RESUMO
Biomarkers of transplant tolerance would enhance the safety and feasibility of clinical tolerance trials and potentially facilitate management of patients receiving immunosuppression. To this end, we examined blood from spontaneously tolerant renal transplant recipients and patients enrolled in two interventional tolerance trials using flow cytometry and gene expression profiling. Using a previously reported tolerant cohort as well as newly identified tolerant patients, we confirmed our previous finding that tolerance was associated with increased expression of B cell-associated genes relative to immunosuppressed patients. This was not accounted for merely by an increase in total B cell numbers, but was associated with the increased frequencies of transitional and naïve B cells. Moreover, serial measurements of gene expression demonstrated that this pattern persisted over several years, although patients receiving immunosuppression also displayed an increase in the two most dominant tolerance-related B cell genes, IGKV1D-13 and IGLL-1, over time. Importantly, patients rendered tolerant via induction of transient mixed chimerism, and those weaned to minimal immunosuppression, showed similar increases in IGKV1D-13 as did spontaneously tolerant individuals. Collectively, these findings support the notion that alterations in B cells may be a common theme for tolerant kidney transplant recipients, and that it is a useful monitoring tool in prospective trials.
Assuntos
Fator Ativador de Células B/genética , Regulação da Expressão Gênica , Memória Imunológica/genética , Transplante de Rim/efeitos adversos , Tolerância ao Transplante/genética , Adulto , Aloenxertos , Linfócitos B/imunologia , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Rejeição de Enxerto/genética , Sobrevivência de Enxerto/genética , Humanos , Transplante de Rim/métodos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Medição de Risco , Transplantados , Imunologia de Transplantes/genética , Tolerância ao Transplante/imunologia , Resultado do TratamentoRESUMO
We report here the long-term results of HLA-mismatched kidney transplantation without maintenance immunosuppression (IS) in 10 subjects following combined kidney and bone marrow transplantation. All subjects were treated with nonmyeloablative conditioning and an 8- to 14-month course of calcineurin inhibitor with or without rituximab. All 10 subjects developed transient chimerism, and in seven of these, IS was successfully discontinued for 4 or more years. Currently, four subjects remain IS free for periods of 4.5-11.4 years, while three required reinstitution of IS after 5-8 years due to recurrence of original disease or chronic antibody-mediated rejection. Of the 10 renal allografts, three failed due to thrombotic microangiopathy or rejection. When compared with 21 immunologically similar living donor kidney recipients treated with conventional IS, the long-term IS-free survivors developed significantly fewer posttransplant complications. Although most recipients treated with none or two doses of rituximab developed donor-specific antibody (DSA), no DSA was detected in recipients treated with four doses of rituximab. Although further revisions of the current conditioning regimen are planned in order to improve consistency of the results, this study shows that long-term stable kidney allograft survival without maintenance IS can be achieved following transient mixed chimerism induction.
Assuntos
Transplante de Medula Óssea , Sobrevivência de Enxerto/imunologia , Terapia de Imunossupressão , Nefropatias/cirurgia , Transplante de Rim , Complicações Pós-Operatórias , Tolerância ao Transplante/imunologia , Adulto , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/sangue , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.
