Carlo B. Ramirez

The role of basiliximab induction therapy in organ transplantation

Basiliximab is a chimeric monoclonal antibody that selectively binds to the α-subunit (CD25) of IL-2 receptors on the surface of activated T lymphocytes, and is a highly effective prophylaxis agent against rejection in organ transplant recipients. Its pharmacokinetic profile is characterized by a biphasic and slow clearance with long terminal half-life and a volume of distribution within the central compartment and outside the circulatory system. Basiliximab induction demonstrated an excellent safety profile, with no increase in the incidence of malignancy, infections or death. It has also been used effectively in high-risk recipients, steroid-sparing and steroid-minimization protocols, and in post-transplant patients with renal dysfunction who would benefit from delayed introduction of calcineurin inhibitors. Basiliximab induction therapy given at days 0 and 4 after transplantation appears to be safe and cost-effective for immunoprophylaxis in solid organ transplant recipients, specifically in kidney and liver transplantation, when given in conjunction with dual or triple immunosuppressive therapy.

The adipose tissue production of adiponectin is increased in end-stage renal disease

Adiponectin has anti-diabetic properties and patients with obesity, diabetes and insulin resistance have low plasma adiponectin levels. However, although kidney disease is associated with insulin resistance, adiponectin is elevated in end stage renal disease. Here we determine if adipose tissue production of adiponectin is increased in renal disease in a case-control study of 36 patients with end stage renal disease and 23 kidney donors. Blood and tissue samples were obtained at kidney transplantation and donation. The mean plasma adiponectin level was significantly increased to 15.6 mg/ml in cases compared to 8.4 mg/ml in controls. Plasma levels of the inflammatory adipokines tumor necrosis factor α, interleukin 6 and high sensitivity C-reactive protein were significantly higher in cases compared to controls. Adiponectin mRNA and protein expression in visceral and subcutaneous fat was significantly higher in cases than controls while adiponectin receptor 1 mRNA expression was significantly increased in peripheral blood cells, muscle and adipose tissue in cases compared to controls. Thus, our study suggests that adipose tissue production of adiponectin contributes to the high plasma levels seen in end stage renal disease.

Completely steroid-free immunosuppression in liver transplantation: a randomized study.

Corticosteroids (CS) have been standard immunosuppression to prevent and treat rejection. However, CS are associated with increased risk of infection, obesity, hypertension, hyperlipidemia, diabetes, and accelerated hepatitis C virus (HCV) recurrence post‐orthotopic liver transplantation (OLT). This study assesses the safety and efficacy of CS‐free immunosuppressive regimen in adult OLT.

Pregnancy after liver transplantation.

Women constitute >30% of patients undergoing liver transplantation (orthotopic liver transplantation, OLT) and about 8% are of reproductive age, and 5% are pediatric females who will mostly survive into adulthood and will consider pregnancy. Although pregnancy in OLT recipients is associated with an increased incidence of hypertension, preeclampsia, anemia, preterm deliveries, and cesarean section, acute rejection and liver allograft loss do not appear to be increased and pregnancy-related maternal death is uncommon. The incidence of structural malformations in the newborn of liver transplant recipients is reported to be 4.4%, which is similar to the rate of 3-5% in the US general population. Patients are advised to defer conception for at least 1-2 years after OLT, while maintaining effective contraception. Pregnancy after OLT usually results in a favorable maternal and neonatal outcome when there is coordinated pre- and perinatal care by a multidisciplinary team composed of obstetric-gynecologists, and a transplant team.

Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations.

Singh P, Farber JL, Doria C, Francos GC, Gulati R, Ramirez CB, Maley WR, Frank AM. Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations. 
Clin Transplant 2012 DOI: 10.1111/j.1399‐0012.2011.01584.x. 
© 2012 John Wiley & Sons A/S.

Use of enteric-coated mycophenolate sodium in liver transplant patients with intestinal intolerance caused by mycophenolate mofetil.

