Primary Immunosuppressive Therapy Research Articles

Plasmacytic hyperplasia—the early form of posttransplant lymphoproliferative disorder—with atypical morphology and clinical course in patient after liver transplantation: a case report

This case report describes an early lesion of posttransplant lymphoproliferative disorder (PLTD)—plasmacytic hyperplasia with atypical morphology. The 54-year-old patient was 4 months after liver transplantation due to alcoholic cirrhosis. The postoperative course had been uneventful without graft rejection episodes. Primary immunosuppressive therapy included tacrolimus and prednisone. On admission to the hospital the patient showed rapidly increasing jaundice, hepatomegaly, anemia, thrombocytopenia, and significant leukocytosis. A biopsy suggested generalized infection. Acute Epstein-Barr virus (EBV) infection was confirmed using serological methods. Despite treatment the patient died. On autopsy we found features of generalized infection. Histological examination of the enlarged lymph nodes showed plasmacytic hyperplasia despite lymph node atrophy. Plasmacytic hyperplasia, an early lesion of PTLD despite usually a good prognosis with multifactor therapy may display a rapid course that leads to death through intensified immunosuppression. In accordance with other reports we confirmed reactivation of EBV infection as the probable cause of plasmacytic hyperplasia. The lymph node morphology of plasmacytic hyperplasia may be atypical with atrophy of lymphoid components accompanying plasma cell proliferation.

Pediatric Post‐Transplant Diabetes: Data From a Large Cohort of Pediatric Heart‐Transplant Recipients

A retrospective analysis of 381 pediatric heart‐transplant recipients was performed to determine the frequency, characteristics, and risk factors for post‐transplant diabetes. The rate of post‐transplant diabetes was 1.8% with antithymocyte globulin, cyclosporine and azathioprine as primary immunosuppressive therapy. Time from transplant to diabetes was 0.25–13 years. Diabetes was characterized by reversibility, and lack of insulinopenia and autoimmunity. The post‐transplant diabetes rate in tacrolimus‐converted children (n = 45) was 8.8%. In tacrolimus‐converted children, age at transplant, mean and maximum tacrolimus blood levels, and first‐year rejection episodes were higher in the post‐transplant diabetes group, which also consistently had DR‐mismatched transplants and HLA DR3/DR4 haplotypes. Body mass index was not different between diabetic and control tacrolimus‐converted children. In conclusion, pediatric post‐transplant diabetes may be related to reversible insulin resistance. Tacrolimus levels, HLA DR mismatch, and older age at transplant may predispose to post‐transplant diabetes.

Calcineurin inhibitor-induced chronic nephrotoxicity in liver transplant patients is reversible using rapamycin as the primary immunosuppressive agent.

The purpose of this study was to determine whether calcineurin inhibitor (CNI)-induced chronic nephrotoxicity in liver transplant patients is reversible by replacement of the CNI with rapamycin as the primary immunosuppressive agent. CNIs, while providing potent immunosuppression for liver transplant patients, exhibit nephrotoxicity as a major side-effect. Whereas acute CNI-induced nephrotoxicity is reversible by withdrawal of the CNI, chronic nephrotoxicity due to CNIs is a progressive process thought to be irreversible. Eight liver transplant patients with CNI-induced chronic nephrotoxicity were converted to rapamycin as the primary immunosuppressive agent. The CNI was either discontinued (four patients) or the dosage lowered to maintain a subtherapeutic level (four patients). Renal function as assessed by serum creatinine was measured before and after conversion to rapamycin. Two patients progressed to dialysis dependence following conversion to rapamycin. These two patients had been on CNIs for a mean of 112 months (range 93-131 months) prior to conversion to rapamycin. Five patients experienced improvement in renal function. These patients had been on calcineurin inhibitors for a mean of 60 months (range 42-75 months) prior to conversion. One patient with chronic nephrolithiasis as a contributing factor to his renal dysfunction has progressed to dialysis dependence despite conversion to rapamycin following exposure to a CNI for 24 months. In the five patients with improved renal function, serum creatinine levels decreased significantly (2.4 +/- 0.3 mg/dL to 1.5 +/- 0.1 mg/dL, p < 0.05) by a mean of 7.2 months (range 5-10 months) after conversion from CNI to rapamycin-based immunosuppression. Liver function remained stable after conversion to rapamycin. CNI-induced chronic nephrotoxicity can be reversed upon withdrawal of the CNI. Rapamycin is an effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant patients with CNI-induced chronic nephrotoxicity.