Assuntos
Embolização Terapêutica , Hiperoxalúria Primária/terapia , Falência Renal Crônica/terapia , Transplante de Rim , Transplante de Fígado , Veia Porta , Adulto , Terapia Combinada , Humanos , Masculino , Oxalatos/metabolismo , Prognóstico , Transplante HomólogoRESUMO
We recently reported long-term organ allograft survival without ongoing immunosuppression in four of five patients receiving combined kidney and bone marrow transplantation from haploidentical donors following nonmyeloablative conditioning. In vitro assays up to 18 months revealed donor-specific unresponsiveness. We now demonstrate that T cell recovery is gradual and is characterized by memory-type cell predominance and an increased proportion of CD4⺠CD25⺠CD127â» FOXP3⺠Treg during the lymphopenic period. Complete donor-specific unresponsiveness in proliferative and cytotoxic assays, and in limiting dilution analyses of IL-2-producing and cytotoxic cells, developed and persisted for the 3-year follow-up in all patients, and extended to donor renal tubular epithelial cells. Assays in two of four patients were consistent with a role for a suppressive tolerance mechanism at 6 months to 1 year, but later (≥ 18 months) studies on all four patients provided no evidence for a suppressive mechanism. Our studies demonstrate, for the first time, long-term, systemic donor-specific unresponsiveness in patients with HLA-mismatched allograft tolerance. While regulatory cells may play an early role, long-term tolerance appears to be maintained by a deletion or anergy mechanism.
Assuntos
Transplante de Medula Óssea , Haplótipos , Transplante de Rim , Doadores de Tecidos , Transplante de Medula Óssea/imunologia , Humanos , Imunofenotipagem , Transplante de Rim/imunologiaRESUMO
An idiopathic capillary leak syndrome ('engraftment syndrome') often occurs in recipients of hematopoietic cells, manifested clinically by transient azotemia and sometimes fever and fluid retention. Here, we report the renal pathology in 10 recipients of combined bone marrow and kidney allografts. Nine developed graft dysfunction on day 10-16 and renal biopsies showed marked acute tubular injury, with interstitial edema, hemorrhage and capillary congestion, with little or no interstitial infiltrate (≤10%) and marked glomerular and peritubular capillary (PTC) endothelial injury and loss by electron microscopy. Two had transient arterial endothelial inflammation; and 2 had C4d deposition. The cells in capillaries were primarily CD68(+) MPO(+) mononuclear cells and CD3(+) CD8(+) T cells, the latter with a high proliferative index (Ki67(+) ). B cells (CD20(+) ) and CD4(+) T cells were not detectable, and NK cells were rare. XY FISH showed that CD45(+) cells in PTCs were of recipient origin. Optimal treatment remains to be defined; two recovered without additional therapy, six were treated with anti-rejection regimens. Except for one patient, who later developed thrombotic microangiopathy and one with acute humoral rejection, all fully recovered within 2-4 weeks. Graft endothelium is the primary target of this process, attributable to as yet obscure mechanisms, arising during leukocyte recovery.
Assuntos
Injúria Renal Aguda/etiologia , Transplante de Medula Óssea/efeitos adversos , Síndrome de Vazamento Capilar/etiologia , Transplante de Rim/efeitos adversos , Injúria Renal Aguda/patologia , Medula Óssea/patologia , Transplante de Medula Óssea/patologia , Síndrome de Vazamento Capilar/patologia , Creatinina/sangue , Feminino , Rejeição de Enxerto/patologia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Transplante de Rim/patologia , Contagem de Leucócitos , MasculinoRESUMO
Chronic humoral rejection (CHR) is an important cause of late graft failures following kidney transplantation. Overall, the pathophysiology of CHR is poorly understood. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, has been implicated in chronic kidney disease and allograft rejection in previous studies. We examined the presence of MMP-2 in allograft biopsies and in the urine of kidney transplant recipients with CHR. MMP-2 staining was detected by immunohistochemistry in podocytes for all CHR patients but less frequently in patients with other renal complications. Urinary MMP-2 levels were also significantly higher in CHR patients (median 4942 pg/mL, N = 27) compared to non-CHR patients (median 598 pg/mL, N = 65; p < 0.001). Elevated urinary MMP-2 correlated with higher levels of proteinuria in both CHR and non-CHR patients. Longitudinal analysis indicated that increase in urine MMP-2 coincided with initial diagnosis of CHR as documented by the biopsies. Using an enzymatic assay, we demonstrated that MMP-2 was present in its active form in the urine of patients with CHR. Overall, our findings associate MMP-2 with glomerular injury as well as interstitial fibrosis and tubular atrophy observed in patients with CHR.
