Tacrolimus-based Immunosuppressive Regimen Research Articles

Comparison of single bolus ATG and Basiliximab as induction therapy in presensitized renal allograft recipients receiving tacrolimus-based immunosuppressive regimen

Presensitized renal allograft recipients require special management to improve their outcome, and there is no consensus on the optimal immunosuppressive strategy. We retrospectively analyzed clinical data of 82 patients, who were PRA positive pre-transplant (above 10%) and received single bolus ATG and basiliximab as induction therapy, and assessed safety and efficacy of two kinds of induction therapies. Patients of ATG group (n=40) received single bolus ATG (Fresenius, 9 mg/kg preoperatively) and those of basiliximab group (n=42) were given two doses of basiliximab (Simulect, Novartis, 20 mg) on days 0 and 4 post-transplant. All patients received standard triple immunosuppressive therapy with tacrolimus (FK-506), mycophenolate mofetil (MMF), and steroids. The follow-up time was 12 months. There was no hyperacute rejection in two groups, and delayed graft function occurred in two patients of ATG group and three of basiliximab group. After 12-month follow-up, more acute rejection (AR) episodes were observed in basiliximab group than ATG group (35.7% vs. 15%, P=0.032). Although highly significant differences were observed between ATG group and basiliximab group with respect to the incidence of thrombocytopenia (P=0.001), single bolus ATG was well tolerated. Incidences of other adverse events and infection episodes did not differ between two groups (P>0.05). One-year patient and graft survival was 95%, 92.5% and 95.2%, 88.1% in ATG and basiliximab group respectively (P>0.05). Both single bolus ATG and basiliximab induction therapy achieved similar one-year graft/patient survival. However, single bolus ATG yielded much lower AR rate than basiliximab without increase in infection episodes and severe adverse events.

Liver Transplantation in Greek Patients: Epidemiological Data, Morbidity, and Mortality of 71 Patients from a Single Center With 6 Years of Mean Follow-up

Liver transplantation remains an underdeveloped technique in Greece; currently there is no information on outcomes in Greek patients. In this study, data were provided on the outcomes of liver transplantation in 71 patients with a mean follow-up of 6 (0.1 to 16) years in our center. Mean age at transplantation was 46 ± 13 years, while the main cause for transplantation was hepatitis B (16 patients, 23%) or C (six patients, 8%) virus. In the first posttransplantation year, three patients died, while 18 (25%) required at least one hospitalization with a median stay of 30 days. At the end of follow-up, 56 patients (79%) are alive. The leading cause of death was de novo malignancies (40%), appearing at a mean of 5.2 ± 3.3 years. Late adverse effects of immunosuppressive therapy included hypertension (42%), hyperlipidemia (24%), chronic renal failure (21%), and diabetes mellitus (24%). With the exception of diabetes, all the above abnormalities were significantly associated with cyclosporine-based but not with tacrolimus-based immunosuppressive regimens. Relapse of primary disease in liver transplants occurred in 21 (29.6%) patients at a mean time of 1.5 ± 1.4 years, of whom 67% were related to viral hepatitis. The quality of life (Karnofsky scale 1 to 6) was excellent in 64% of surviving patients, affordable in 21%, and poor in 15%. In conclusion, after 6 mean years, the majority of Greek liver transplant recipients conduct a normal life, although metabolic abnormalities are often observed. A national registry is needed to provide more solid evidence of outcomes.

Late Mortality from Thrombotic Microangiopathy After Liver Transplantation: Report of a Case

Thrombotic microangiopathy (TMA) after liver transplantation is thought to be a rare event. We report a case of TMA after living donor liver transplantation for hepatitis C virus-related cirrhosis. The patient was initially placed on a tacrolimus-based immunosuppressive regimen, and received combined ribavirin and interferon treatment as pre-emptive therapy for hepatitis C virus. His post-transplantation course was complicated by cytomegalovirus (CMV) antigenemia, and intra-abdominal hemorrhage after percutaneous liver biopsy, necessitating laparotomy. On postoperative day (POD) 53, we noted a marked thrombocytopenia with a sudden rise in lactate dehydrogenase. Blood smear indicated prominent fractionated erythrocytes. Treatment included immediate conversion from tacrolimus to cyclosporine (CsA) and successive plasma exchange (PE), despite which the TMA progressed. CsA was discontinued 32 days after initiating the PE, and the TMA progression seemed to cease. However, the patient's condition deteriorated and he died of multiple organ failure on POD 119. We report this case to stress that careful management of calcineurin inhibitor administration is critical in TMA.