Virus associated glomerulonephritis

Virus associated glomerulonephritis is considered to be a para- or post-infectious autoimmune phenomena. The disease is mediated by immune complexes which usually contain the viral antigen. Virus associated glomerulonephritis due to chronic viral infection with hepatitis B or C virus, or with human immunodeficiency virus (HIV) shows a typical histomorphological picture for each virus. Hepatitis B virus usually leads to a membranous glomerulonephritis, while hepatitis C virus is associated with a membranoproliferative glomerulonephritis due to cryoglobulins, and HIV is associated with a focal segmental sclerosing glomerulonephritis. Knowledge of the relationship between the primary viral infection and secondary glomerulonephritis is important, as a primary immunosuppressive therapy might lead to more severe viral disease. On the other hand, a primary reduction in the viral load due to antiviral therapy with immunostimulants or inhibitors of viral replication could lead to an amelioration of the secondary glomerulonephritis.

Tacrolimus is superior to cyclosporine in liver transplantation

WITH the addition of cyclosporine (CyA) to azathioprine and corticosteroids in the early 1980s, rejection rates were decreased and graft survival and patient survival rates were dramatically increased in liver allograft recipients. While CyA-based regimens became the standard for orthotopic liver transplant (OLT) recipients, issues such as the frequency and severity of acute and chronic rejection, steroid-induced adverse effects, and outcomes in pediatric liver transplants remained problematic. Tacrolimus (TAC) was approved by the Food and Drug Administration (FDA) in 1994 for primary immunosuppressive therapy in adult and pediatric OLT recipients. In animal models, TAC inhibited both T-cell-mediated immune, and to a lesser extent, humoral immune responses (B-cell proliferation). When compared to CyA, TAC appears to be 10 to 100 times more potent in its ability to inhibit interleukin-2 (IL-2). On the molecular level, TAC, once bound to its intracellular binding protein (FKBP), is believed to form a drug-isomerase complex with calcineurin and reduce its phosphatase activity. As a result, translocation of the nuclear factor of activated T cells (NF-AT) is prevented which ultimately results in a reduction of the transcription of IL-2. By limiting IL-2 transcription, TAC inhibits the proliferation of helper, cytotoxic T lymphocytes, and natural killer cells, which ultimately can be responsible for graft loss. The premise of the present position is that TAC is superior to CyA in liver transplantation. To validate this hypothesis, the following points will be demonstrated based on an analysis of the results of randomized controlled trials involving over 1000 patients in whom TAC was compared to CyA as the primary immunosuppressive therapy in liver transplantation and of several open-labeled trials enrolling up to 1500 patients. Data from these studies confirm the following advantages of TAC over CyA in liver transplant recipients: (1) TAC usage decreases acute rejection rates versus CyA (from 65% in CyA-treated patients to 56% in TAC-treated patients; P 5 .0001) and improves outcome; (2) use of TAC spares corticosteroid dose (cumulative prednisone dosages were significantly lower [P 5 .003] over 3 years in TAC-treated patients vs CyA-treated patients, with CyA patients receiving a mean of 25 mg/kg more steroid than TAC-treated patients) and reduces OKT3 usage (19% vs 36% in adults; 21% vs 32% in pediatric patients); (3) TAC is superior in preventing and treating chronic rejection (1.5% in TAC-treated patients vs 5.3% in CyA-treated patients; P 5 .032); (4) TAC use results in an improved 5-year patient and graft survival compared to CyA in patients transplanted with hepatitis C (78.9% and 73.7% vs 60.5% and 58.7%, respectively); (5) TAC is well tolerated over the long term; (6) TAC-based regimens improve cardiovascular risk profile; (7) TAC-based regimens improve long-term patient (80% vs 73%, respectively; P 5 .02) and graft survival (76% vs 68%, respectively; P 5 .04); (8) TAC demonstrates superior patient and graft half-lives compared to CyA-based regimens (25.1 6 5.1 and 20.6 6 4.0 vs 15.2 6 2.5 and 15.7 6 2.7 years, respectively); and of significant importance (10) TAC use results in improved outcomes in pediatric OLT recipients. Thus, the current data provide compelling evidence that TAC is the drug of choice in OLT recipients. TAC is superior to CyA in reducing acute rejection rates and improving outcome, as demonstrated by the US and European multicenter trials. In these trials involving over 1000 OLT recipients, A Kaplan-Meier estimate of the incidence of acute rejection at 1 year shows a marked reduction from 65% in CyA-treated patients to 56% in TAC-treated patients (P 5 .0001). The importance of achieving freedom from acute rejection cannot be underestimated. In fact, freedom from acute rejection is strongly associated with long-term patient and graft survival. As shown in Fig 1, TAC-treated patients who were free from early rejection had significantly better survival at 3 years compared to CyA-treated patients (80% vs 68%; P 5 .004). A similar advantage in graft survival was observed in the TAC group with a 3-year graft survival rate of 73% versus 61% for CyA (P 5 .007). In addition to decreasing acute rejection and improving outcome, another advantage of TAC is that it is steroid sparing and decreases the need for OKT3. For instance, in the European multicenter liver study, cumulative pred-

