Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.     

Effects of sirolimus vs. calcineurin inhibitors on renal dysfunction after orthotopic liver transplantation

Small uncontrolled series have suggested that sirolimus favorably impacts renal function after orthotopic liver transplantation (OLT). We sought to retrospectively compare renal dysfunction between cohorts exposed to sirolimus-based and calcineurin inhibitor-based immunosuppression. We retrospectively studied 79 patients converted to sirolimus-based immunosuppression and 100 control subjects continued on calcineurin inhibitor-based immunosuppression after OLT at our institution from 2000 to 2005. We collected clinical, demographic, and medication history. Renal dysfunction was defined as two or more wk of creatinine > or =2.0 mg/dL. Cohorts were compared using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Patients began sirolimus a median 83 d post-OLT and were followed on the medication for median 359 d. Patients in both the sirolimus and calcineurin inhibitor cohorts had median creatinine 1.2 mg/dL at study entry. Sirolimus-based immunosuppression was associated with a 1.8 (0.8-4.3, p = 0.17) hazards ratio for renal dysfunction. Adjusting for presence of hepatocellular carcinoma, combined kidney/liver transplantation, and age, the hazards ratio was 2.0 (0.8-4.8, p = 0.13). These point estimates were not substantially altered after subgroup analysis of sirolimus as the lone immunosuppressant, duration of exposure, and time between OLT and sirolimus conversion. In conclusion, our retrospective, controlled study showed that conversion to sirolimus after OLT did not protect against renal dysfunction. The effect of sirolimus on renal function will need to be prospectively evaluated in a prospective, randomized trial.     

Immunosuppression for liver transplantation in HCV-infected patients: mechanism-based principles.

We retrospectively analyzed 42 hepatitis C virus (HCV)-infected patients who underwent cadaveric liver transplantation under two strategies of immunosuppression: (1) daily tacrolimus (TAC) throughout and an initial cycle of high-dose prednisone (PRED) with subsequent gradual steroid weaning, or (2) intraoperative antithymocyte globulin (ATG) and daily TAC that was later space weaned. After 36 +/- 4 months, patient and graft survival in the first group was 18/19 (94.7%) with no examples of clinically serious HCV recurrence. In the second group, the three-year patient survival was 12/23 (52%), and graft survival was 9/23 (39%); accelerated recurrent hepatitis was the principal cause of the poor results. The data were interpreted in the context of a recently proposed immunologic paradigm that is equally applicable to transplantation and viral immunity. In the framework of this paradigm, the disparate hepatitis outcomes reflected different equilibria reached under the two immunosuppression regimens between the relative kinetics of viral distribution (systemically and in the liver) and the slowly recovering HCV-specific T-cell response. As a corollary, the aims of treatment of the HCV-infected liver recipients should be to predict, monitor, and equilibrate beneficial balances between virus distribution and the absence of an immunopathologic antiviral T-cell response. In this view, favorable equilibria were accomplished in the nonweaned group of patients but not in the weaned group. In conclusion, since the anti-HCV response is unleashed when immunosuppression is weaned, treatment protocols that minimize disease recurrence in HCV-infected allograft recipients must balance the desire to reduce immunosuppression or induce allotolerance with the need to prevent antiviral immunopathology.     

Experience with daclizumab in liver transplantation: renal transplant dosing without calcineurin inhibitors is insufficient to prevent acute rejection in liver transplantation

BACKGROUND: Daclizumab is a monoclonal antibody directed against the alpha chain of the interleukin 2 receptor. We review our experience with the use of daclizumab in liver transplant recipients. METHODS: Thirty-two patients were given daclizumab as induction therapy in the setting of hepatic transplantation. Seven of these patients were enrolled in a pilot study to determine the efficacy of daclizumab in conjunction with corticosteroids and mycophenolate mofetil without the initial use of calcineurin inhibitors (CI). The remaining 25 patients received daclizumab, mycophenolate mofetil, and steroids, with the institution of CI generally within the first postoperative week. The majority of these patients (n = 17) had some degree of renal insufficiency. RESULTS: The pilot study was halted after the first seven patients were enrolled because of an unacceptably high rate of rejection (7/7 = 100%). The patients outside of this pilot study, however, had a much lower rate of rejection (36%). The incidence and severity of rejection correlated with the delay in institution of CI. The described dosing schedule resulted in subtherapeutic daclizumab levels in liver transplant recipients. CONCLUSIONS: Daclizumab used in liver transplant recipients without any CI was ineffective and can potentially lead to steroid-resistant rejection. The dosing regimen used in renal transplant recipients is most likely insufficient for liver transplant patients. However, daclizumab can be used safely in patients with preexisting or postoperative renal dysfunction in conjunction with low doses of CI given within the first week postoperatively.     

Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation.

The appropriate time point for starting immunosuppressive treatment with calcineurin inhibitors after orthotopic liver transplantation (OLT) has been a subject of debate. The aim of the study was to analyze the effects of anti-thymocyte globulin (ATG) induction therapy on rejection, renal function, infection, tumor rate, and survival. We retrospectively analyzed 391 patients after OLT who had either received calcineurin inhibitors immediately after OLT (n = 129) or after an initial short-term Thymoglobulin induction therapy (n = 262). The 1-year acute rejection rate was 14.5% vs. 31.8% in favor of ATG (P = 0.0008). Rejection grades and the need for treatment also differed significantly (7.3% vs. 23.3%; P = 0.001). Serum creatinine at transplantation was similar in both groups (1.14 mg/dL vs.1.18 mg/dL; P = NS). Postoperative hemofiltration was less frequently seen after induction therapy (P < 0.05). Reduced renal function at 1 year was commonly observed, but serum creatinine (1.26 mg/dL vs. 1.37mg/dL; P = 0.015) and glomerular filtration rate (81 mL/min vs. 75 mL/min; P = 0.02) were far better in the ATG group. Undesired side effects occurred at a similar rate in both groups. Five-year patient survival was also similar in the 2 groups (70.1% and 74.3%; P > 0.05). Short-term ATG induction therapy with delayed administration of calcineurin inhibitors led to a more favorable rejection rate and an improved clinical course in case of a rejection episode. It has beneficial effects on renal function immediately after OLT as well as later, and no additional harmful effects.     

Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 micromol/L and <300 micromol/L. Patients were randomized in 2 groups. Study group: combination of MMF (2 to 3 g/day) and reduced dose of CNI >or=50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 +/- 24.2 micromol/L at day 0 to 143.4 +/- 19 micromol/L at month 12 and a significant increase in creatinine clearance, from 42.6 +/- 10.9 mL/min to 51.7 +/- 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 +/- 23.4 micromol/L at day 0 to 181.6 +/- 63 micromol/L at month 12, and in creatinine clearance, from 42.8 +/- 12.8 mL/min to 44.8 +/- 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects.     

Long-term renal function after liver transplantation is related to calcineurin inhibitors blood levels

BACKGROUND: Renal dysfunction is common after liver transplantation (LT). The aim of our study was to assess the prevalence of renal dysfunction 5 yr after LT and to identify risk factors for the development of this complication. PATIENTS AND METHODS: A total of 134 adult patients underwent LT from 1987 to 1998 and 74.6% of them were alive 5 yr after. Pre-LT, 1 and 5 yr post-LT renal function were calculated by Cockroft and modification of diet in renal disease (MDRD) formula. Since 1987 glomerular filtration rate (GFR) has been measured by radiolabeled tracers clearance (RTC). Risk factors for GFR < 50 mL/min were analyzed using a multivariate logistic regression model. RESULTS: Mean pre-LT GFR was 79 and 85 mL/min with Cockroft and MDRD respectively; 11% of the patients had a GFR or= 150 microg/L or tacrolimus (FK) >or= 10 microg/L at 1 yr and CyA >or= 100 microg/L or FK >or= 8 microg/L at 5 yr. CONCLUSION: 5 yr after LT, patients have lost 26% of their initial GFR and 25% of them have a GFR < 50 mL/min. This complication is predicted by high levels of calcineurin inhibitors (CNI). Therefore CNI levels should be reduced as low as possible and use of alternative drugs should be considered.     