Anti-IL2 Induction in Liver Transplantation with 93% Rejection-Free Patient and Graft Survival at 18 Months

Induction with the use of monoclonal antibodies targeting the alpha-chain (CD25) of the high-affinity IL2 receptor may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLT). Forty-two consecutive deceased donor primary OLT were retrospectively analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after OLT) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels), and steroids (methylprednisolone 1 g intraoperatively followed by tapering doses). Mycophenolate mofetil (MMF) 1 g every 12 h was added to the drug combination as needed. The mean follow-up period was 19.3 months (range: 4.8-35.9 months). The average Model for End-Stage Liver Disease score was 26 (range: 15-40). A total of 39 patients (93%) remained rejection-free during follow-up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 2 years was 93%. Twenty-five patients (60%) were completely off steroids within 3 months post-OLT (mean: 51.1 days, range: 10-90 days). By the 10th month post-OLT, 30/39 (77%) of the patients were completely off steroids. At last follow-up, 30/39 (77%) are on tacrolimus monotherapy with an average dose of 4 mg per day. Six patients (15%) are on double therapy, receiving a combination of tacrolimus and prednisone (two patients) or tacrolimus and MMF (two patients) or tacrolimus and mycophenolic acid (two patients). Only three patients (8%) are receiving triple therapy at last follow-up. Nine patients (21%) experienced at least one episode of infection. Only six (26%) of a total of 23 hepatitis C virus (HCV) recipients developed histology-proven HCV recurrence, with a mean onset of recurrence post-OLT of 3.2 months (range: 1.3-6.3 months). Of these six patients, two are presently undergoing treatment with interferon and ribavirin, one was treated and became HCV RNA negative, one was not treated, one declined treatment, and two died of HCV recurrence. None of the 42 study patients developed cytomegalovirus infection or posttransplant lymphoproliferative disease. These preliminary data suggest that basiliximab, given in combination with a tacrolimus-based immunosuppressive regimen, is safe and associated with a low incidence of acute rejection and excellent short-term rejection-free graft and patient survival rate after OLT.

Dual, triple, and quadruple oral tacrolimus-based immunosuppression regimens after orthotopic liver transplantation: a randomised comparative study of regimens

To investigate the effects of tacrolimus-based immunosuppression regimens after orthotopic liver transplantation and search a reasonable regimen of combination therapy and suitable blood concentration of tacrolimus. Ninety-four adult recipients of cadaveric livers were randomly divided into 3 groups to undergo different tacrolimus-based immunosuppression regimens: dual (tacrolimus + glucocorticoid), triple [tacrolimus + mycophenolate mofetil (MMF) + glucocorticoid]; quadruple [tacrolimus + MMF + glucocorticoid in addition of induction treatment by daclizumab]. The efficacy and safety of the 3 groups 6 months after the transplantation were compared. The frequencies of acute rejection were 25.9%, 11.1%, and 7.5% for the dual, triple, and quadruple therapy groups, that of the quadruple therapy group being significantly lower than that of the dual therapy group (P = 0.038). There were no significant differences in the rates Three months after transplantation, the levels of ALT and total cholesterol of the dual therapy groups were significantly higher than those of the quadruple therapy group (P(ALT) = 0.011, P(Tch) = 0.002). Within the first month post-operatively the concentration of tacrolimus of the triple therapy group could be controlled at the level 8 ng x ml(-1)-13 ng x ml(-1). Quadruple tacrolimus-based immunosuppression regimen is the most effective and safest, followed by the triple therapy and dual therapy. Low-dose tacrolimus combination therapy provides an effective protection to the liver graft with mild drug toxicity to the patient.