Tacrolimus as a Primary Immunosuppressive Therapy in Cadaveric Renal Transplantation: Five Years’ Experience at a Single Center

Tacrolimus as a Primary Immunosuppressive Therapy in Cadaveric Renal Transplantation: Five Years’ Experience at a Single Center

FK 506 as Primary Immunosuppressive Therapy in Renal Transplantation

FK 506 as Primary Immunosuppressive Therapy in Renal Transplantation

TACROLIMUS AND RETRANSPLANTATION: EQUIVALENT RESULTS TO PRIMARY RENAL TRANSPLANTATION

660 The role of FK506 for kidney retransplantation is unclear. We retrospectively examined our experience with retransplantation from 1/94 through 5/97 to examine the role of tacrolimus on outcome following kidney transplantation. Renal transplant recipients were divided into three groups: nonprimary transplants receiving FK506 (n=57) and nonprimary transplants receiving CSA (n=69). The results were compared to primary renal transplants performed during the same time period (n=566). Demographic variables were similar except for higher PRA and fewer living donor transplants in the retransplantation groups. All patients received lymphocyte induction: primary transplants ATG; retransplants OKT3. Patient survival was similar for primary and both retransplantation groups. One-year graft survival for retransplant patients with FK506 was 91% vs 83% of retransplant patients receiving CSA (p=0.08). The FK506 treatment group had equivalent survival to the primary transplant group (91% 1-year survival). Most of the benefit was in retransplants from living donors with a 1-year graft survival of 94% for FK506 retransplants, 80% for CSA retransplants, and 96% for primary transplants (p=0.002). For cadaver recipients, patients retransplanted with FK506 had a 1-year graft survival which was superior but not statistically significantly better than primary and retransplants with CSA. Patients retransplanted with FK506 had significantly less rejection. At 6 months, the rejection incidence was 25% for FK506 retransplants, 47% for CSA retransplants, and 34% for primary transplants (p=0.02). Similarly, steroid resistant rejection was lower in FK506 treated patients (p=0.03). Despite more potent immunosuppression, there was no increased incidence of opportunistic infection with FK506. Graft loss due to rejection was uncommon for all three groups. Acute or chronic rejection resulted in 1 graft loss for FK506 retransplants (1.8%), 6 CSA retransplants (8.6%), and 16 primary transplants (2.9%). The incidence of posttransplant diabetes mellitus was 3% in all three groups. This study demonstrates that the use of FK506 as primary immunosuppressive therapy for retransplant recipients results in graft survival which is equivalent to primary transplants. The incidence of rejection was also significantly less than primary or retransplant recipients receiving CSA.

A randomized, double-blind study of Neoral vs. Sandimmune in primary liver transplant recipients with two year follow up.

