DNA , Ativação Enzimática , Gangliosídeos/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Ionomicina/farmacologia , Ionóforos/farmacologia , Acetato de Tetradecanoilforbol , Fatores de TempoRESUMO
Studies have demonstrated abnormalities of the CD3/T-cell antigen receptor (TCR) and pathways of signal transduction in T lymphocytes from animals and patients with advanced malignancy. Diminished expression of TCRzeta and p56(lck) that are associated with the TCR and reduced nuclear localization of RelA containing nuclear factor kappaB (NFkappaB) complexes have been noted. These defects have been described in T cells from patients with malignant melanoma, renal cell carcinoma (RCC), ovarian cancer, and colorectal cancer. Preliminary observations also indicate possible correlation with clinical variables such as stage in selected instances. To further characterize altered expression of TCRzeta, p56(lck), and impaired activation of NFkappaB, T lymphocytes were obtained from 65 patients with RCC, the majority of whom were receiving combination cytokine therapy [interleukin (IL)-2, IFN alpha-containing regimens] and 37 control individuals. In 29 of these patients, levels of TCRzeta and p56(lck) were determined by Western blots of T-cell lysates and semiquantitated using densitometry. Relative levels were then correlated with a series of clinical variables including response to therapy, performance status, survival, disease sites, age, and others. In another group of 28 patients (three individuals from the first group), the frequency of abnormal NFkappaB activation was studied using electrophoretic mobility shift assays after activation of T cells with phorbol myristate acetate/ionomycin or anti-CD3 monoclonal antibody. Changes in these signaling molecules during cytokine treatment were also investigated. TCRzeta and p56(lck) were detected in the peripheral blood T cells in 27 of 29 patients, and overall, reduced levels were noted visually in 12 of 29 (41%) and 13 of 29 (45%) individuals, respectively. When levels were semiquantitated using densitometry, significant decreases of TCRzeta (P = 0.029) and p56(lck) (P = 0.029) but not CD3epsilon (P = 0.131), compared with control levels, were found. In patients treated with IL-2/IFN alpha-based therapy, relative levels of TCRzeta increased significantly (P = 0.002) on day 15 of cycle one compared with the baseline. Correlations of TCRzeta or p56(lck) levels with response or disease variables, except for lower TCRzeta levels (P < 0.001) in the presence of bone metastases, were not found. Abnormal NFkappaB activation after stimulation with phorbol myristate acetate/ionomycin and/or anti-CD3 monoclonal antibody was found in 59% of patients (17 of 28) and was not accounted for by the advanced age of the study cohort. Activation of NFkappaB in peripheral blood T cells was inducible during cytokine therapy in four of six individuals who displayed impaired NFkappaB activity prior to therapy. Moreover, impaired activation of NFkappaB does not appear linked to a reduction of TCRzeta expression, because in five patients, normal TCRzeta levels were present although kappaB binding was not inducible. In the majority of patients with advanced RCC, peripheral blood T cells express TCRzeta and p56(lck), and in a subset, reduced levels of these TCRzeta associated molecules are seen that may increase during cytokine-based therapy. Abnormal activation of NFkappaB is also present in >50% of patients and may also revert to normal during IL-2/IFN alpha-based treatment. This alteration in NFkappaB activation occurred in the presence of normal expression of TCRzeta-associated signaling elements. The clinical significance of these findings remains unclear.