Basiliximab Induction in Adult Liver Transplant Recipients With 93% Rejection-Free Patient and Graft Survival at 24 Months

Induction with the use of interleukin-2 receptor monoclonal antibodies may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLTx). We describe our experience with the use of basiliximab induction therapy in adult OLTx recipients on tacrolimus-based immunosuppression. Forty-six consecutive deceased donor primary OLTx were analyzed. All patients received standard doses of basiliximab, tacrolimus, and steroids. Mycophenolate mofetil was also used as indicated. The mean follow-up period was 17.9 months. Forty-three patients remained rejection-free during follow-up. The actuarial patient and graft survival rate at 2 years was 93%. The rate of histology-proven hepatitis C virus (HCV) recurrence was 24%, with two progressing to severe cholestatic recurrent HCV. None of the study patients developed (cytomegalovirus (CMV) infection or posttransplant lymphoproliferative disease (PTLD). Results were compared to a historical group of 46 OLTx recipients on tacrolimus-based immunosuppression without basiliximab induction. The historical group had a rejection rate of 34% with lower patient and graft survival rates of 71.74% and 69.5%, respectively, at 24 months as well as a higher histological HCV recurrence rate of 77% (17/22), with three patients progressing to graft failure within 2 years. CMV infection and disease developed in 4.5% of the patients. Although PTLD was not observed, three recipients with hepatocellular carcinoma (HCC) developed and died of metastatic HCC. Induction with basiliximab in combination with tacrolimus-based immunosuppressive regimen reduces the incidence of rejection and improves rejection-free survival rate after OLTx without increasing the incidence of CMV, PTLD, or HCV recurrence.

41 Renal Transplant Surveillance Biopsy Results in Children Receiving Steroid Free Immunosuppression

Introduction: Interstitial fibrosis (IF) is frequently present in renal biopsy specimens obtained from transplant recipients who receive tacrolimus (TAC) and prednisone as maintenance immunosuppression, especially in those in whom the associated trough TAC levels are elevated. In contrast, little information exists on the kidney histology of patients on a steroid free (SF) immunosuppression regimen. The role that the exposure to TAC [trough levels or area under the curve (AUC)] has on biopsy findings remains poorly defined.Aims: To report the 6 month renal transplant surveillance biopsy results of patients receiving SF immunosuppression. The relationship between TAC usage and the biopsy findings was also investigated.Methods: Medical records from 14 pediatric renal transplant recipients who received a maintenance immunosuppression regimen consisting of TAC & mycophenolate mofetil were reviewed for age at time of transplant, gender, ethnicity, donor type, cold ischemia time, TAC dose and trough level and estimated GFR at time of biopsy. TAC AUC was assessed in 7 patients. Data is presented as mean (±SD). Results: Of the 14 patients (mean age: 11.8±5.23 yrs), 10/14 (71%) were caucasian, 9/14 (64%) were male, and 10/14 (71%) received a living related donor transplant, with a cold ischemia time of 7.66±8 hrs. Surveillance biopsies were performed at a mean time of 200.92±33.3 days post transplantation. Serum creatinine at the time of biopsy was 0.94±0.46 mg/dl with a Schwartz estimated GFR of 86.88±34.29 ml/min/1.73 m2. TAC dose at time of biopsy was 0.17±0.25 mg/kg/day and the associated trough level was 6.36±1.52 ng/ml. In the 7 patients who had done TAC pharmacokinetics, the mean C0 was 6.75±1.28 ng/ml and AUC 110.8±32.37 [h × (ng/ml)]. Based on the Banff ‘97 working classification of renal allograft pathology, interstitial fibrosis (IF) involved a mean 17.3±7.66% of the biopsy specimen and was present in 10/14 (71%) biopsies. There was no correlation found between trough TAC level and % IF. A mean of 18.75±3.77 % IF was found in those who had TAC pharmacokinetics performed.Conclusion: IF is frequently found in “well-functioning” renal transplants as early as 6 months post transplant in association with a SF, TAC based immunosuppression regimen in children. The potential correlation between transplant histology, trough TAC levels and TAC pharmacokinetics requires further study in a larger number of patients.