46 A double-blind, multi-center, randomized, two-year trial was conducted to compare the Neoral formulation (NEO) of cyclosporine to the traditional Sandimmune formulation (SIM) in de novo liver transplant patients.Aim: The primary purpose of the study was to assess the safety of NEO relative to SIM. Methods: 325 patients from 15 centers were randomized(1:1) and received either NEO (n=161) or SIM (n=164) as primary immunosuppressive therapy. Following initial IV cyclosporine therapy, patients were started on oral cyclosporine at 10 mg/kg/day and dose titrated to target trough levels according to study protocol. Steroid and azathiprine were administred according to local protocol. No antilymphocyte preparations were used for induction. Frequent study visits to assess vital sign, laboratory values and other safety and efficacy parameters were scheduled at specified intervals. Key endpoints being patient and graft survival, acute cellular rejection episodes (ACR) and adverse event profiles. Patients who discontinued from study medication were asked to participate in a follow-up phaseof data collection to complete the two years duration of the study: These data were used for an ITT analysis. Results: Key patient demographics were comparable between the two groups. One and two year patient survival rates also did not differ between groups, (Actual 1yr patient SR = NEO 93.6%vs SIM 90.8%. Retransplantation with in 1 year: N -6.5% vs S- 6.8%. Actual 2 yr patient SR was identical N- 84.2% vs S-86.6%. Retransplantation by the end of the second year occurred in N- 9.3% vs S-7.7% (p=ns). The number of patients experiencing biopsy-confirmed ACR was comparable in the two groups - NEO = 98(62.7%) vs. SIM = 94 (59.1%), with the severity of the rejection and the incidence of steroid resistant rejection (18.5% for NEO and 20.0% for SIM) also being comparable. The incidence of major adverse events, i.e., hypertension, hyperlipidemia, renal insufficiency, infections, and neurologic symptoms were also comparable for the two groups. Patients randomized to the NEO group were weaned off cyclosporine I.V. more rapidly, median days 6 vs 7(p =0.02). Patients discontinued from study medications during the follow-up period totaled 129, 66 in the NEO group vs. 63 in the SIM group; primary reasons for discontinuations were adverse events including patient death,(N-14% vs. S-13%). Discontinuation for treatment failurewasN- 15.5% vs. S-15.8%. Mean cyclosporine doses after 24 months in study were 3.7 ±1.7 vs. 3.9 ± 2.1 mg/kg/day and trough cyclosporine levels 202 ± 95 vs. 213 ± 101 ng/mL for the NEO and SIM groups respectively.Conclusion: Excellent patient and graft survival were seen in both NEO and SIM treatments arms, with less IV. cyclosporine use in the NEO treated group. This is as good or better than any other liver recipient patient and graft survival published to date. In spite of the greater exposure provided by the NEO formulation, there were no more adverse events in the NEO group.

Neoral in de novo liver transplantation: Adequate immunosuppression without intravenous cyclosporine

Absorption of cyclosporine from the traditional oral formulation Sandimmune (Novartis Pharma, Basel, Switzerland) is particularly unpredictable in the early stages after liver transplantation. The absorption of cyclosporine is influenced by liver function, postoperative paralytic ileus, and graft dysfunction. Oral absorption of cyclosporine from Sandimmune is also bile dependent; cholestasis and external biliary drainage are associated with low cyclosporine absorption. Postoperative administration of intravenous Sandimmune is therefore often necessary to obtain adequate immunosuppression, despite the increased risk of renal and neurological toxicity. A microemulsion formulation of cyclosporine, Neoral (Novartis), has been developed to overcome the problems of poor and variable absorption of cyclosporine from Sandimmune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine. (Liver Transpl Surg 1997 Nov;3(6):571-7)

Neoral in de novo liver transplantation: adequate immunosuppression without intravenous cyclosporine.