Assuntos
Rejeição de Enxerto/patologia , Transplante de Rim/efeitos adversos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/urina , Podócitos/enzimologia , Feminino , Fibrose , Rejeição de Enxerto/imunologia , Humanos , Nefropatias/patologia , Glomérulos Renais/patologia , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Proteinúria/complicaçõesRESUMO
Five patients with end-stage kidney disease received combined kidney and bone marrow transplants from HLA haploidentical donors following nonmyeloablative conditioning to induce renal allograft tolerance. Immunosuppressive therapy was successfully discontinued in four patients with subsequent follow-up of 3 to more than 6 years. This allograft acceptance was accompanied by specific T-cell unresponsiveness to donor antigens. However, two of these four patients showed evidence of de novo antibodies reactive to donor antigens between 1 and 2 years posttransplant. These humoral responses were characterized by the presence of donor HLA-specific antibodies in the serum with or without the deposition of the complement molecule C4d in the graft. Immunofluorescence staining, ELISA assays and antibody profiling using protein microarrays demonstrated the co-development of auto- and alloantibodies in these two patients. These responses were preceded by elevated serum BAFF levels and coincided with B-cell reconstitution as revealed by a high frequency of transitional B cells in the periphery. To date, these B cell responses have not been associated with evidence of humoral rejection and their clinical significance is still unclear. Overall, our findings showed the development of B-cell allo- and autoimmunity in patients with T-cell tolerance to the donor graft.
Assuntos
Linfócitos B/imunologia , Transplante de Medula Óssea/métodos , Tolerância Imunológica , Transplante de Rim/métodos , Linfócitos T/imunologia , Linhagem Celular , Complemento C4b/química , Ensaio de Imunoadsorção Enzimática/métodos , Rejeição de Enxerto/imunologia , Antígenos HLA/química , Humanos , Sistema Imunitário , Microscopia de Fluorescência/métodos , Fragmentos de Peptídeos/química , Análise Serial de Proteínas , Fatores de TempoRESUMO
INTRODUCTION: There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients aged >or=60 years with outcomes in younger recipients. MATERIALS AND METHODS: From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recipients (28.1%) >60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed. RESULTS: Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P < .001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups. CONCLUSION: Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.
Assuntos
Envelhecimento/fisiologia , Sobrevivência de Enxerto/fisiologia , Transplante de Rim/fisiologia , Idoso , Creatinina/sangue , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Humanos , Transplante de Rim/mortalidade , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Fatores de Tempo , Doadores de Tecidos/estatística & dados numéricos , Resultado do TratamentoRESUMO
The detection of anti-donor-HLA antibodies in a renal allograft recipient's serum, either at the time of or after transplantation, is usually associated with specific antibody-mediated clinical syndromes. These can be divided temporally into three categories: hyperacute rejection, acute humoral rejection and chronic humoral rejection. With the identification of new immunosuppressive drug combinations, more-effective control of alloantibody production has been recently achieved in humans. Thus, prevention and/or treatment of antibody-mediated allograft injury are now possible. Ultimately, the induction of mixed hematopoietic chimerism may allow us to overcome the problem of allosensitization and accept an allograft without chronic immunosuppression.
