S. Tomlanovich

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

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.

The role of donor-specific HLA alloantibodies in liver transplantation

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.

Alterations in skeletal muscle structure are minimized with steroid withdrawal after renal transplantation.

Background. Limitations in exercise capacity in kidney transplant recipients are thought to result in part from changes in muscle structure and function associated with immunosuppression therapy. Methods. We compared the percent distribution of skeletal muscle fiber types, cross-sectional areas, and ultrastructural morphologies in kidney transplant recipients treated with standard prednisone maintenance therapy (n=21) to those undergoing rapid withdrawal of prednisone using Simulect (interleukin 2 receptor inhibitor) (n=13). Skeletal muscle biopsy specimens from the vastus lateralis were analyzed at 3 and 12 months after transplantation and compared with sedentary controls (n=15). Results. Compared with the control group, the group receiving prednisone maintenance therapy had a significantly lower percentage of type I fibers and a higher percentage of type IIB/x fibers, evident at 3 and 12 months. Fiber type distribution in patients withdrawn from prednisone did not differ from controls. In patients withdrawn from prednisone, the cross-sectional areas of type I and IIA fibers were lower and the area of type IIB/x fibers was higher compared with controls. Likewise, ultrastructural studies revealed reduced volume densities of myofibrils and higher densities of interfibrillar and subsarcolemmal mitochondria. At 12 months there were no ultrastructural differences between the patients withdrawn from prednisone and controls. Conclusions. We conclude that prednisone maintenance therapy contributes to the lower exercise capacity by altering the ratio of type I to type IIB/x fibers and by reducing myofilament density. The increase in mitochondria in patients receiving prednisone may reflect a switch from carbohydrate to lipid metabolism resulting from the glucocorticoid therapy.

Determination of blood flow to the transplanted kidney. A novel application of phase-contrast, cine magnetic resonance imaging.

There is at present no noninvasive method that reliably measures blood flow in the poorly functioning renal allograft. The present study was designed to evaluate phase-contrast cine magnetic resonance imaging (PC-cine-MRI) for this purpose. We recruited for study 18 patients who had received kidney transplants 13-66 months earlier from closely related living donors. As judged by the glomerular filtration rate, which was elevated for a single kidney (76 +/- 4 ml/min 1.73 m2), allograft function was excellent, permitting the assumption of unimpaired renal extraction of paminohippuric acid (PAH). Allograft blood flow was determined consecutively on the same day, first by the standard PAH clearance technique and they by the product of the velocity of protons and renal vein cross-sectional area using PC-cine-MRI. MRI determinations could not be completed because of claustrophobia in two patients and failure to image the terminus of the allograft vein another two. Comparison of blood flow in the remaining 14 subjects revealed the two techniques to be strongly related (r = 0.91, P < 0.001). On the average, the renal blood flow rate was similar by each method; 732 +/- 62 by PAH clearance and 703 +/- 69 ml/min by PC-cine-MRI, but the agreement among individuals between the two methods was only modest, with a 95% confidence interval of agreement from -214 to +254 ml/min. We conclude that PC-cine-MRI provides a fairly accurate and noninvasive method for determining the rate of blood flow in the transplanted kidney. With further refinement it should permit the role of depressed blood flow in a variety of acute and chronic forms of human allograft dysfunction to be elucidated in humans for the first time.

Efficacy and Safety of Everolimus Plus Low‐Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard‐Dose Tacrolimus in De Novo Renal Transplant Recipients: 12‐Month Data

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.

Effect of Everolimus With Low Dose Tacrolimus Vs Mycophenolate With Standard Tacrolimus Regimen in African-American De Novo Renal Transplant Recipients.: Abstract# B955