Immunosuppression without calcineurin inhibition: optimization of renal function in expanded criteria donor renal transplantation

Abstract: Introduction: To assess the efficacy of calcineurin inhibitor (CNI)‐free immunosuppression vs. calcineurin‐based immunosuppression in patients receiving expanded criteria donor (ECD) kidneys. Patient and methods: Thirteen recipients of ECD kidneys were enrolled in this pilot study and treated with induction therapy and maintained on sirolimus, mycophenolate mofetil (MMF) and prednisone. A contemporaneous control group was randomly selected comprised of 13 recipients of ECD kidneys who had been maintained on CNI plus MMF and prednisone. Results: For the study group vs. the control group, two‐yr graft survival was 92.3% vs. 84.6% (p = NS), two‐yr patient survival was 100% vs. 92.3% (p = NS) and the acute rejection rates were 23% vs. 31% (p = NS), respectively. Renal function was significantly better in the study group compared with control up to the six‐month mark, after which, it remained numerically but not statistically significant. Complications were more common in the study group, but serious adverse events requiring discontinuation were rare. Conclusion: This pilot study demonstrates that CNI‐free regimens can be safely implemented in patients receiving ECD kidneys with excellent two‐yr patient and graft survival and good renal allograft function. Longer follow‐up in larger randomized controlled trials are necessary to establish these findings.     

Cerebellar ataxia in a patient receiving calcineurin inhibitors after living donor liver transplantation: a case report

Neurological complications of calcineurin inhibitors are frequent problems after transplantation. Cerebellar ataxia with other neurological findings and an abnormal density area in the subcortical white matter are found by MRI in the brains of most patients with central nervous system complications caused by calcineurin inhibitors. Such neurological complications are not life-threatening, but have a negative impact on the quality of life. We describe a 58-year-old woman who developed cerebellar ataxia at 4 days after living donor liver transplantation. She walked with a swaying gait, and after walking for 5 minutes she was unable to stand. Her symptoms persisted after a change from tacrolimus to cyclosporine, but dose reduction of cyclosporine and addition of mycophenolate mofetil cured the ataxia. We diagnosed a case of cerebellar ataxia without leukoencephalopathy or other neurological symptoms, as a new complication of calcineurin inhibitor treatment. We concluded that careful attention should be paid to neurological complications of calcineurin inhibitors.     

Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

BACKGROUND: The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resuited in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. METHODS: Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2Ralpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 month and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy end-point was biopsy-proven rejection during the first 6 months posttransplant. RESULTS: Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 micromol/L (95%, confidence interval [CI], 100.7 to 125.3 micromol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 micromol/L (95% CI, 135.0 to 173.0 micromol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2Ralpha saturation. CONCLUSIONS: This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.     

Renal function after liver transplantation: calcineurin inhibitor nephrotoxicity

Renal failure, mainly due to calcineurin inhibitor (CNI) nephrotoxicity, is the most common complication following orthotopic liver transplantation (ltx). The aim of this study was to evaluate the incidence and course of renal failure in adult ltx patients. Severe acute renal failure in early postoperative period due to impaired hemodynamics and CNI nephrotoxicity, occurred in 14 patients, 3 of whom required dialysis. The creatinine clearance after ltx showed a tendency to decrease, but there was no statistically significant difference (P >.05) in the change in serum creatinine clearance levels between patients treated with tacrolimus (TAC) versus Cyclosporine (CsA) during the first 2 years of follow-up. Fourteen patients required conversion of their regimen because of CNI nephrotoxicity namely, dose reduction (n = 7) or discontinuation of CNI therapy with the replacement by mycophenolate mofetil (MMF) (n = 5) or SRL (n = 5). Dose reduction or CNI withdrawal significantly improved the creatinine clearance (P <.05) without affecting lives graft function. No episode of acute rejection was observed after conversion. Neither conversion of CsA to TAC nor the reverse maneuver significantly influenced the serum creatinine level (P >.05). Reduction of the CNI dose or CNI discontinuation or replacement with MMF or SRL in patients with stable liver but impaired renal function is safe, resulting in a significant improvement in renal function.     

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.