Steroid-Free Immunosuppression in Kidney Transplant Recipients and Prograf Monotherapy: An Interim Analysis of a Prospective Multicenter Trial

This report described an interim analysis of a investigator-driven multicenter trial in renal transplant recipients: the Prospective Quality of life Renal Transplantation Switch Study; Tacrolimus-based immunosuppression (“PQRST study”). Patients included in the trial initially treated with cyclosporine-based immunosuppression after renal transplantation who experienced side effects, such as hypertension, hyperlipidemia, hypertrichosis, or other adverse reactions, were converted to a tacrolimus-based immunosuppressive regimen ( n = 31). Steroids were subsequently discontinued between 3 and 6 months after the conversion. As of today 19/31 (50%) patients have been successfully weaned off steroids with the remaining patients in this process. In this interim analysis, with a follow-up ranging from 1 to 18 months both patient and graft survivals were 100%. No patient experienced an acute rejection episode; none of the grafts were lost. Blood pressure decreased in 22/31 (71%) of the patients. No patient developed de novo diabetes or other serious side effect related to the conversion. Three patients were withdrawn from the trial because of side effects: bleeding, depression, and proteinuria. However, none of these adverse events were felt to be directly related to the change of the immunosuppressive regimen to tacrolimus monotherapy. In conclusion, conversion from cyclosporine to tacrolimus-based therapy was safe and well tolerated; it may improve the cardiovascular risk profile after kidney transplantation.

Orlistat treatment is safe in overweight and obese liver transplant recipients: a prospective, open label trial

Obesity is a frequent complication following liver transplantation and is insufficiently responsive to dietary and life style advice. We studied the safety of orlistat treatment in obese and overweight liver transplant recipients (n = 15) on a stable tacrolimus-based immunosuppressive regimen. For safety reasons, the treatment period was restricted (6 months 120 mg t.i.d., 3 months 120 mg daily). Three patients dropped out, tacrolimus dose was adjusted in six of 12 remaining patients (dose reduction in 4, increase in 2, P = N.S.). All dose adjustments occurred during the 6 months of orlistat 120 mg t.i.d. therapy. No drug intolerance, adverse events or episodes of rejection occurred during the study. Efficacy of orlistat treatment in this population could not be shown, because a formal control population was not included in this safety trial. Moreover, only a significant decrease of waist circumference (P < 0.01 versus start of the study), but not of weight or body mass index, was achieved in the treated group. Orlistat treatment is well tolerated in liver transplant recipients and can be started safely, provided immunosuppressive drug levels and dietary adherence are closely monitored.

Untreated Rejection in 6-Month Protocol Biopsies Is Not Associated with Fibrosis in Serial Biopsies or with Loss of Graft Function

Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased- and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve-controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (rtau = -0.26; P = 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.

Antibody Response to Cryptococcus neoformans Capsular Polysaccharide Glucuronoxylomannan in Patients after Solid-Organ Transplantation

Cryptococcosis is an important complication of solid-organ transplantation, but the risk factors for disease are poorly understood. The goal of this study was to investigate whether specific or nonspecific serum immunoglobulin levels determined in samples obtained before and after solid-organ transplantation differed in patients who did or did not develop cryptococcosis after transplantation. We analyzed pretransplantation sera from 25 subjects, 15 who subsequently developed cryptococcosis and 10 who did not, and posttransplantation sera from 24 subjects, 13 who developed cryptococcosis and 11 who did not. All subjects received a tacrolimus-based immunosuppressive regimen. Total immunoglobulin levels were measured by immunodiffusion, and Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM)-specific serum antibody levels were determined by enzyme-linked immunosorbent assays. The results showed that solid-organ transplantation had a significant effect on total immunoglobulin and GXM-reactive antibody levels. GXM-reactive antibody levels differed in subjects who did and did not develop cryptococcosis. In pretransplant serum samples, the levels of GXM-reactive immunoglobulin M (IgM) were significantly lower in subjects who developed cryptococcosis after transplantation than in those who did not. For posttransplant serum samples, the levels of GXM-reactive IgM and IgG were significantly higher among the subjects who developed cryptococcosis than among those who did not. These findings suggest that perturbations in the preexisting antibody or B-cell repertoire and/or related to treatment of rejection, transplantation, or immunosuppressive therapy could translate into an increased risk for transplant-associated cryptococcosis.

