Benjamin T. Duhart

Risk factors and consequences of delayed graft function in deceased donor renal transplant patients receiving antithymocyte globulin induction

Background. Induction rabbit antithymocyte globulin (rATG) is largely used in renal allograft recipients at risk for delayed graft function (DGF) and immunologic rejection. The purpose of our study was to characterize risk factors and outcomes associated with DGF when it occurs in recipients undergoing routine rATG induction. Methods. We retrospectively reviewed our experience in a predominantly high-risk population receiving modern immunosuppressive regimens. Results. Of 231 deceased-donor transplants, high-risk characteristics included African American race (68%), retransplants (12%), peak panel reactive antibody of atleast 20% (19%), expanded criteria donor kidney (15%), and cold ischemia time exceeding 24 hr (27%). DGF occurred in 29% of patients. rATG was continued to a dose of 7.3 mg/kg in DGF patients and 5 mg/kg in non-DGF patients (P<0.0001). Risk factors for DGF were recipient body mass index greater than 30 kg/m2 (odds ratio [OR]=1.5, P=0.02), female donor/male recipient pairings (OR=1.5, P=0.033), sirolimus use (OR=1.7, P=0.003), and donor creatinine more than 1.5 mg/dL (OR=1.6, P=0.016). One-year patient survival (99% non-DGF, 91% DGF; P=0.001) and acute rejection incidence through 36 months (11% non-DGF, 22.4% DGF; P=0.025) differed between groups. DGF patients experienced a higher rejection rate during the second and third years posttransplant. Death-censored graft survival was similar throughout 36 months. Conclusion. In kidney transplantation with routine rATG induction, DGF was related to size and gender, donor creatinine, and immunosuppressive protocol. Despite low first-year rejection rates, DGF was associated with inferior patient survival. Importantly, patients with DGF continued to be at risk for rejection beyond the first year. Donor and recipient selection impacts short-term outcomes, and induction alone may not confer a long-term advantage without further modification of baseline therapy.

Rabbit antithymocyte induction and dosing in deceased donor renal transplant recipients over 60 yr of age

Patel SJ, Knight RJ, Suki WN, Abdellatif A, Duhart BT, Krauss AG, Mannan S, Nezakatgoo N, Gaber AO. Rabbit antithymocyte induction and dosing in deceased donor renal transplant recipients over 60 yr of age.
Clin Transplant 2011: 25: E250–E256.

Retrospective evaluation of the risk of hepatitis B virus reactivation after transplantation

Abstract: Numerous case reports describe patients with previously documented immunity developing active hepatitis B virus (HBV) infection after transplantation. However, the risk of reactivation of HBV under long‐term immunosuppression in hepatitis B core antibody (HBcAb)‐positive, hepatitis B surface antigen (HBsAg)‐negative transplant recipients has not been clearly described. Herein, we present a long‐term follow‐up for 49 HBcAb‐positive, HBsAg‐negative recipients (27 liver, 18 kidney, 4 pancreas) transplanted between June 1996 and April 2001. Among these, 37 recipients (76%) were HBsAb positive at transplantation. Immunosuppression consisted of various antibody induction regimens in 20 (41%) of the recipients with either tacrolimus (33 [67%])‐ or cyclosporine (16 [33%])‐based maintenance immunosuppression. The incidence and duration of HBV prophylaxis was not significant. No patient received hepatitis B immunoglobulin (HBIG) before or after transplantation. Additionally, only two patients received lamivudine, which was started post transplant without clinical indication. The mean length of follow‐up was 3.1±1.4 years. At the last follow‐up, overall patient and graft survival were 98% and 96%, respectively. Patient survival was 96% in liver, 100% in kidney, and 100% in pancreas transplant recipients. The graft survival for each organ type was 93% in liver, 100% in kidney, and 75% in pancreas transplant recipients at the end of follow‐up. There was no incidence of HBV reactivation defined as recurrence of HBsAg and/or HBV DNA positivity. These data suggest that the risk of reactivation of HBV in HBcAb‐positive, HBsAg‐negative transplant recipients under immunosuppression is negligible, regardless of immunosuppressive regimen, lamivudine prophylaxis, or HBsAb status. These patients should have access to transplantation as they enjoy excellent patient and graft survival rates.

