摘要:

Background.Actual prednisone exposure in low-dose prednisone regimens, in part determined by cytochrome P450 metabolism, has been shown to be important for allograft survival.Methods.Prednisolone (the principal active metabolite of prednisone) metabolism was determined in eight nontransplant patients and in transplant recipients receiving oral prednisone maintenance therapy (20 kidney and 6 liver recipients receiving cyclosporine [CsA] and eight lung recipients receiving ketoconazole and CsA or tacrolimus [FK506]).Results.Prednisolone area under the curve (AUC)–dose-normalized (PNAUCn) to 1 mg/kg was 8,288±1,513 ng·hr/mL in kidney recipients, versus 4,826±999 ng/mL per hr in healthy subjects (P<0.001); it was also increased in liver recipients versus healthy subjects (11,456±1,214 ng·hr/mL,P<0.001). Liver recipients also metabolized prednisolone more slowly than kidney recipients (P<0.001). PNAUCn in lung recipients was similar in kidney recipients despite the effect of ketoconazole to slow CsA metabolism. In kidney transplant recipients, the rate of CsA metabolism was correlated with the rate of prednisolone metabolism (r=0.54,P=.026). Basal cortisol levels in all transplant recipients were lower than in healthy subjects, suggesting more prednisolone exposure in transplant patients.Conclusions.Prednisolone metabolism is slower in solid-organ transplant recipients than in healthy subjects. The slower metabolism of prednisolone, particularly in liver recipients, may help explain the immunologic effectiveness of low-dose prednisone regimens in these patients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients.Methods.This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil.Results.The median time from transplant to SRR was 30 days (range, 8 days–23 months). Five children received two doses of basiliximab (10 mg, 3–7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5–32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease.Conclusion.Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The results of renal transplantation are dependent on many variables. To simplify the decision process related to a kidney offer, the authors wondered which variables had the most important influence on the graft failure risk.Methods.All transplant patients (n=1,124) between January 1981 and July 2000 were included in the analysis (2.6% had missing values). The variables included were donor and recipient age and gender, recipient original disease, race, donor origin, current smoking, cardiovascular disease, body weight, peak and current panel reactive antibody (PRA), number of preceding transplants, type and duration of renal replacement therapy, and time since failure of native kidneys. Also, human leukocyte antigen (HLA) identity or not, first and second warm and cold ischemia times, left or right kidney and fossa, donor kidney anatomy, donor serum creatinine and proteinuria, and transplantation year were included.Results.In a multivariate model, cold ischemia time and its time-dependent variable significantly influenced the graft failure risk censored for death (P<0.0001) independent of any of the other risk factors. The influence primarily affected the risk in the first week after transplantation; thereafter, it gradually disappeared during the first year after transplantation. Donor serum creatinine also significantly influenced the graft failure risk in a time-dependent manner (P<0.0001). The risk of a high donor serum creatinine is already enlarged in the immediate postoperative phase and increases thereafter; the curve is closely related to the degree of the elevation. The other variables with a significant influence on the graft failure rate were, in order of decreasing significance, recipient age, donor gender, donor age, HLA identity, transplantation year, preceding transplantations, donor origin, and peak PRA.Conclusions.Donor serum creatinine and cold ischemia time are important time-dependent variables independently influencing the risk of graft failure censored for death. The best strategy for improving the results of cadaveric transplantations is to decrease the cold ischemia time and to allocate kidneys from donors with an elevated serum creatinine to low-risk recipients.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.The amino acid (AA) metabolism in cirrhosis is deranged, reflected by an altered plasma AA profile. Alanine is a unique AA with predominant production by muscle and the highest hepatic extraction rate.Methods.We studied circulating levels and hepatic alanine extraction in 52 patients with advanced cirrhosis, 16 stable patients more than 6 months after orthotopic liver transplant (OLT), and 50 controls. In addition, hepatic hemodynamics (portal pressure, hepatic blood flow, and splanchnic percent indocyanine green extraction) and parameters of hepatic metabolism (splanchnic oxygen uptake and splanchnic glucose production) were assessed.Results.Circulating alanine levels decreased independently of the clinical stage in cirrhosis (262±15 &mgr;mol/L vs. 330±14 &mgr;mol/L in controls,P<0.001) and decreased even further after OLT (209±10 &mgr;mol/L,P<0.001). Hepatic alanine extraction decreased dependently on the clinical stage in cirrhosis (59±7 &mgr;mol/min) and was normalized after OLT (100±10 &mgr;mol/min,P<0.001), indicating that decreased plasma alanine levels in OLT patients are the result of changes in extrahepatic metabolism. Hepatic alanine extraction correlated with splanchnic oxygen uptake (r=0.64,P<0.001) and hepatic glucose production (r=0.65,P<0.001).Conclusions.These results demonstrate that significant alterations in muscular AA metabolism persist even in the clinically stable long-term course after OLT when the hepatic AA metabolism is normalized.