Assuntos
Carcinoma de Células Renais/imunologia , Citocinas/uso terapêutico , Neoplasias Renais/imunologia , Transdução de Sinais , Linfócitos T/metabolismo , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/terapia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/análise , Proteínas de Membrana/análise , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos T/análiseRESUMO
Interleukin 12 (IL-12) is known to play an important role in the development of an antitumor response. Its activity has been shown to be dependent upon the intermediate production of IFN-gamma and the influx into the tumor of CD8 lymphocytes. In a murine model, tumor regression induced by IL-12 treatment correlated with IFN-gamma, IP-10, and Mig expression in the tumor bed and was abrogated by antibodies to both chemokines. Here we examined the effects of rHuIL-12 on IFN-gamma and CXC chemokine gene expression in patients with renal cell carcinoma (RCC) in an attempt to determine whether a similar series of molecular events leading to IL-12-mediated tumor regression in mice is also detectable in humans. As in the murine RENCA model, cultured RCC cells themselves could be induced by IFN-gamma to synthesize IP-10 and Mig mRNA. Explanted RCC produced IFN-gamma and IP-10 mRNA in response to IL-12 treatment, which was consistent with the finding that biopsied RCC tumors from IL-12-treated patients also variably expressed augmented levels of those molecules after therapy. Although Mig mRNA was present in the majority of biopsied tumors prior to treatment, both the Mig and IP-10 chemokines as well as IFN-gamma were induced in the peripheral blood mononuclear cells of IL-12-treated patients. Skin biopsies of IL-12-treated patients also all synthesized IP-10 mRNA. This study demonstrates that recombinant human IL-12 therapy of patients with RCC has the potential to induce the expression of gene products within the tumor bed that may contribute to the development of a successful antitumor response.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Quimiocinas CXC/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular , Interferon gama/biossíntese , Interleucina-12/farmacologia , Neoplasias Renais/tratamento farmacológico , Animais , Quimiocina CXCL10 , Quimiocina CXCL9 , Quimiocinas CXC/genética , Humanos , Camundongos , RNA Mensageiro/análise , Proteínas Recombinantes/farmacologia , Células Tumorais CultivadasRESUMO
Tumors may escape immune recognition and destruction through the induction of apoptosis in activated T lymphocytes. Results from several laboratories suggest that FasL (L/CD95L) expression in tumors may be responsible for this process. In this study of patients with renal cell carcinoma (RCC), we provide evidence for two mechanisms of T-cell apoptosis. One mechanism involves the induction of apoptosis via FasL expression in tumor cells. This is supported by several observations, including the fact that tumor cells in situ as well as cultured cell lines expressed FasL mRNA and protein by a variety of techniques. The FasL in RCC is functional because in coculture experiments, FasL+ tumors induced apoptosis in Fas-sensitive Jurkat T cells and in activated peripheral blood T cells but not in resting peripheral blood T cells. Most importantly, antibody to FasL partially blocked apoptosis of the activated T cells. Moreover, Fas was expressed by T cells derived from the peripheral blood (53% median) and tumor (44.3% median) of RCC patients. Finally, in situ staining for DNA breaks demonstrated apoptosis in a subset of T cells infiltrating renal tumors. These studies also identified a second mechanism of apoptosis in RCC patient peripheral T cells. Whereas these cells did not display DNA breaks when freshly isolated or after culture for 24 h in medium, peripheral blood T cells from RCC patients underwent activation-induced cell death after stimulation with either phorbol 12-myristate 13-acetate/ionomycin or anti-CD3/CD28 antibodies. Apoptosis mediated by exposure to FasL in tumor cells or through T-cell activation may contribute to the failure of RCC patients to develop an effective T-cell-mediated antitumor response.
