The impact of donor‐specific HLA alloantibodies (DSA) on short‐ and long‐term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt ...clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody‐mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody‐mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell–mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver–kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under‐appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.
Assembled experts provide insights, explore controversies, and develop recommendations for future research on the consequences of donor‐specific alloantibodies in liver transplantation.
In this 12‐month, multicenter, randomized, open‐label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low‐dose tacrolimus ...(EVR+LTac) or mycophenolate mofetil plus standard‐dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti‐thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy‐proven acute rejection tBPAR/graft loss/death/loss to follow‐up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% −3.0, 11.4). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow‐up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 22.0 vs. 63.1 19.5 mL/min/1.73 m2) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.
This 12‐month, multicenter, randomized, open‐label study in de novo renal transplant recipients reports statistically better graft survival, similar renal function, and comparable safety, despite missing the noninferiority margin of composite efficacy failure rate, with an everolimus plus low‐dose tacrolimus regimen versus mycophenolate mofetil plus standard dose tacrolimus.
Abstract A 34-year-old female recipient of a simultaneous pancreas–kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction, thrombocytopenia, and microangiopathic ...hemolytic anemia. Renal biopsy revealed acute antibody-mediated rejection (AMR) and acute thrombotic microangiopathy (TMA). Clinical and laboratory manifestations, which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin, resolved rapidly and completely to eculizumab (Soliris, Alexion Pharmaceuticals, Inc., Cheshire, Conn), a complement factor C5 antibody. De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases. This is the first report of successful treatment of de novo TMA with eculizumab, which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR. Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA, especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease.
Human immunodeficiency virus (HIV)-infected patients have historically been excluded from consideration for transplantation out of concern for the effects of immunosuppression on the progression of ...HIV disease. Improvements in HIV-related morbidity and mortality with the use of highly active antiretroviral therapy (HAART) have prompted a reevaluation of transplantation as a treatment option for HIV-infected patients with end-stage kidney and liver disease.
Eligible patients met standard transplant criteria. They had undetectable plasma HIV-1 RNA levels (viral load) for 3 months (kidney) or were predicted to achieve viral load suppression posttransplantation if unable to tolerate HAART (liver); a CD4+ T-cell count of more than 200 cells/microL (kidney) or more than 100 cells/microL (liver) for 6 months; and no history of opportunistic infections and neoplasm. Standard immunosuppression included prednisone, mycophenolate mofetil (CellCept, Roche Pharmaceuticals, Basel, Switzerland), and cyclosporine (Neoral, Novartis, East Hanover, NJ).
Fourteen patients received transplants (10 kidney transplants, mean follow-up 480 days; four liver transplants, mean follow-up 380 days). All of the kidney transplant recipients (100%) are alive and with functioning grafts, and three of four liver transplant patients (75%) are alive and well with functioning grafts (all liver transplant patients with normal liver function tests). The one death occurred 445 days posttransplantation in a liver recipient coinfected with hepatitis C virus, who died as the result of its rapid reoccurrence. Rejection occurred in 5 of 10 kidney transplant recipients but did not occur in any of the four liver transplant recipients. HIV viral loads have remained undetectable in all patients maintained with HAART. CD4 counts have remained stable in patients not treated for rejection. Patients receiving protease inhibitors require 25% of the dose of cyclosporine compared with patients receiving nonnucleoside reverse transcriptase inhibitors.
There has been no evidence of significant HIV progression and no adverse effect of HIV on allograft function. Rejection is a concern in kidney transplant recipients, as is the possible poor outcome in hepatitis C virus-coinfected liver transplant recipients. Preliminary data are encouraging and indicate that transplantation should be a treatment option for individuals with well-controlled HIV disease.
The pharmacokinetics of cyclosporine were studied in the blood of five normal healthy volunteers (two men and three women) after each received oral and intravenous cyclosporine alone and with ...concomitant oral ketoconazole. Administration of ketoconazole caused a significant decrease in intravenous cyclosporine clearance (0.18 ± 0.05 L/kg/hr versus 0.32 ± 0.09 L/hr/kg) and a significant increase in cyclosporine oral bioavailability (56.4% ± 11.7% versus 22.4% ± 4.8%) compared with values before ketoconazole administration. Steady‐state volume of distribution for intravenously administered cyclosporine was unchanged (1.26 ± 0.44 L/kg versus 1.10 ± 0.27 L/kg). Hepatic bioavailability (1 — hepatic extraction ratio) calculated for intravenous cyclosporine increased by 11% in the presence of ketoconazole (86.3% ± 3.7% versus 75.2% ± 6.6% without ketoconazole), which accounts for only one third of the observed increase in cyclosporine oral bioavailability. Because it is unlikely that ketoconazole had a significant effect on either cyclosporine absorption or hepatic blood flow, the increase in cyclosporine bioavailability observed in this study is most likely explained by inhibition of gastrointestinal cytochrome P450 enzymes.