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Early recurrence of massive proteinuria after renal transplantation occurs in 20% to 30% of patients with steroid-resistant idiopathic nephrotic syndrome and is responsible for graft failure in approximately half of cases. We report our experience with the use of intravenous (IV) cyclosporine (CsA) in children with recurrent proteinuria after renal transplantation.Methods.Between March 1991 and August 2001, 36 renal transplantations were performed in 35 patients with steroid-resistant idiopathic nephrotic syndrome in our institution. Recurrence, defined by proteinuria higher than 50 mg/kg per day in the absence of acute rejection or urinary tract infection, was observed in 17 grafts performed in 16 patients. In patients with recurrence, CsA was administered IV, at an initial dose of 3 mg/kg per day, which was afterward adapted to maintain whole-blood levels between 250 and 350 ng/mL.Results.In 14 of 17 cases (82%) with recurrence, proteinuria completely disappeared after 20.8±8.4 (range 12–40) days. The treatment was ineffective in the remaining three patients with persistent proteinuria at the end of the second month posttransplantation. Plasma exchanges were performed in four patients during the first 2 months, and proteinuria regressed in three cases and persisted in one. Persistent remission was observed in 11 patients with a follow-up of 3.7±3 (range 0.3–9) years. Actuarial graft survival was 92% and 70% at 1 and 5 years.Conclusion.IV CsA is a safe and effective treatment in children with recurrent nephrotic syndrome after renal transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Pulmonary edema caused by increased microvascular permeability is an important feature of lung ischemia-reperfusion (I/R) injury.Methods.We investigated the impact of co-aerosolized prostaglandin (PG)I2and the 3',5-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor rolipram on microvascular leakage following I/R injury. Buffer-perfused rabbit lungs were exposed to 270 minutes of warm ischemia while anoxic ventilation and a positive intravascular pressure were maintained.Results.On reperfusion, a massive increase of the capillary filtration coefficient and severe edema formation were noted, whereas microvascular pressures displayed only minor changes. Short-time aerosolization of subthreshold doses of either rolipram (33 &mgr;g) or PGI2(2.6 &mgr;g) at the beginning of ischemia did not attenuate the leakage response, whereas the co-aerosolization of both agents largely blocked any permeability increase and edema formation, independent of hemodynamic effects. The same was true when the co-aerosolization was undertaken before onset of ischemia. Similarly, the intravascular administration of rolipram and PGI2showed a synergistic reduction of I/R-induced vascular leak but demanded 10-fold higher doses. Intravascular release of cAMP was markedly enhanced on combined PGI2-rolipram administration but depended on the mode of delivery of these agents.Conclusions.Low doses of aerosolized prostacyclin and rolipram synergistically protect against severe lung I/R injury and can be used independently of lung perfusion. This strategy may be suitable for an improvement of organ preservation in lung transplantation including early management of non-heart-beating donors.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Both undernutrition and overnutrition can affect the quality of life and survival of patients with pulmonary disease and lead to quantitative and functional alterations of fat-free mass (FFM). This longitudinal study determines the changes in weight, FFM, and body fat before and up to 4 years after lung transplant (LTR).Methods.Height, weight, and body composition measurements (bioelectrical impedance) were obtained in 37 LTR patients. FFM and body fat were measured before and at 1, 3, 6, 9, 12, 18, 24, 36, and 48 months after LTR.Results.Weight changed by +16.6%, +3.2%, −0.2%, and −3.2% and FFM by +14.0%, +2.5%, −0.3%, and −1.0% during years 1, 2, 3, and 4, respectively. A diagnosis of obliterative bronchiolitis after LTR was associated with loss of body weight, FFM, and body fat, compared with stable weight or gain in weight, FFM, and body fat in obliterative bronchiolitis-negative subjects; 76.2% and 85.7%, and 28% and 38% of men and women, respectively, demonstrated low FFM at 1 month and at 2 years after LTR, respectively. The FFM change was higher (39% of weight) during year 1 than during year 2 (25%) or year 3 (21%).Conclusions.After LTR, patients gained weight, FFM, and body fat, and two-thirds reached normal levels of FFM by year 2. A weight increase resulted in an FFM increase. Contrary to studies after heart or liver transplantation, our results suggest that despite posttransplant infections and grafts rejection, LTR permits FFM recovery.