Abstract:  Background:  Post‐transplant gastrointestinal (GI) side effects can impair a patient’s quality of life (QoL). This study investigates the improvement in GI side effects and related QoL changes in recipients of liver transplantation (OLT) after converting patients from mycophenolate mofetil (MMF) to enteric‐coated mycophenolate sodium (EC‐MPS).

Acute hypotensive transfusion reaction during liver transplantation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity

Acute hypotensive transfusion reactions are newly characterized transfusion reactions in which hypotension is the prominent feature. The pathophysiology of acute hypotensive transfusion reactions is related to the bradykinin function and its metabolism. A liver transplant recipient on treatment with an angiotensin converting enzyme inhibitor developed sudden hypotension, that is, systolic pressure of 60 mm Hg, after receiving 200 mL of a blood product mixture without significant surgical blood loss. He responded to the resuscitation measure, although hypotension developed again after a challenge transfusion of 200 mL of the blood mixture. A severe hypotensive reaction to the blood transfusion and diffuse bleeding from the dissection surfaces forced the transplantation to be aborted after the common bile duct had been divided. We hypothesized that the patient had an acute hypotensive transfusion reaction due to disordered bradykinin metabolism. Analysis of his blood showed low levels of both angiotensin converting enzyme and aminopeptidase P enzyme activity, confirming that the patient experienced an acute hypotensive transfusion reaction that was due to the use of the angiotensin converting enzyme inhibitor and was precipitated by an abnormality in the metabolic enzyme pathway. It is recommended to discontinue angiotensin converting enzyme inhibitors and switch to a different class of antihypertensive medications for patients with a high Model for End‐Stage Liver Disease score on the waiting list for liver transplantation. Liver Transpl 14:684–687, 2008.

Optimizing use of basiliximab in liver transplantation

Antibody induction therapy has not been part of standard immunosuppressive regimens in liver transplantation. However, in recent years there has been an upward trend in the use of antibody induction therapy in orthotopic liver transplantation (OLT), attributed mainly to the growing number of OLT recipients with renal dysfunction after the Model for End Stage Liver Disease (MELD) scoring system was adopted in 2002. Basiliximab, a chimeric monoclonal antibody, is the most frequently used induction antibody in OLT. Basiliximab targets the alpha chain of interleukin-2 receptors in activated T-lymphocytes, inhibiting T-lymphocyte proliferation responsible for acute cellular rejection. Basiliximab (given in two 20 mg doses intravenously on post OLT day 0 and 4) has an excellent efficacy and safety profile. Basiliximab induction also allows early steroid withdrawal or avoidance, as well as delayed introduction and minimization of calcineurin inhibitors (CNI) in the setting of renal insufficiency. Although its long-term effect on hepatitis C virus (HCV) recurrence post OLT is currently unknown, studies using basiliximab induction in steroid-free protocols suggest no harmful effect on histologic HCV recurrence and survival rates. Basiliximab is a well tolerated, effective and safe anti-rejection drug in pediatric and adult OLT recipients when given in conjunction with a CNI-based immunotherapy.

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.

An Alternative Surgical Technique for Caval Preservation in Liver Transplantation

IntroductionThe results of orthotopic liver transplantation in patients with end-stage liver disease continue to improve. Refinements in surgical techniques represent an important part of this improvement.Materials and MethodsWith the advent of split-liver and living-donor liver transplantation, inferior vena cava (IVC) preservation transitioned from being a potential option to being mandatory for many cases. Preserving the IVC can be a demanding technical maneuver in many liver transplants and several different approaches have been developed. When utilizing IVC preservation, there are several options for implantation of the graft. The piggyback technique, when feasible, is considered safe and provides hemodynamic stability for the recipient.Results and DiscussionIn some cases it may be difficult to perform the piggyback technique if intense inflammatory adhesions and severe significant collateral circulation exist between the IVC and the posterior segments of the liver. In these cases, the retro-hepatic dissection can be carried out with a different approach: the infrahepatic vena cava and the confluence of the three hepatic veins can be cross-clamped en-bloc without dissection.ConclusionThis technique broadens the transplant surgeons’ armamentarium and can be used in the setting of a very difficult retro-hepatic dissection. It is safe, and allows a shorter anhepatic phase with caval preservation.