Anti-IL2 induction in liver trasplantation with 93% rejection free and 97% patient and graft survival at 24 months

Background. Induction with the use of monoclonal antibodies targeting the alpha chain (CD25) of the high affinity IL2 receptor may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in liver transplantation (OLTx). Methods. Forty-two consecutive deceased donor primary OLTx were prospectively analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after OLTx) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/ml target trough levels), mycophenolate mofetil 1 gm every 12 hours and steroids (methylprednisolone 1 gm intraoperatively followed by tapering doses). The mean follow up period was 12.5 months (range: 1-26 months). Results. The average MELD score was 26 (range15-40). A total of 39 patients (93%) remained rejection-free during follow up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 2 years was 97%. Twenty-two patients (52%) became steroid-free within 100 days post-OLTx (mean: 54 days, range: 10-100 days). By the 10th month post-OLTx, 64% of the patients were steroid-free. Seventeen patients (40%) are only on tacrolimus with an average dose of 4 mg per day. Nineteen patients (45%) are on double-therapy receiving tacrolimus and prednisone (8 patients) or tacrolimus and mycophenolate mofetil (3 patients) or tacrolimus and mycophenolic acid (8 patients). Only five patients (12%) are receiving triple therapy at last follow-up. Nine patients (21%) experienced at least one episode of infection. Only six (26%) out of a total of 23 HCV recipients developed histologic HCV recurrence, with a mean onset of recurrence post-OLTx of 98 days (range: 39-188 days). Out of these 6 patients, 2 are presently undergoing treatment with interferon and ribavirin, 1 was treated and became HCV RNA negative, 1 was not treated, 1 declined treatment, and 1 died of HCV recurrence (the only death of this series). None of the 42 study patients developed CMV infection nor PTLD. Conclusions. Induction with basiliximab, in combination with tacrolimus-based immunosuppressive regimen reduces the incidence of acute rejection and improves rejection-free survival rate after OLTx, without increasing the incidence of CMV, PTLD nor HCV recurrence. The low HCV recurrence rate observed in this series could be attributed to the steroid sparing strategy used with basiliximab induction, and the modulatory effect of basiliximab on serum IL2 receptor concentrations, which correlates with the degree of histologic HCV recurrence.

Impaired erythropoietin production in liver transplant recipients: The role of calcineurin inhibitors

Anemia is common following liver transplantation. Because cyclosporine inhibits erythropoietin (Epo) production in experimental models, we investigated whether Epo production was impaired in liver transplant recipients receiving a cyclosporine- or tacrolimus-based immunosuppressive regimen. First, serum Epo levels were measured before and 1 year after transplantation in 35 liver transplant recipients. Second, serum Epo levels were compared in a large series of liver transplant recipients with stable graft and renal functions: 27 receiving a cyclosporine-based and 31 receiving a tacrolimus-based immunosuppressive regimen. A reference group was made up of 22 blood donors and 21 nontransplanted subjects with iron-deficiency anemia. Serum Epo levels were significantly lower after than before liver transplantation, especially in cyclosporine-treated patients. Serum Epo concentrations correlated with hematocrit values in both transplant recipients and control subjects. Using multiple linear regression models, the polynomial relationship between hematocrit and serum Epo values was similar to the control group in patients under tacrolimus, whereas Epo production was significantly reduced in patients under cyclosporine-based immunosuppression. Hematocrit values and the type of calcineurin inhibitor were the only parameters independently related to Epo levels. In conclusion, cyclosporine, but not tacrolimus, inhibits Epo production at the doses used in clinical practice.

Initial Experience with ABO-incompatible Live Donor Renal Transplantation

The serious shortage of cadaveric organs has prompted the development of ABO-incompatible live donor renal transplantation. We report our experience of the initial two live donor ABO incompatible renal transplants at our hospital. The first patient was a 55-year-old type A female who received a kidney from her AB type husband. The second patient was a 27-year-old type O male who received renal transplantation from his type A father. Preconditioning immunosuppressive therapy in the two patients with tacrolimus, mycophenolate mofetil and methylprednisolone was started 7 days before transplantation. During the period of preconditioning, double filtration plasmapheresis (DFPP) was employed to remove anti-A and -B antibodies. Laparoscopic splenectomy and renal transplantation were performed after the anti-donor ABO antibodies were reduced to a titer of 1:4. Rituximab, a humanized monoclonal anti-CD20 antibody, was administered to the second patient due to a rebound in the anti-A antibody titer during the preconditioning period. Under a tacrolimus-based immunosuppressive regimen, both patients recovered very well without any evidence of rejection. Serum creatinine levels were 1.0 and 1.4 mg/dL at 6 and 3 months after transplantation, respectively. These cases illustrate that with new immunosuppressive agents, DFPP and splenectomy, ABO-incompatible renal transplantation can be successfully conducted in end-stage renal disease patients whose only available live donors are blood group incompatible.