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Kidney grafts with multiple renal arteries have been considered a relative contraindication because of the increased risk of complications. In the present study, we retrospectively reviewed multiple renal artery reconstruction in kidney transplantation to elucidate the usefulness of these grafts.Methods.From January 1997 until August 2001, 431 recipients underwent kidney transplantation at our institution; 393 patients are reviewed. The surgical techniques of vascular reconstruction and short-term outcome are reported. The living kidney transplant recipients were divided into vascular reconstructed and nonreconstructed groups, and mean serum creatine levels, warm and total ischemic times, and incidences of acute rejection and posttransplantation hypertension were compared.Results.We noted multiple renal arteries in 96 (24.4%) of the 393 grafts. Arterial reconstruction was performed on 53 (13.5%) grafts, whereas 43 (10.9%) small polar arteries were simply ligated. Surgical management of the multiple arteries was variable. The most common reconstruction was conjoined anastomosis (17 cases) between two arteries of equal size and end-to-side anastomosis (14 cases) of smaller arteries to larger arteries. In nine cases, autogenous hypogastric or epigastric artery grafts were used to reconstruct multiple renal arteries. Multiple anastomosis was performed in six cases. In seven cases, complicated surgical vascular reconstruction was performed. The mean total ischemic times in the reconstructed and nonreconstructed groups were 102.6 and 71.0 min, respectively (P<0.01). The incidences of posttransplantation hypertension in the reconstructed and nonreconstructed groups were 68.2% (30/44) and 48.6% (141/290), respectively (P<0.05). There was no significant difference between the reconstructed and nonreconstructed groups in mean warm ischemic times, mean creatinine levels, and incidences of acute rejection.Conclusions.Allografts with multiple renal arteries can be used successfully in kidney transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Previous data indicate that a transfer of specific humoral and cellular immunity by way of allogeneic hematopoietic cell transplantation (HCT) should, in principle, be possible.Methods.In the HCT setting with a follow-up of up to 55 months, we studied the transfer of hepatitis B virus (HBV) specific immunity from electively immunized donors into HLA compatible recipients suffering from chronic myeloid leukemia (CML). After excluding preexisting HBV specific immunity in donor–recipient pairs, 27 prospective donors were vaccinated against HBV. In addition, on an average of 22 months postHCT, 8 of the 19 recipients were immunized once for HBV.Results.Donor vaccination resulted in detectable hepatitis B surface (HBs) antibodies in 85% of donors and specific cellular in vitro responses in 77%. Two weeks postHCT, 86 and 67% of the recipients displayed positive humoral and cellular HBV reactions, respectively, which then decreased. Afterwards, HBV immunity reappeared in 83% of the recipients without revaccination. Following a single vaccination in recipients, seven of eight displayed a typical memory response. An HBV specific response was already detectable 1 week after vaccination, approximately 1,300-fold (humoral) and 60-fold (cellular) higher than observed in the corresponding donors after a single immunization.Conclusions.The “spontaneous” recurrence of HBV immunity and the memory response in recipients give evidence for an elective immune transfer (e.g., for viral antigens) by way of allogeneic HCT.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background.Transplant coronary artery disease (TxCAD) is a major cause of long-term mortality after heart transplantation. Although vascular remodeling has been implicated in the pathophysiology of TxCAD, its determinants remain unknown.Methods.Twenty-nine consecutive heart-transplant recipients prospectively received intravascular ultrasound (IVUS) of the left-anterior descending artery 1 and 12 months after transplant, with volumetric reconstruction of the proximal 30 mm.Results.Overall, patients exhibited intimal volume increase (+83%,P<0.001), wheras vessel volume remained largely unchanged (+4%,P=0.270); consequently, overall lumen volume decreased (−6%,P=0.058). Among the clinical and laboratory variables, cytomegalovirus (CMV) infection requiring treatment (occurring in 12 patients), as assessed by pp65 antigenemia, was independently associated with the impaired ability of the vessel wall to enlarge in response to intimal volume increase, ultimately resulting in lumen loss (OR [95% CI]=0.098 [0.010–0.920];P=0.042). However, adequate vessel response to intimal hyperplasia with consequent lumen preservation was observed in the remaining 17 patients who did not present CMV infection requiring treatment.Conclusions.The present study demonstrates that either adequate or inadequate coronary remodeling may occur during the first year after transplantation. Moreover, for the first time, it strongly suggests that remodeling modalities may be negatively influenced by the occurrence of clinically relevant CMV infection. Randomized prospective trials are warranted to investigate whether aggressive treatment of CMV infection may help prevent TxCAD.

ISSN:0041-1337    

出版商:OVID    

年代:2003

数据来源: OVID