Assuntos
Apoptose/fisiologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Linfócitos do Interstício Tumoral/citologia , Glicoproteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Linfócitos T Citotóxicos/citologia , Apoptose/efeitos dos fármacos , Células Sanguíneas/imunologia , Carcinoma de Células Renais/sangue , Fragmentação do DNA , Proteína Ligante Fas , Humanos , Marcação In Situ das Extremidades Cortadas , Ionomicina/farmacologia , Células Jurkat/imunologia , Neoplasias Renais/sangue , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Muromonab-CD3/farmacologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Linfócitos T Citotóxicos/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas , Receptor fas/fisiologiaRESUMO
Although surgical repair of renal artery stenosis occasionally improves renal function, it is not yet known when revascularization is indicated for that reason. We report the results observed in a patient with renovascular hypertension and additional stenosis in the contralateral kidney whose renal function deteriorated on repeated occasions during antihypertensive therapy. Renal hemodynamic studies during sodium nitroprusside infusion showed severely impaired autoregulation of blood flow, and glomerular filtration rate was corrected after revascularization of the contralateral kidney alone. After surgery, normal BPs were tolerated without loss of function. These findings demonstrate a specific clinical indication for renal revascularization to preserve kidney function.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Renovascular/tratamento farmacológico , Obstrução da Artéria Renal/cirurgia , Feminino , Humanos , Hipertensão Renovascular/cirurgia , Pessoa de Meia-IdadeRESUMO
To better define the intrarenal hemodynamic effects of angiotensin in human renovascular hypertension, 10 patients underwent renal hemodynamic and functional measurements before and during infusion of a competitive angiotensin analog, [Sar1, Thr8] AII. Eight had technically satisfactory split function studies. Despite a fall in mean arterial pressure (132 +/- 6 to 121 +/- 6 mm Hg, p less than 0.05) and humoral changes consistent with angiotensin-mediated hypertension, the intrarenal effects of this analog were commonly those of an angiotensin agonist, producing vasoconstriction and sodium retention. This was quantitatively greatest in the contralateral kidney, whose preinfusion sodium excretion (86 +/- 30 microEq/min vs 25 +/- 9 microEq/min, p less than 0.02) and glomerular filtration rate (76 +/- 7 ml/min vs 41 +/- 7 ml/min, p less than 0.01) were higher than the stenotic kidney. In some cases, an increase in renal blood flow and rise in sodium excretion were evident during angiotensin blockade, suggesting a tonic intrarenal action of angiotensin. Although renin vein renin values differed markedly between the stenotic and contralateral kidney (ratio = 2.05 +/- 0.30), relative changes in effective renal plasma flow were correlated (r = 0.84: p less than 0.01) during infusion of this analog. These results underscore the differences in sensitivities between vascular beds to the effects of angiotensin II and the major role of the contralateral kidney in renal function and sodium homeostasis in human renovascular hypertension.
Assuntos
Angiotensina II/análogos & derivados , Hipertensão Renovascular/fisiopatologia , Rim/efeitos dos fármacos , Obstrução da Artéria Renal/fisiopatologia , Adulto , Idoso , Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Pressão Sanguínea , Feminino , Humanos , Infusões Intra-Arteriais , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Sódio/metabolismoRESUMO
Changes in regional hemodynamics and function of the kidney during inhibition of angiotensin converting enzyme were studied in 25 patients with renovascular hypertension. A variety of patterns were observed depending upon (1) the activity of the renin-angiotensin system and concomitant administration of diuretics, and (2) the presence of bilateral renal artery stenosis. Increase in blood flow, glomerular filtration rate and sodium excretion during angiotensin blockade, in some instances, indicated tonic renal vasoconstriction before therapy. Release of the kidney from these effects may explain, in part, the sustained effectiveness of converting enzyme inhibition in chronic congestive heart failure. When compared with blood pressure reduction due to nitroprusside administration, initial captopril therapy in patients with unilateral stenosis produced a selective decrease in glomerular filtration, despite well-preserved renal blood flow. These results confirm the importance of efferent arteriolar vasoconstriction due to angiotensin II in man. Experimental studies demonstrate that angiotensin may become critical to sustaining glomerular filtration rate in the presence of stenosis during vasodilation. In patients with bilateral stenosis, this effect produces a syndrome of functional renal insufficiency. Taken together, these data demonstrate an intrarenal action of angiotensin II in human renovascular hypertension and underscore the importance of evaluating the functional impact of changes in regional hemodynamics.