Absorption of cyclosporine from the traditional oral formulation Sandimmune (Novartis Pharma, Basel, Switzerland) is particularly unpredictable in the early stages after liver transplantation. The absorption of cyclosporine is influenced by liver function, postoperative paralytic ileus, and graft dysfunction. Oral absorption of cyclosporine from Sandimmune is also bile dependent; cholestasis and external biliary drainage are associated with low cyclosporine absorption. Postoperative administration of intravenous Sandimmune is therefore often necessary to obtain adequate immunosuppression, despite the increased risk of renal and neurological toxicity. A microemulsion formulation of cyclosporine, Neoral (Novartis), has been developed to overcome the problems of poor and variable absorption of cyclosporine from Sandimmune. Uptake of cyclosporine from Neoral is rapid and less dependent on bile secretion so that higher peak concentrations are reached and absorption is less variable than with Sandimmune. A review of several open studies in which Neoral was administered to liver transplant patients immediately after transplantation is presented. The results suggest that the use of Neoral as a primary immunosuppressive therapy provides adequate cyclosporine trough levels, minimizing or obviating the need for intravenous cyclosporine administration. In addition, Neoral appears to reduce the risk of acute rejection episodes compared with immunosuppressive regimens involving intravenous cyclosporine.

Tacrolimus: a new immunosuppressive agent

The mechanism of action, pharmacokinetics, drug interactions, clinical efficacy, and adverse effects of tacrolimus, a newly approved immunosuppressant drug for use in the prophylaxis of organ rejection after transplantation, are reviewed. Tacrolimus prevents rejection of the transplanted organ by inhibiting the expression of interleukin-2 in T cells and inhibiting T-cell growth and proliferation. Bioavailability after oral administration is 5-67%, and the half-life is 4-41 hours. Tacrolimus is extensively metabolized by cytochrome P-450 3A4 isoenzyme, resulting in several known drug interactions. Most experience with tacrolimus has been at one institution, where clinical trials have been conducted in liver, kidney, heart, lung, and intestinal transplantation. Clinical trials have shown that tacrolimus is an effective alternative to cyclosporine for both primary immunosuppression and rescue therapy in liver transplant patients. Fewer reports have been published regarding tacrolimus use in other types of transplantation, but the results show that tacrolimus may be a useful alternative to cyclosporine. The major adverse effects of tacrolimus therapy are nephrotoxicity and neurotoxicity. Tacrolimus is an effective alternative to cyclosporine as a primary immunosuppressant in the prevention of organ rejection and may reduce the incidence of rejection after organ transplantation.

A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14%) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67%. In children with congenital heart disease (> 6 months of age) the perioperative (30 day) mortality was 66% before mid-1988 (n = 10) and 0% since mid-1988 (n = 11). The late mortality (> 30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66% (n = 14) and 7% since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82% in children with congenital heart disease and 90% in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82% at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60% at 3 and 6 months after transplantation versus 20% and 12%, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83%) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4% in the FK 506 group versus 70% in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression.

SELECTIVE SPARING OF SUPPRESSOR CELLS GENERATED IN MIXED LYMPHOCYTE RESPONSE BY AN ANTI-INTERLEUKINN-2 RECEPTOR ANTIBODY

Recent investigations have shown that anti-IL-2 receptor antibodies can prolong cardiac allograft survival in animal models and can be used effectively as primary immunosuppressive therapy in human renal transplantation. While previous studies have established that helper and cytotoxic T cells require IL-2 for proliferation, the role of this lymphokine in suppressor cell development is uncertain. We therefore studied the effects of SA36.6G (a monoclonal antibody directed at the 55 kD chain of the high-affinity IL-2 receptor) on events occurring in the mixed lymphocyte reaction. As expected, when added at culture initiation, SA36.6G inhibited both the proliferative response to allogeneic stimulation, and the generation of cytotoxic T cells. These effects were not the result of altered growth kinetics. In contrast, the generation of suppressor cells with a polymorphic pattern of specificity was not blocked by SA36.6G. Cultures containing SA36.6G had decreased numbers of activated lymphoblasts, but among this activated cell population the proportion of 2H4+ cells was doubled (53 +/- 13% vs. 27 +/- 9%). SA36.6G also blocked the appearance of IL-2 receptors on activated cells as determined by flow cytometry. This relative sparing of suppressor cells by an anti-IL-2 receptor antibody suggests that these cells may either exhibit IL-2 independent proliferation, or utilize an IL-2 receptor not recognized by SA36.6G.