Influence of Cyclosporine and Tacrolimus on Serum Uric Acid Levels in Stable Kidney Transplant Recipients

Although hyperuricemia is a well-known adverse effect of cyclosporine (CsA) treatment, there are contradictory data regarding the effect of tacrolimus on uric acid levels. The aim of this study was to examine the influences of CsA and tacrolimus–based treatment regimens on serum uric acid levels in 155 renal transplant recipients with normal allograft function who underwent renal transplantation between 1999 and 2002. Serum uric acid levels were recorded at 1, 6, 12, 18, and 24 months follow-up. The patients were treated with CsA-based (n = 73), tacrolimus-based (n = 47), or conversion from CsA-based to tacrolimus-based (n = 35) immunosuppressive regimens. Serum uric acid levels for patients in the CsA and tacrolimus groups were 6.3 ± 1.6 versus 7.9 ± 1.9 mg/dL and 6.5 ± 1.8 versus 8.0 ± 1.8 mg/dL at the study outset and 24 months, respectively. Both of the treatment regimens showed progressively increasing serum uric acid levels ( P < .001). Serum uric acid levels of patients with treatment conversion from CsA to tacrolimus were 8.6 ± 2.8 mg/dL before conversion and 8.1 ± 1.9 mg/dL after conversion. There was no alteration in serum uric acid levels after the change of treatment ( P > .05). These findings indicate that, compared with CsA, tacrolimus offers no advantage for serum uric acid levels in renal transplant recipients.

Use of Hepatitis B Core Antibody–Positive Liver Allograft in Hepatitis C Virus–Positive and –Negative Recipients With Use of Short Course of Hepatitis B Immunoglobulin and Lamivudine

Introduction With the shortage of donor organs, increasing number of hepatitis B core antibody (HBcAb)–positive [HBcAb(+)] liver allografts are being used for liver transplantation (LTx) in patients who are HBcab-negative [HBsAb(−)]. This study was aimed at assessing outcomes for hepatitis C virus (HCV)-positive [HCV(+)] and HCV-negative [HCV(−)] patients who received HBcAb(+) liver grafts from deceased donors and also received a short course of hepatitis B immunoglobulin (HBIg) with long-term lamivudine therapy after LTx. Materials and methods From February 1995 through February 2003, 28 patients (mean age 53.8 ± 10.2 years, 19 men and nine women, 16 HCV[−]; 12 HCV[+]) received HbcAb(+) liver allografts. All recipients received a short course of HBIg prophylaxis (10,000 units/day for 4 days) and long-term lamivudine 100 mg/d after LTx in addition to a tacrolimus-based immunosuppressive regimen. Results Seven (25%) of the 28 recipients died during follow-up and three recipients required retransplantation. Three recipients (10.7%) developed HBV infection during follow-up, one of whom died 36 months after LTx and the other two had YMDD mutant HBV. The overall 6-year actuarial patient survival after transplantation was 74.4% and those for HCV(−) and HCV(+) recipients were 81.3% and 66.6%, respectively ( P = .46). The overall 6-year actuarial graft survival was 63.9% and those for HCV(+) and HCV(−) recipients were 68.8% and 57.1%, respectively ( P = .6). Conclusion We conclude that HBcAb(+) liver grafts can be used for both HCV(+) patients and HCV(−) patients who are critically ill, have early hepatocellular carcinoma, or have been exposed to HBV in the past. A short course of HBIg-lamivudine combination therapy provides effective prophylaxis against HBV infection in 89% of recipients of HBcAb(+) grafts.