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Captopril/uso terapêutico , Hipertensão Renovascular/tratamento farmacológico , Rim/irrigação sanguínea , Prolina/análogos & derivados , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Animais , Cães , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Renovascular/etiologia , Hipertensão Renovascular/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Natriurese/efeitos dos fármacos , Nitroprussiato/uso terapêutico , Obstrução da Artéria Renal/complicações , Circulação Renal/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: Based on their chemoattractant properties, it is likely that chemokines play a role in recruiting alloantigen-primed T cells to allografts and in amplifying inflammation within the graft. The graft-infiltrating leukocytes producing specific chemokines remain largely unknown. METHODS: We tested the intragraft RNA expression of the chemokine RANTES (regulated on activation normal T expressed and secreted) and granzyme B during rejection of full thickness, allogeneic skin grafts by C57BL/6 mice. Grafts with different immunogenetic disparities were chosen to test expression when rejection was mediated by CD4+, CD8+, or both CD4+ and CD8+ T cells. RNA expression was also tested in purified CD4+ and CD8+ T cell populations from skin graft recipients. Immunohistology was performed on graft sections to test colocalization of RANTES protein and graft-infiltrating CD4+ and CD8+ T cells. RESULTS: Intra-allograft RANTES RNA expression was not observed during CD4+ T cell-mediated rejection. Expression of RANTES and granzyme B RNA was observed at low levels in purified populations of CD8+, but not CD4+, T cells from the spleen and lymph nodes of graft recipients beginning at day 7 after transplantation and increased thereafter. Intra-allograft RANTES protein was associated with a small number of graft-infiltrating CD8+ T cells but was also associated with endothelial cells and with many graft-infiltrating CD4+ T cells. CONCLUSIONS: CD8+ T cells produce RANTES during allogeneic skin graft rejection. In the allograft, the chemokine also colocalizes with CD4+ T cells that do not produce RANTES.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL5/biossíntese , Rejeição de Enxerto , Transplante de Pele/imunologia , Doença Aguda , Animais , Quimiocina CCL5/genética , Granzimas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/análise , Serina Endopeptidases/genética , Transplante HomólogoRESUMO
BACKGROUND: Patients with von Hippel-Lindau (VHL) disease are at risk for the development of end-stage renal failure from the treatment of localized renal cell carcinoma. Transplantation with its attendant immunosuppression may predispose patients to tumor recurrence; however, there is little information regarding the outcome with this approach. In this article, we review the North American and European experience with renal transplantation in this patient population. METHODS: The study group comprises 32 patients who have VHL rendered anephric secondary to localized renal cell carcinoma and who have undergone renal transplantation. Patients were identified from North American (n=18) and European (n=14) registries. The outcome of the study group is compared with a cohort of 32 renal transplant recipients without VHL from the Cleveland Clinic Unified Transplant Data Base, who were matched for donor source, gender, age, transplant status (primary vs. regraft), and date of transplantation. RESULTS: The 23 men and 9 women in the study group received transplants between 1974 and 1996. The average age at transplantation was 36 years, and the average duration of dialysis before transplantation was 26 months. Patients have been followed for 48+/-35 months. There was no statistically significant difference in graft survival, patient survival, or renal function between the study and control groups. There were five deaths in both the study and control groups. In the study group, three patients died with metastatic disease. There was no difference in the duration of dialysis before transplantation between patients who developed metastatic disease and those who did not. CONCLUSION: These data support the utility of renal transplantation as an effective form of renal replacement therapy in this unique population, with a limited risk of recurrent cancer.