Biotransformation of protriptyline by filamentous fungi and yeasts

1. The potential of various fungi to metabolize protriptyline (an extensively used antidepressant) was studied to investigate similarities between mammalian and microbial metabolism. 2. Metabolites produced by each organism were isolated by high-pressure liquid chromatography and identified by nuclear magnetic resonance and mass spectrometry. The metabolites identified in one or more fungi were 2-hydroxyprotriptyline, N-desmethylprotriptyline, N-acetylprotriptyline, N-acetoxyprotriptyline, 14-oxo-N-desmethylprotriptyline, 2-hydroxy-acetoxyprotriptyline and 3-(5-hydrodibenzo[bf][7]annulen-5-yl)propanoic acid. 3. Among 27 filamentous fungi and yeast species screened, Fusarium oxysporum f. sp. pini 2380 metabolized 97% of the protriptyline added. Several other fungi screened gave significant metabolism of protriptyline, including Cunninghamella echinulata ATCC 42616 (67%), C. elegans ATCC 9245 (17%), C. elegans ATCC 36112 (22%), C. phaeospora ATCC 22110 (50%), F. moniliforme MRC-826 (33%) and F. solani 3179 (12%). 4. F. oxysporum f. sp. pini produced phase I and phase II metabolites and thus is a suitable microbial model for protriptyline metabolism.

Breast cancer patient with everolimus-induced angioedema: A rare occurrence with potential for serious consequences.

Background The development of angioedema is a rare yet serious clinical event that may develop due to an adverse drug reaction. Rapid recognition and treatment of this adverse reaction is critical for optimal patient outcomes; however, prevention of this occurrence is preferred. Case report A 59-year-old woman presented to the emergency department with lingual angioedema caused by the addition of everolimus to her medication regimen. The patient improved after withdrawal of the offending agent and standard treatment. Early recognition by healthcare providers and management of everolimus-induced angioedema is vital for successful patient outcomes. This report increases awareness of everolimus as a potentially causative agent for the development of angioedema.

Disagreement in Estimates of Kidney Function for Drug Dosing in Obese Inpatients

Background: The Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are used to estimate kidney function. However, utility has been questioned in the obese population. Objective: To evaluate differences in estimates of kidney function in obese patients and implications for drug dosing. Methods: This was a retrospective study of adult inpatients with a body mass index ≥30 kg/m2 and stable kidney function. Patients were categorized based on creatinine clearance (CrCl): group 1—CrCl ≥ 60 mL/min and group 2—CrCl 15 to 59 mL/min. Mean estimates of kidney function and recommended doses of 8 renally eliminated medications were compared. Results: For the 166 patients included, mean estimates using CG, MDRD, and CKD-EPI for group 1 were 87 (23) mL/min, 91 (21) mL/min, and 96 (23) mL/min, respectively. Group 2 estimates were 42 (13) mL/min, 51 (15) mL/min, and 51 (16) mL/min, respectively. MDRD and CKD-EPI estimates were significantly higher than CG in 125 (75%) and 140 (84%) patients, respectively. Dose discrepancies were most often due to higher dose recommendations using MDRD or CKD-EPI compared to CG. Conclusion: Careful consideration of the method used to estimate kidney function, the method used for developing dosing recommendations, and the risk–benefit profile is warranted when designing drug regimens in obese individuals.

Belatacept conversion in African American kidney transplant recipients with severe renal dysfunction

Objectives: Conversion from calcineurin inhibitor–based maintenance immunosuppression to belatacept in kidney transplant recipients has been demonstrated to improve renal function while maintaining efficacy against rejection. However, conversion studies to date have excluded patients with an estimated glomerular filtration rate < 35 mL/min/1.73 m2. Methods: We describe two patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m2 who underwent conversion from maintenance calcineurin inhibitor to belatacept. Results: Both patients experienced improvement in renal function following conversion. Conclusions: These results suggest that patients with more severe degrees of allograft impairment may benefit from conversion of maintenance calcineurin inhibitor to belatacept-based immunosuppression. Larger, randomized studies are warranted to evaluate the impact of such an approach.

The Benefit of Sirolimus Maintenance Immunosuppression and Rabbit Antithymocyte Globulin Induction in Liver Transplant Recipients That Develop Acute Kidney Injury in the Early Postoperative Period

Published data are limited describing renal outcomes in orthotopic liver transplant (OLT) recipients prescribed sirolimus (SRL) maintenance immunosuppression (MIS) and rabbit antithymocyte globulin (rATG) induction. We investigated whether SRL MIS and rATG induction facilitated recovery of acute kidney injury in the early postoperative period. This retrospective descriptive study screened 308 consecutive OLTs performed between 2006 and 2009. All patients received rATG induction with steroid avoidance. MIS consisted of SRL or TAC with mycophenolate mofetil. A total of 197 patients were included: 168 (85%) received TAC and 29 (15%) received SRL for a median of 365 days. Demographics were similar between groups except for a higher incidence of pretransplant renal dysfunction in the SRL recipients (SRL 59% versus TAC 21%; P < 0.05). The eGFR was significantly (P < 0.05) higher for all time points in the TAC group with the exception of month 2. However, improvement in eGFR was significantly (P < 0.05) greater in the SRL group postoperatively. Our study suggests that rATG induction and SRL maintenance immunosuppression facilitate renal recovery for liver transplant recipients that develop acute kidney injury in the early postoperative period.