B954 One Agent-Once a Day: 2 Year Outcomes of a Prospective Randomized Trial of Once Daily (Extended Release) Tacrolimus Maintenance Monotherapy vs Twice Daily (Standard Release) Tacrolimus After Alemtuzumab Induction & Early Steroid Cessation (TAESR Trial). Rejection and Variation in Tacrolimus Levels. A. McLean,1 P. Brookes,2 R. Charif,1 T. Cook,3 J. Galliford,1 D. Goodall,1 J. Lee,1 C. Roufosse,3 M. Willicombe,1 D. Taube.1 1Imperial College Kidney & Transplant Centre, Imperial College Healthcare NHS Trust, London, United Kingdom; 2Dept of Clinical Immunology, Imperial College Healthcare NHS Trust, London, United Kingdom; 3Dept of Histopathology, Imperial College Healthcare NHS Trust, London, United Kingdom. Introduction: The availability of once-daily extended-release tacrolimus (Advagraf), provides the opportunity to develop a one-agent, once-a-day, maintenance immunosuppressive regimen from the well established combination of tacrolimus monotherapy after alemtuzumab induction with early steroid cessation. Methods: We have undertaken a prospective, randomized, controlled trial comparing graft and patient outcomes, and tacrolimus trough level intra-patient variability with once vs twice daily tacrolimus monotherapy (n=52 vs 50 patients). Results: At 2 years post-transplant, patient survival, graft survival, and the incidence of all rejection (biopsy proven acute cellular, and acute and chronic antibody mediated) did not differ signifi cantly between the two arms: Standard Release Extended Release Patient survival 98.0% 100% p=0.31 Survival with Functioning Graft 96.0% 92.3% p=0.44 Rejection 19.9% 16.6% p=0.75 Intra-patient variability (coeffi cient of variation) of tacrolimus levels did not differ signifi cantly between the two groups, although after the fi rst year post-transplant there was a trend to increased variability in the twice daily, standard release group, and decreasing variability in the once daily, extended release group. Conclusions: Once daily extended release tacrolimus provideds safe and effective maintenance monotherapy after alemtuzumab induction and early steroid cessation, with graft and patient survival, and rejection levels comparable to twice daily, standard release tacrolimus. DISCLOSURES: McLean, A.: Grant/Research Support, Astellas pharma UK. Abstract# B955 Effect of Everolimus With Low Dose Tacrolimus Vs Mycophenolate With Standard Tacrolimus Regimen in African-American De Novo Renal Transplant Recipients. V. Peddi, Y. Qazi, D. Shaffer, F. Luan, B955 Effect of Everolimus With Low Dose Tacrolimus Vs Mycophenolate With Standard Tacrolimus Regimen in African-American De Novo Renal Transplant Recipients. V. Peddi, Y. Qazi, D. Shaffer, F. Luan, F. Shihab, S. Tomlanovich, K. McCague, D. Patel, S. Mulgaonkar. CRAD001AUS92 Study Group. Background: African American (AA) de novo renal transplant recipients (RTxR) are at high risk of graft loss and rejection. This sub-analysis reports data in AA de novo RTxR from a 12M, multicenter randomized, open-label non-inferiority study that evaluated the effi cacy and safety of everolimus (EVR)+low-dose tacrolimus (LTac) vs mycophenolate mofetil (MMF)+standard-dose Tac (STac). Methods: In this de novo RTxR (n=613) received EVR (starting at 0.75 mg bid)+LTac or MMF (2 g/day)+STac. All patients (pts) received induction therapy based on immunological risk factors (basiliximab if PRA<20%; or Rabbit anti-thymocyte globulin if PRA ≥20% or high risk) and steroids per local practice. Composite effi cacy failure rate at 12M included BPAR, graft loss, death, or lost to follow-up. Renal function (eGFR [MDRD]) was also measured at 12M. Results: Of 613 pts, 144 were AA (EVR+LTac=70, 22.7%; MMF+STac=74, 24.3%). The EVR+LTac (vs MMF+STac) group had fewer living donor recipients (18.6% vs 24.3%) and PRA ≥20% (22.9% vs 35.1%). Moreover, recipients of organs from ECD (11.4% vs 6.8%) and pts with HLA mismatches ≥3 (92.9% vs 85.1%) were more frequent in EVR+LTac vs MMF+STac. Other donor and recipient characteristics were comparable between treatment groups. Composite effi cacy failure rates were comparable between treatment groups (Table). Mean eGFR at 12M was also similar (EVR+LTac, 60.8 vs MMF+STac, 60 mL/min/1.73m2). Incidence of any serious adverse event 12M post-transplant