Assuntos
Carcinoma de Células Renais/cirurgia , Transplante de Rim , Doença de von Hippel-Lindau/cirurgia , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Masculino , Nefrectomia , Recidiva , Diálise Renal , Análise de SobrevidaRESUMO
The factors mediating trafficking of alloantigen-primed T cells and mononuclear phagocytes to the site of an allograft during the graft rejection process remain largely undefined. Based upon their demonstrated chemoattractant properties, chemokines may play a role in directing inflammatory cells to graft sites and initiate rejection. To begin to investigate the role of chemokines in graft rejection, we used Northern blot analysis to examine the temporal expression of 6 chemokine genes in murine allogeneic skin grafts disparate at the entire MHC and minor antigens and grafts with a disparity at either single class I or class II MHC determinants. Two general patterns of chemokine gene expression in each of the allografts were observed. Intragraft expression of 1 group of chemokine genes, including macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, JE, and KC was observed at peak levels 3 days posttransplant in each of the 3 different allograft models. Expression of these genes in control isografts was at low levels, with the exception of JE, which was expressed at equivalent levels in all iso- and allografts for the first 4-5 days posttransplant, and KC, which was expressed at equivalent levels in C57BL/6 isografts and bm1 and bm12 allografts. A second group of chemokine genes, including RANTES (regulated upon activation normal T cell expressed and secreted) and IP-10 (interferon-gamma inducible protein), was expressed at low levels at early times after transplantation but at high levels 3-4 days before rejection of the allografts was complete. Isograft expression of RANTES and IP-10 was undetectable at the late time points. The results suggest that these 2 patterns of chemoattractant cytokine gene expression may be representative of the early inflammatory and the late T cell-mediated phases of the allograft rejection process, respectively.
Assuntos
Quimiocinas/biossíntese , Quimiocinas/genética , Regulação da Expressão Gênica , Rejeição de Enxerto/metabolismo , Transplante de Pele , Animais , Feminino , Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante de Pele/imunologia , Transplante Homólogo , Transplante IsogênicoRESUMO
Herein are presented the results of a controlled prospective randomized double-blind evaluation of antilymphoblast globulin as an immunosuppressive adjunct to azathioprine and prednisone in cadaver renal transplantation. There were 31 patients and 36 patients randomly assigned to therapeutic and control groups, respectively. ALG-treated patients experienced no major side-effects, a delayed onset of rejection following transplantation (P less than .005), a reduced total number of rejection episodes (P less than .05), fewer days in the hospital (P less than .05), a reduced cost of transplantation (P less than .02), improved graft survival (P less than .05), and patient survival equivalent to that of the control group. These data indicate that ALG is safe, cost-effective, and of immunologic benefit in cadaver renal transplantation.
Assuntos
Soro Antilinfocitário/uso terapêutico , Terapia de Imunossupressão , Transplante de Rim , Adulto , Azatioprina/uso terapêutico , Cadáver , Método Duplo-Cego , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Masculino , Prednisona/uso terapêutico , Estudos Prospectivos , Distribuição Aleatória , Fatores de TempoRESUMO
The purpose of this prospective randomized trial was to evaluate an immunosuppressive protocol involving reduced maintenance and antirejection steroid dosages in cadaver renal transplantation. The study comprises 23 first cadaver graft recipients who experienced an acute rejection episode. All patients received an initial 14-day course of antilymphocyte globulin (ALG) and azathioprine 1.5 to 2.0 mg/kg/day. In 11 patients (group 1), a low maintenance dose of prednisone (30 mg/day) was administered and first rejection episodes were treated with a second 10-day course of ALG. The remaining 12 patients (group 2) received high maintenance doses of prednisone (2 mg/kg/day with tapering) and intravenous methylprednisolone (IVMP) for first rejection episodes. Subsequent rejections in both groups were treated with high doses of steroids. In group 1, all first rejection episodes were reversed with ALG alone, 6 patients experienced no subsequent rejection, and 10 patients currently have a functioning graft. In Group 2, the first rejection episode was reversed with IMVP alone in 10 patients; in two patients in whom IVMP therapy was unsuccessful, ALG was then administered, and subsequent rejection reversal was effected. In group 2, 4 patients experienced no subsequent rejection, and 9 patients currently have a functioning graft. Patients in group 1 received significantly lower (P less than .01) cumulative steroid doses in the first six months following transplantation, which resulted in a reduced number of major infections, as compared with patients in group 2. We conclude that the steroid-sparing regimen of low maintenance prednisone and ALG for first rejection is as effective immunologically as the established high steroid protocol.