Clinical Pharmacology & Therapeutics (1995) 58, 15–19; doi: 10.1016/0009‐9236(95)90067‐5
Significant health benefits result from regular physical activity, many which are important for transplant recipients. Although exercise capacity improves initially after transplant, it is not ...normalized, and only two studies have reported the effects of exercise training in this population. We report a randomized clinical trial of exercise after renal transplantation (RTX).
One hundred sixty-seven patients were randomized at 1 month after RTX into two groups: exercise intervention (EX) and usual care (UC), with repeat testing at 6 and 12 months. Ninety-five patients completed the following testing at both testing times: symptom-limited treadmill testing with measurement of peak oxygen uptake (peak Vo2); isokinetic muscle testing for muscle strength; and dual-energy X-ray absorptiometry scans for body composition. The SF-36 Health Status Questionnaire assessed self-reported functioning. The exercise intervention consisted of individually prescribed programs to be conducted at home with regular phone follow-up to enhance adherence. Repeated measures analysis of variance was performed to determine differences between the groups for the three testing times.
At 1 year 67% of the EX group were exercising regularly compared with 36% of the UC group (P=0.01). Compared with the UC group, the EX group had significantly greater gains in peak Vo2 (P=0.016), percent age-predicted Vo2 (P=0.03), and muscle strength (P=0.05), and a trend toward higher self-reported physical functioning (P=0.06). There were no differences between the groups in changes in body composition. At 1 year, peak Vo2 was significantly correlated with age, percent fat, muscle strength, hematocrit, and self-reported physical functioning.
Exercise training after RTX results in higher levels of measured and self-reported physical functioning; however, exercise alone does not affect body composition.
Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the ...kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.
Health-related fitness and quality of life following steroid withdrawal in renal transplant recipients.
Exercise capacity increases significantly soon after transplantation; however, over time it ...does not further improve and patients remain low compared to normal levels. The limitations to exercise following transplantation have not been identified, but may be related to immunosuppression therapy regimens that include prednisone.
We studied health-related fitness measures (cardiorespiratory fitness, muscle strength, and body composition) and quality of life in renal transplant recipients randomized into two groups: those using standard maintenance immunosuppression, including prednisone therapy (N = 14); and those undergoing rapid withdrawal of steroids using Simulect®interleukin-2 (IL-2) receptor inhibitor (N = 9). Testing was done at 3 and 12 months following transplant and the 12-month data were compared to 15 normal sedentary controls.
Compared to those maintained on steroids, the steroid withdrawal group showed greater gains in VO2peak (P = 0.05) and quadriceps peak torque (P = 0.05) and greater gains in the vitality score and the Physical Composite Scale on the SF-36 questionnaire (P < 0.05). At 1 year, all patients had significantly lower exercise capacity compared to the sedentary controls (P = 0.01). No differences were observed in body composition, with both patient groups increasing in body weight (primarily body fat) over time. At 12 months, all patients were not different in body fat percentage compared to the sedentary controls.
We conclude that prednisone is not the cause for increased body fat following transplantation; however, it may contribute to lower spontaneous improvements in exercise capacity possibly by limiting increases in muscle strength. The low exercise capacity in all transplant recipients studied at 1 year suggests a need for exercise training to optimize physical functioning following transplant.
Transplant glomerulopathy as a cause of late graft loss Suri, Deepika L.; Tomlanovich, Stephen J.; Olson, Jean L. ...
American journal of kidney diseases,
04/2000, Letnik:
35, Številka:
4
Journal Article, Conference Proceeding
Recenzirano
Several pathophysiological processes contribute to chronic kidney transplant rejection. Among the most distinctive is transplant glomerulopathy, characterized by widening of the subendothelial space ...with accumulation of flocculent material and duplication of the basement membrane. The current study assessed the course of graft loss in patients with and without this form of injury. Twenty-five patients with prominent transplant glomerulopathy were identified from biopsies performed at a single center during 4 years. These patients were compared with control patients with a similar degree of renal dysfunction in whom biopsies showed chronic rejection without transplant glomerulopathy. Patients with transplant glomerulopathy showed an increased rate of graft loss after biopsy. Biopsies were performed longer after transplantation in these patients, however, than in control patients with an equal degree of graft dysfunction. Graft survival from the time of transplantation was therefore not different between the two groups. Morphological studies showed that transplant glomerulopathy was not associated with increased severity of chronic vascular injury characterized by arterial and arteriolar intimal thickening or hyalinosis. These findings show that transplant glomerulopathy may develop late after transplantation and separately from chronic vascular rejection. The appearance of transplant glomerulopathy on a biopsy specimen is followed by accelerated graft loss.
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