Ashesh P. Shah

Promising early results with immunosuppression using rabbit anti-thymocyte globulin and steroids with delayed introduction of tacrolimus in adult liver transplant recipients

Induction therapy with T‐cell depleting drugs in liver transplantation is controversial. This study examined the use of rabbit antithymocyte globulin (RATG) with delayed introduction of tacrolimus in liver transplant recipients. Additional subgroup analysis compared patients with or without hepatitis C (HCV) cirrhosis. Over 17 months, 116 adults received 120 liver allografts. Four patients who died before receiving RATG were excluded. Immunosuppression included steroids, 3 doses of RATG (2 mg/kg), and tacrolimus started on postoperative day 3 to 4. Ninety‐six percent of patients were alive with a mean follow‐up of 12.9±4.5 months. No graft was lost to rejection. Two patients developed hepatic artery thrombosis. Six percent of patients had acute rejection. No patient had steroid resistant or recurrent rejection. RATG related drug events were limited to fever, chills, tachycardia, and oxygen desaturation. There were no cases of lymphoproliferative disease. Forty‐two percent of patients were transplanted for HCV. Thirty‐two percent of HCV‐patients had biopsy proven hepatitis C recurrence occurring at 4 weeks to 10 months posttransplant. RATG induction therapy is associated with good patient and graft survival, a low incidence of rejection, and minimal side effects. In addition, RATG induction is safe in patients transplanted for HCV. (Liver Transpl 2004;10:404–407.)

Comparison of pulsatile perfusion and cold storage for paired kidney allografts.

Use of pulsatile perfusion to optimize outcomes in deceased donor kidney transplantation remains controversial. This study is a retrospective analysis of all cadaveric renal allografts procured locally by our center over a 3-year period. Kidney pairs were identified in which one kidney underwent pulsatile perfusion and transplantation at our center, whereas the contra-lateral kidney underwent cold storage and transplantation at another center. Eighty-eight percent of the exported kidneys were six-antigen matches. Study outcomes included 1-year graft and patient survival, delayed graft function, and need for posttransplant dialysis. Recipients had similar demographic and disease characteristics. Survival for pulsatile perfusion and cold storage were 95% and 88% (graft, P=0.43) and 98% and 90% (patient, P=0.36), respectively. The incidence of delayed graft function was 5% and 35% (P<0.01), whereas posttransplant dialysis was 5% and 30% (P<0.01), for pulsatile perfusion and cold storage, respectively. These data support routine use of pulsatile perfusion.

Impact of recipient age on whole organ pancreas transplantation

The goal of this study was to assess the impact of recipient age on post‐transplant outcome.

Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized.

Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non‐sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post‐failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II ≥80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet‐based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post‐failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re‐transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post‐AF can be lessened.

Successful treatment of donor‐derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)‐negative donor to three HCV‐negative recipients—two renal transplants and one liver. Both renal recipients underwent standard deceased‐donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39‐year‐old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV‐infected male partner. Recipient 1 was a 45‐year‐old man with a history of end‐stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62‐year‐old woman with a history of end‐stage renal disease caused by hypertension and insulin‐dependent diabetes. Recipient 3 was a 42‐year‐old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post‐transplant follow‐up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipients liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor‐derived HCV in transplant recipients.

Incidence and outcomes of cytomegalovirus in pancreas transplantation with steroid-free immunosuppression.

Cytomegalovirus (CMV) is a common opportunistic infection encountered after pancreas transplantation. The records of 407 pancreas transplant recipients (226 simultaneous pancreas and kidney transplant (SPK), 101 pancreas transplant after kidney (PAK), and 97 pancreas transplants alone [PTA]) performed at a single center with at least 1‐yr follow‐up were reviewed. Immunosuppression included rabbit antithymocyte globulin induction, steroid withdrawal, and maintenance therapy of tacrolimus and sirolimus (± mycophenolate). In addition, PTA recipients received a single dose of rituximab. All recipients received valganciclovir prophylaxis. Donor (D)+/recipient (R)− recipients received 6 months of prophylaxis; all others received 3 months. The overall CMV infection rate was 12%. The cumulative incidences of CMV infection at 3, 6, 9, and 12 months after transplant were 0.25%, 3%, 7%, and 8%, respectively. CMV infection rates were 20.2% in the D+/R− group, 16.5% in the D+/R+ group, 5.0% in the D−/R+ group, and 2.8% in the D−/R− group. Infections were less common in SPK recipients. Most infections developed at least 3 months post‐transplant, and 24% demonstrated tissue‐invasive disease. Immunosuppression was NOT reduced in 72% of patients with infections. Ganciclovir‐resistant CMV occurred in four patients. No patients died or lost their allografts due to CMV‐related infection; one graft was lost due to chronic rejection associated with a reduction in immunosuppression. In many cases, CMV infections may be treated in pancreas transplant recipients without necessarily reducing immunosuppression.