Assuntos
Linfócitos B/imunologia , Antígenos HLA/imunologia , Imunossupressores/uso terapêutico , Tolerância ao Transplante/imunologia , Animais , Humanos , Imunização/efeitos adversos , Isoanticorpos/biossínteseRESUMO
We sought evidence for non-MHC antibody-mediated rejection in renal allografts by a systematic study of rejected HLA-identical sibling renal allografts. Among 162 recipients of HLA-identical, ABO-compatible sibling donor kidneys transplanted at the Massachusetts General Hospital from 1964 to 2005, we identified 15 grafts that were lost from rejection and two additional grafts with reversible acute rejection, which provided 30 samples for study. All samples were stained for C4d by immunofluorescence in frozen tissue (n = 7) or by immunohistochemistry in paraffin embedded tissues (n = 10). We found that two of 17 grafts had positive C4d staining of peritubular capillaries. Histology revealed acute antibody-mediated rejection in one and acute cellular rejection type 1 in the other. Both grafts were matched at HLA-A, B, and C loci and had a nonreactive mixed lymphocyte response. Genotyping and serological analysis were not available. Compared with a published series, C4d+ irreversible rejection was more common in HLA nonidentical than HLA-identical grafts (75% vs 6.7%, respectively, P < .002). We conclude that antibody-mediated rejection, presumably due to non-MHC antigens other than ABO-blood groups does occur, but infrequently. This may account for some of the HLA antibody negative cases that develop antibody-mediated rejection.
Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Complemento C4b/imunologia , Rejeição de Enxerto/imunologia , Isoanticorpos/sangue , Transplante de Rim/imunologia , Fragmentos de Peptídeos/imunologia , Adulto , Incompatibilidade de Grupos Sanguíneos , Teste de Histocompatibilidade , Humanos , Masculino , Estudos Retrospectivos , Irmãos , Transplante Homólogo/imunologiaRESUMO
The effects of sequential prostacyclin infusions at 2, 4, and 8 ng/kg/min for 1 hr were determined in six patients with chronic renal failure. Diastolic blood pressure decreased in a dose-dependent fashion from 74 +/- 4 mm Hg (mean +/- SEM) to 70 +/- 4, 66 +/- 5, and 55 +/- 5 during the 2, 4, and 8 ng/kg/min infusions, respectively; systolic blood pressure was not affected by prostacyclin. The fall in diastolic blood pressure was associated with a progressive rise in heart rate from 77 +/- 3 to 91 +/- 4 bpm and lowering of body temperature from 36.7 +/- 0.1 to 36 +/- 0.2 degrees. The threshold concentration of adenosine diphosphate that evoked reversible and irreversible platelet aggregation increased progressively from 1.2 to 2.8 and from 2.8 to 6 microM, respectively, during the prostacyclin infusions. Prostacyclin infusions had no effect on prothrombin time, activated partial thromboplastin time, or platelet count, but template bleeding time increased (not statistically significantly) from 5.8 to 12.3 min. In three of six patients, the 8 ng/kg/min infusion was terminated prematurely due to nausea, vomiting, and/or hypotension. We conclude that platelet aggregability can be inhibited in patients with chronic uremia by infusing 4 ng/kg/min prostacyclin without causing untoward side effects. When infused at hemodynamically tolerable doses, prostacyclin might serve as an in vivo inhibitor of platelet aggregation during hemodialysis or cardiopulmonary bypass.
Assuntos
Epoprostenol/farmacologia , Hemodinâmica/efeitos dos fármacos , Prostaglandinas/farmacologia , Uremia/sangue , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Epoprostenol/efeitos adversos , Feminino , Humanos , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Renina/sangue , Uremia/fisiopatologiaRESUMO
The term urinary tract infection encompasses a broad range of clinical entities, each with its own pathology and each requiring its own form of treatment. There are at least four different modes in which antimicrobial therapy may be prescribed for urinary tract infection: single-dose therapy aimed at patients with superficial mucosal infection; a conventional seven- to 14-day course of therapy; a prolonged four- to six-week course of therapy for patients with deep tissue infection; and low-dose prophylactic therapy. Increasingly, the response to single-dose therapy is being utilized to delineate the mode of therapy needed by a patient. Patients with underlying renal disease and/or structural abnormalities of the urinary tract are prone to the development of recurrent urinary tract infection, frequently with bacteria resistant to antimicrobial agents conventionally employed to treat the infection. There has been a steady increase, even among otherwise normal persons with urinary tract infection, in the level of antimicrobial resistance exhibited by bacterial uropathogens to the drugs commonly used to treat these infections. The quinolones in general, and ciprofloxacin in particular, appear to be very promising for the treatment of urinary tract infection. It will be important to evaluate the performance of this drug in the four different therapeutic modes and in patients with renal dysfunction or anatomic abnormalities of the urinary tract.
Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Infecções Bacterianas/complicações , Ciprofloxacina/uso terapêutico , Feminino , Humanos , Masculino , Pielonefrite/tratamento farmacológico , Infecções Urinárias/complicaçõesRESUMO
The incidence of infection in the renal transplant patient is directly related to the net immunosuppressive effect achieved and the duration of time over which this therapy is administered. A second major factor in the causation of infections in this population is the nosocomial hazards to which these patients are exposed, ranging from invasive instrumentation to environmental contamination with Aspergillus species, Legionella pneumophila, Pseudomonas aeruginosa and other microbial pathogens. Careful surveillance is necessary to identify and eliminate such nosocomial sources of infection. The major types of infection observed can be categorized according to the time period post-transplant in which they occur: postsurgical bacterial infection in the first month after transplantation; opportunistic infection, with cytomegalovirus playing a major role, and transplant pyelonephritis in the period one to four months post-transplant; and a mixture of conventional and opportunistic infections in the last post-transplant period. Conventional infection in this late period occurs primarily in patients with good renal function who are receiving minimal immunosuppressive therapy; opportunistic infection occurs primarily in patients with poor renal function who are receiving higher levels of immunosuppression.
Assuntos
Infecção Hospitalar/epidemiologia , Transplante de Rim , Complicações Pós-Operatórias/epidemiologia , Doenças do Sistema Nervoso Central/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Humanos , Terapia de Imunossupressão , Pneumonia/epidemiologia , Sepse/epidemiologia , Transplante Homólogo , Infecções Urinárias/epidemiologiaRESUMO
This report describes a patient with end stage IgA nephropathy who received a renal transplant from his asymptomatic HLA-identical brother. A biopsy of the donor kidney performed at the time of transplantation showed evidence of widespread electron-dense mesangial deposits. On immunofluorescence these deposits stained with IgA, documenting clinically occult IgA nephropathy in this otherwise healthy donor. These findings are of particular interest in view of the association of IgA nephropathy with the HLA-Bw35 alloantigen, and raise the possibility that asymptomatic disease, already present in a donor kidney, may have accounted for what has previously been called "recurrence" of this disease in renal allograft recipients.
Assuntos
Antígenos HLA/imunologia , Imunoglobulina A , Nefropatias/imunologia , Adulto , Humanos , Rim/patologia , MasculinoRESUMO
Ninety-two adult renal allograft recipients, receiving baseline immunosuppression with CsA and prednisone, were assigned randomly to one of the following regimens. CsA was discontinued (D/C group) in 47 recipients who were then maintained on Aza and prednisone; or Aza was added to continued low-dose CsA and prednisone (triple drug [TD] group) in 45 patients. Entry into the study required an absence of rejection and a stable creatinine for at least four months prior to randomization. The mean month of randomization was 8.34 +/- 2.9 for the D/C group, and 7.2 +/- 3.2 for the TD group. Following randomization, a significantly greater rate of rejection (P less than .01) was observed in the D/C group (40%) than in the TD group (13%). With a mean follow-up of 30 months, 41/47 of D/C allografts (87.2%) and 39/45 TD allografts (86.6%) were functioning. Nevertheless, rejection had a persistent adverse effect on allograft function, in both the D/C and TD groups, up to 36 months following randomization. Parameters such as donor-type and rejection prior to randomization did not identify recipients at risk for rejection following randomization. Therefore, although the CsA withdrawal regimen might be ideal, the opportunity to select appropriate candidates remained elusive. In contrast, the safety of the TD regimen became apparent. Neither significant nephrotoxicity nor hypertension was observed, and the opportunity for less daily prednisone was evident. Despite its additional cost, the TD regimen utilizing indefinite low-dose CsA, is preferred.