Quadruple immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil and prednisone is safe and effective for renal transplantation

Recent immunosuppression with tacrolimus and mycophenolate mofetil has improved the results of renal transplantation. In this study, we analyzed the effect and safety of basiliximab as an induction therapy. Forty-nine kidney recipients were given tacrolimus, mycophenolate mofetil and prednisone (non-Bas group), and 31 recipients were given basiliximab as an induction therapy in addition to the triple immunosuppressants (Bas group). Graft function, incidence of acute rejection (AR), findings of protocol graft biopsy and adverse effects were compared. Serum creatinine within 1 yr post-transplant was comparable between the two groups. Incidence of biopsy-proven AR within 6 months post-transplant was less in the Bas group than in the non-Bas group. Borderline change at 3 months post-transplant was less in the Bas group when compared to the non-Bas group. The frequency and severity of tubulitis were higher in the non-Bas group than in the Bas group. The addition of basiliximab did not increase opportunistic infection, but reduced tacrolimus nephrotoxicity. The addition of basiliximab to the tacrolimus-based triple immunosuppressive regimen enabled us to reduce the doses of immunosuppressants and tacrolimus nephrotoxicity without increasing early rejection or infection. This regimen is safe and effective for application during the early period after renal transplantation.

Steroid Withdrawal or Steroid Avoidance in Renal Transplant Recipients: Focus on Tacrolimus-Based Immunosuppressive Regimens

Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.

Outcome of renal transplants from pediatric donors &lt;5 yr of age

Outcomes of single renal transplants from donors <5 yr old have traditionally been inferior to those from older donors. We retrospectively studied our experience with patients who received renal transplants, either individually or en bloc, from young donors (<5 yr of age) to determine the utility of these organs. We also compared the outcomes of these transplant patients maintained on either cyclosporine- (CyA) or tacrolimus-based (TRL) immunosuppression regimens. Ninety-eight patients received transplants at our center from donors <5 yr of age between August 1993 and August 2003. They were followed-up from 12 months to 11 yr. Patients were divided into four groups based on whether they received single or en bloc transplants, and whether CyA or TRL was the base immunosuppressive agent. Patients in group I (n = 13) received single pediatric kidneys and were treated with CyA regimens; group II patients (n = 26) also received single pediatric kidneys, but were treated with TRL regimens; group III patients (n = 31) were transplanted en bloc and were treated with CyA; and group IV patients (n = 28) received en bloc transplants and were treated with TRL. One-year patient and death-censored graft survival was not significantly different between recipients of en bloc vs. single grafts (i.e. 88 and 85% vs. 90 and 87%, respectively), or between the four treatment groups (group I: 85 and 85%, group II: 92 and 88%, group III: 87 and 84%, and group IV: 89 and 86%, respectively). The overall 1-yr rejection rate was 30% (29 of 98), which was significantly higher in the CyA-treated patients 19 of 44; i.e. 43%, than in TRL-treated patients 10 of 54, i.e. 19%, p = 0.03). In the en bloc recipients, seven grafts (12%) were lost as a result of vascular thrombosis. Notably, none of the single kidneys were lost because of vascular thrombosis. At the end of follow-up the creatinine levels of both groups were comparable. Pediatric donor kidneys transplanted individually provide for equal patient and graft survival when compared with en bloc transplants. TRL can be used reduce the detrimental effect of acute rejection on graft growth and function when compared with CyA. Single use of such kidneys can safely and efficaciously be transplanted into adult recipients, greatly expanding the donor pool.

A Prospective, Randomized, Multicenter, Double-Blind Study of Early Corticosteroid Cessation Versus Long-Term Maintenance of Corticosteroid Therapy With Tacrolimus and Mycophenolate Mofetil in Primary Renal Transplant Recipients: One Year Report

This report summarizes year 1 blinded data from a 5-year prospective, randomized (1:1, stratified by race and donor type), multicenter, double-blind study comparing treatment failure rates between early cessation of corticosteroid therapy and long-term corticosteroid maintenance therapy in 397 primary renal transplant recipients receiving tacrolimus and mycophenolate mofetil with antibody induction. Sixteen (4.1%) patients died or experienced graft loss during year 1 (9 deaths, 6 graft losses, and 1 death with a graft loss). Fifty-nine (15.3%) patients experienced rejection; 40 (10.4%) of these cases were biopsy-confirmed. Values for 10-year predictive risk of coronary heart disease (CHD) estimated from the Framingham Heart Study scores showed a shift from baseline toward a more favorable risk profile. Renal transplant recipients treated with a tacrolimus-based immunosuppressive regimen and either early cessation or maintenance of corticosteroid therapy experienced excellent patient and graft survival, low acute rejection rates, low rate of posttransplantation diabetes mellitus (9.0%), and improved CHD risk profile at 1 year posttransplantation.