Need to consider full societal impact of hepatitis B virus-positive donors.

Keywords: ethics and public policy; clinical research / practice; organ procurement and allocation; organ transplantation in general; infection and infectious agents; viral: hepatitis B; liver disease: infectious; donors and donation: donor-derived infections; organ allocation

Induction immunosuppression with rabbit antithymocyte globulin in pediatric liver transplantation

Routine use of rabbit antithymocyte globulin (RATG) induction therapy remains controversial in pediatric liver transplantation. We reviewed our experience of 18 cadaveric liver transplants in 18 children over a span of 2 years. All patients received the same immunosuppression: perioperative steroid therapy with taper, 3 doses of RATG, and maintenance therapy of steroids and tacrolimus started on postoperative day 3. Mean follow‐up was 2.2 ± 0.2 years. End‐stage liver disease was secondary to biliary atresia in 10 patients (56%) and metabolic disorders in 4 patients (22%). Graft and patient survival were 89%. Serum bilirubin was 1.2 mg/dL, 1.1 mg/dL, 0.5 mg/dL, and 0.5 mg/dL at 1, 3, 6, and 12 months, respectively. The 2 mortalities were secondary to multiple organ system failure. Overall rejection rate was 17% (3/18). Rejection episodes occurred at 4, 6, and 7 months. Two patients were treated with steroids; the third was treated with OKT3. No patient has developed posttransplant lymphoproliferative disease. Serum creatinine was 0.7 mg/dL, 0.6 mg/dL, 0.6 mg/dL, and 0.6 mg/dL at 1, 3, 6, and 12 months, respectively, among surviving patients. In conclusion, our data suggest that RATG induction with steroid and tacrolimus maintenance therapy is safe, easy to use, and effective in the prevention of rejection. Liver Transpl 12:1210–1214, 2006.

Association of Inflammation prior to Kidney Transplantation with Post-Transplant Diabetes Mellitus.

Background/Objective: Post-transplant diabetes mellitus (PTDM) is both common and associated with poor outcomes after kidney transplantation. Our objective was to examine relationships of uremia-associated inflammation and adiponectin with PTDM. Methods: Nondiabetic kidney transplant patients were enrolled with donor controls. Inflammatory cytokines and adiponectin were measured before and after transplantation. Adipose tissue was obtained for gene expression analysis. Glucose transport was quantified in vitro in C2C12 cells following cytokine exposure. The patients were monitored up to 12 months for PTDM. Results: We studied 36 controls and 32 transplant patients, of whom 11 (35%) developed PTDM. Compared to controls, plasma TNFα, IL-6, MCP-1, and CRP levels were higher in transplant patients (p < 0.01). In multivariable analysis, TNFα plasma levels before transplantation were associated with development of PTDM (OR = 2.03, p = 0.04). Visceral adipose tissue TNFα mRNA expression was higher in transplant patients than controls (fold change 1.33; p < 0.05). TNFα mRNA expression was also higher in patients who developed PTDM than in those who did not (fold change 1.42; p = 0.05), and adiponectin mRNA expression was lower (fold change 0.48; p < 0.05). The studies on the C2C12 cells demonstrated an increase in glucose uptake following exposure to adiponectin and no significant change after exposure to TNFα alone. Concomitant TNFα and adiponectin exposure blunted adiponectin-induced glucose uptake (11% reduction; p < 0.001). Conclusion: Our in vitro and clinical observations suggest that TNFα could contribute to PTDM through an effect on adiponectin. Our study proposes that inflammation is involved in glucose regulation after kidney transplantation.

Contents Vol. 6, 2016

Michael Bursztyn – Hadassah University Hospital, Jerusalem, Israel Kunal Chaudhary – Harry S. Truman Veterans’ Hospital, Columbia, USA Kevin C. Dellsperger – Georgia Regents Health System, Augusta, USA Vincent DeMarco – University of Missouri, Columbia, USA Jamie P. Dwyer – Vanderbilt University Medical Center, Nashville, USA Keith C. Ferdinand – Tulane University School of Medicine, New Orleans, USA John M. Flack – Southern Illinois University, Springfi eld, USA Elise P. Gomez-Sanchez – University of Mississippi, Jackson, USA Erik J. Henriksen – University of Arizona, Tucson, USA Gianluca Iacobellis – University of Miami, Miami, USA Kamyar Kalantar-Zadeh – University of California, Orange, USA Guido Lastra – University of Missouri, Columbia, USA James M. Luther – Vanderbilt University Medical Center, Nashville, USA Ferid Murad – George Washington University, Washington, USA Naft ali Stern – Sourasky Medical Center, Tel Aviv, Israel Craig S. Stump – University of Arizona, Tucson, USA Adam T. Whaley-Connell – University of Missouri, Columbia, USA