Assuntos
Ciclosporinas/administração & dosagem , Transplante de Rim/métodos , Adulto , Azatioprina/administração & dosagem , Custos e Análise de Custo , Creatinina/sangue , Ciclosporinas/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Hipertensão/induzido quimicamente , Nefropatias/induzido quimicamente , Prednisona/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
Evaluation of whole-organ pancreas transplantation in the therapy of IDDM has been difficult because of generally poor graft survival and significant complications in past experience. We report a technically successful simultaneous pancreas/kidney transplant program with patient and graft survival of 85% over 3 years of follow-up (mean 21 months) in 33 subjects with IDDM. Glucose metabolism was normalized without need for exogenous insulin immediately posttransplant in all but one recipient and remained normal in 85% of recipients. The outcome in pancreas/kidney recipients was compared with that in 18 insulin-dependent diabetic recipients of kidney transplant only performed in the same period. Quality of life was assessed with one general and one diabetes-specific questionnaire. General quality of life issues improved significantly in both pancreas/kidney and kidney recipients, but diabetes specific quality of life improved only in the pancreas/kidney recipients. Pancreas/kidney recipients required twice as long a period of hospitalization for the transplant and two times as many readmissions for a variety of complications. Only a minority of hospital admissions was strictly attributable to the pancreas graft. Of the five deaths in the pancreas/kidney recipients, two were attributable to the pancreas transplant. Pancreas transplantation in IDDM can now be accomplished with a high degree of success, resulting in normalized glucose metabolism and with overall mortality similar to kidney transplantation alone. Successful pancreas transplantation improves quality of life with respect to diabetes but this benefit is accomplished at a cost of increased hospital admissions and complications related to the transplanted pancreas. The effects of pancreas transplantation on the long-term complications of insulin-dependent diabetes remain unknown.
Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Transplante de Rim , Transplante de Pâncreas , Qualidade de Vida , Adulto , Colesterol/sangue , Creatinina/sangue , Feminino , Seguimentos , Hemoglobinas Glicadas/análise , Rejeição de Enxerto , Humanos , Transplante de Rim/mortalidade , Masculino , Transplante de Pâncreas/mortalidade , Triglicerídeos/sangue , Doenças Vasculares/etiologiaRESUMO
BACKGROUND: Recent studies suggest an association between diabetes mellitus and hepatitis C virus (HCV) infection. Our aim was to determine (1) the prevalence and determinants of new onset posttransplant diabetes mellitus (PTDM) in HCV (+) liver transplant (OLT) recipients, (2) the temporal relationship between recurrent allograft hepatitis and the onset of PTDM, and (3) the effects of antiviral therapy on glycemic control. METHODS: Between January of 1991 and December of 1998, of 185 OLTs performed in 176 adult patients, 47 HCV (+) cases and 111 HCV (-) controls were analyzed. We reviewed and analyzed the demographics, etiology of liver failure, pretransplant alcohol abuse, prevalence of diabetes mellitus, and clinical characteristics of both groups. In HCV (+) patients, the development of recurrent allograft hepatitis and its therapy were also studied in detail. RESULTS: The prevalence of pretransplant diabetes was similar in the two groups, whereas the prevalence of PTDM was significantly higher in HCV (+) than in HCV (-) patients (64% vs. 28%, P=0.0001). By multivariate analysis, HCV infection (hazard ratio 2.5, P=0.001) and methylprednisolone boluses (hazard ratio 1.09 per bolus, P=0.02) were found to be independent risk factors for the development of PTDM. Development of PTDM was found to be an independent risk factor for mortality (hazard ratio 3.67, P<0.0001). The cumulative mortality in HCV (+) PTDM (+) versus HCV (+) PTDM (-) patients was 56% vs. 14% (P=0.001). In HCV (+) patients with PTDM, we could identify two groups based on the temporal relationship between the allograft hepatitis and the onset of PTDM: 13 patients developed PTDM either before or in the absence of hepatitis (group A), and 12 concurrently with the diagnosis of hepatitis (group B). In gr. B, 11 of 12 patients received antiviral therapy. Normalization of liver function tests with improvement in viremia was achieved in 4 of 11 patients, who also demonstrated a marked improvement in their glycemic control. CONCLUSION: We found a high prevalence of PTDM in HCV (+) recipients. PTDM after OLT was associated with significantly increased mortality. HCV infection and methylprednisolone boluses were found to be independent risk factors for the development of PTDM. In approximately half of the HCV (+) patients with PTDM, the onset of PTDM was related to the recurrence of allograft hepatitis. Improvement in glycemic control was achieved in the patients who responded to antiviral therapy.