was comparable with EVR+LTac vs MMF+STac (52.9%, n=37 vs 60.8%, n=45). The infection rates were lower with EVR+LTac (58.6%) vs MMF+STac (71.6%). Effi cacy endpoints, n(%) EVR+LTac (N=70) MMF+STac (N=74) Treatment difference (CI 95%) Composite effi cacy failure 19(27.1) 22(29.7) -2.6(-17.9, 13.0) tBPAR 15(21.4) 16(21.6) -0.2(-14.4, 14.2) Graft Loss 1(1.4) 3(4.1) -2.6(-10.9, 5.3) Death 2(2.9) 2(2.7) 0.2(-7.8, 8.5) Lost to follow-up 3(4.3) 3(4.1) 0.2(-8.5, 9.3) Events listed are not mutually exlcusive Conclusions: Despite the higher risk profi le of de novo AA renal transplant recipients in EVR+LTac arm, the effi cacy results were similar to MMF+STac. EVR-facilitated Tac minimization also preserved renal function compared to standard therapy and provided lower infection rates. DISCLOSURES: Peddi, V.: Grant/Research Support, Novartis, Astellas. Shaffer, D.: Grant/Research Support, Novartis. Shihab, F.: Other, Novartis, Consultant and Speaker, Astellas, Consultant. McCague, K.: Employee, Novartis Pharmacutical Corporation. Patel, D.: Employee, Novartis Pharmacutical corporation. Mulgaonkar, S.: Grant/Research Support, Novartis, Other, Novartis, Advisor. Abstract# B956 Opportunistic Viral Infections After Alemtuzumab Induction: Results From a Randomized Controlled Trial (RCT) Comparing Alemtuzumab and Basiliximab Induction in Kidney Transplant Recipients (KTRs). A. Cherukuri,1,2 M. Welberry-Smith,2 B. Saundh,2 A. Hale,2 R. Baker.2 1University of Pittsburgh, Pittsburgh, PA; 2Leeds Teaching Hospitals, Leeds, United Kingdom. B956 Opportunistic Viral Infections After Alemtuzumab Induction: Results From a Randomized Controlled Trial (RCT) Comparing Alemtuzumab and Basiliximab Induction in Kidney Transplant Recipients (KTRs). A. Cherukuri,1,2 M. Welberry-Smith,2 B. Saundh,2 A. Hale,2 R. Baker.2 1University of Pittsburgh, Pittsburgh, PA; 2Leeds Teaching Hospitals, Leeds, United Kingdom. There is confl icting evidence for the incidence of opportunistic viral infections and their outcomes after alemtuzumab induction in KTRs. In an open label single centre prospective RCT of two steroid avoidance regimes comparing alemtuzumab induction with tacrolimus monotherapy and basiliximab induction with tacrolimus and MMF maintenance therapy, we compared the replication rates of four opportunistic viral pathogens (CMV, BK, EBV and JC) viruses in the urine and blood during the fi rst post-transplant year and analysed the impact of their replication on medium term graft outcomes. Patients (n=116) were randomized 1:1 to receive either basiliximab or alemtuzumab and a single 1g i.v dose of methylprednisolone at induction. Longitudinal analysis of the replication of CMV, BK and JC viruses at 1, 3, 6, 9 and 12 months after transplantation by RT-PCR revealed that alemtuzumab group was associated with a modestly reduced prevalence of both viruria and viremia through the fi rst year, although none of these results were statistically signifi cant. With regards to the CMV, 22.4% of KTRs in the alemtuzumab group and 19% in the basiliximab group were in the high risk group (D+R-). These patients received prophylaxis with valganciclovir. A further 40% of patients in the alemtuzumab group who were in the intermediate group (D+R+, D-R+) also received prophylaxis. All the viral replication analysis was blinded to the clinical teams. No patients were treated based on the viral replication results alone. In this study, only one patient developed CMV disease and no patients had BK nephropathy with minimal EBV and JC replication. Interestingly, prevalence of none of these opportunistic viruses in the blood or urine was associated with a decreased graft survival for the entire study population over a fi ve year follow-up period (Kaplan Meier survival analysis). Especially, opportunistic viral replication was not associated with adverse graft survival in the alemtuzumab group over a 5 year follow-up period. Rejection rates were comparable in the presence or the absence of these viruses either in the blood or urine. To conclude, alemtuzumab induction with tacrolimus monotherapy was not associated with higher prevalence of viral replication in the fi rst year after renal transplantation. Importantly, viral replication was not associated with adverse graft outcomes.