Assuntos
Diabetes Mellitus/etiologia , Transplante de Fígado/efeitos adversos , Antivirais/uso terapêutico , Complicações do Diabetes , Diabetes Mellitus/mortalidade , Diabetes Mellitus/fisiopatologia , Feminino , Glucocorticoides/efeitos adversos , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/fisiopatologia , Humanos , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Prevalência , Recidiva , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.
Assuntos
Ciclosporina/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Tacrolimo/efeitos adversos , Adulto , Arteriosclerose/etiologia , Endotélio Vascular/fisiologia , Feminino , Humanos , Masculino , Fatores de Risco , VasodilataçãoRESUMO
BACKGROUND: Hepatic artery thrombosis (HAT) remains a devastating complication after liver transplantation. Various factors have been implicated in the pathogenesis of HAT, such as clotting abnormalities, increased hematocrit, and technical complications, but the role of anticardiolipin antibodies has not been evaluated. We investigated the possible association between HAT and anticardiolipin antibodies in adult patients who underwent liver transplantation. METHODS: Seven patients with HAT after orthotopic liver transplantation, 28 liver recipients without HAT, and 35 normal blood donors were evaluated. Determination of IgM and IgG anticardiolipin antibodies was performed by enzyme-linked immunosorbent assay using pretransplant serum from all allograft recipients. Clinical information was obtained from chart review. Fisher's exact test and Wilcoxon rank sum test were used for statistical analysis, and all P-values were two-tailed. RESULTS: Overall, 22 of 35 (63%) liver recipients had a positive anticardiolipin antibody test (either IgG or IgM titer >4 SD from the normal controls). The test was positive in 7 liver recipients (100%) with HAT compared with 15 out of 28 patients (54%) without HAT (P=0.031). As compared with liver recipients without HAT, patients with HAT also tended to have a higher mean anticardiolipin titer of IgG and IgM and a lower pretransplant platelet count; however, these differences were not significant. CONCLUSIONS: Our findings indicate that anticardiolipin antibodies are frequently elevated in patients with liver failure and may contribute to the pathogenesis of HAT after liver transplantation. Other potential consequences of anticardiolipin antibodies in end-stage liver disease remain to be determined.
Assuntos
Cardiolipinas/imunologia , Artéria Hepática , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Transplante de Fígado/efeitos adversos , Trombose/sangue , Trombose/etiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In recent years, hepatitis C virus infection has been reported to be typically associated with membranoproliferative glomerulonephritis and less frequently with membranous nephropathy. Treatment of hepatitis C with interferon-alpha can reduce viremia and improve renal disease. After liver transplantation for hepatitis C virus-associated liver failure, standard immunosuppressive protocols result in a significant increase in hepatitis C viremia. In this report we describe a patient with end-stage liver disease and biopsy-proven hepatitis C-associated glomerulonephritis who underwent liver transplantation. Within 1 month after transplantation, he developed a severe nephrotic syndrome that paralleled a marked increase in viremia. We discuss the possible pathogenic relationship between hepatitis C virus infection and the nephrotic syndrome that followed liver transplantation.