Bettina J. Steffen

Differential Effects of Donor Age in Liver Transplant Recipients Infected With Hepatitis B, Hepatitis C and Without Viral Hepatitis

The variable impact of specific risk factors on survival outcomes based on pre‐transplantation diagnosis was analyzed in adult liver transplant recipients reported to the Scientific Registry of Transplant Recipients: 778 with hepatitis B (HBV), 3463 with hepatitis C (HCV) and 7429 without viral hepatitis. Graft and patient survival for the HBV and no viral hepatitis groups did not differ significantly. The HCV group had significantly lower graft (p = 0.0019) and patient survival (p < 0.0001) than the no viral hepatitis group. Patient survival was significantly lower (p = 0.0011) for HCV compared to HBV patients; differences in graft survival approached significance (p = 0.0561). Donor age, which was not a risk factor in patients with HBV, was the strongest predictor of graft loss and death in patients with HCV, starting with donors >40 years. Donor age >60 years was the strongest predictor of graft loss and death in patients without viral hepatitis. The risks of graft loss and death were reduced for patients on tacrolimus‐based immunosuppression with mycophenolate mofetil, regardless of disease etiology. There are clear differences in risk factors for poor outcomes based on underlying liver disease, particularly with regard to the impact of donor age.

Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration.

Background. To evaluate the association of long-term continuous mycophenolate mofetil (MMF) versus azathioprine (AZA) therapy and renal allograft function, as measured by the slope of reciprocal creatinine, we analyzed 49,666 primary renal allograft recipients reported to the United States Renal Data System between October 31, 1988 and June 30, 1998. Methods. The primary study endpoint was defined as a greater than 20% decrease below a 6-month baseline of 1/serum creatinine (SCr) (slope of reciprocal creatinine) at or beyond 1 year after transplantation. A secondary endpoint was defined as reaching an SCr value greater than 1.6 mg/dL. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. Multivariate analyses were corrected for potential confounding covariates. Results. According to the Cox proportional hazard model, 12-month continued therapy of MMF versus AZA was associated with a protective effect against declining renal function, as measured by the slope of reciprocal creatinine (relative risk [RR]=0.84, confidence interval 0.78–0.91, P <0.001). For 24-month continued therapy of MMF versus AZA, MMF was associated with a further decreased risk for a decline in renal function (RR=0.66, confidence interval=0.57–0.77, P <0.001). Furthermore, MMF was associated with a protective effect against reaching the SCr threshold of 1.6 mg/dL (RR=0.80, P <0.001) beyond 12 months posttransplantation. Conclusions. Continuous use of MMF versus AZA was associated with a protective effect against declining renal function beyond 1 year after transplantation. Further study is needed to confirm that continued MMF therapy is protective against long-term deterioration in renal function.

Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C.

To evaluate the impact of mycophenolate mofetil (MMF) on long‐term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single‐organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus‐based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.

Long-Term Use of Mycophenolate Mofetil is Associated With a Reduction in the Incidence and Risk of Late Rejection

To evaluate the association of long‐term continuous (minimum 1 year) mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of late acute rejection, we analyzed 47 693 primary renal allograft recipients reported to the United States Renal Data System between 1988 and 1998.

Sirolimus with neoral versus mycophenolate mofetil with neoral is associated with decreased renal allograft survival.

To evaluate the association between a regimen of cyclosporine microemulsion (CsA) + sirolimus (Rapa) treatment versus CsA and mycophenolate mofetil (MMF) and renal allograft survival, we analyzed 23 016 primary recipients reported to the Scientific Registry of Transplant Recipients between January 1, 1998 and July 26, 2003.

Mycophenolate mofetil vs. azathioprine is associated with decreased acute rejection, late acute rejection, and risk for cardiovascular death in renal transplant recipients with pre‐transplant diabetes

Abstract:  Outcomes specifically in mycophenolate mofetil (MMF)‐treated diabetic renal transplant patients have not been previously reported. This study compared acute rejection (AR), late acute rejection (LAR), patient survival [and specifically death from cardiovascular (CV), infectious and malignant causes], incidence of post‐transplant malignancies, and graft loss in MMF‐ or azathioprine (AZA)‐treated renal transplant patients with pre‐transplant diabetes. Outcomes were compared between MMF‐ (n = 14 144) and AZA‐ (n = 3001) treated diabetic patients using the Scientific Registry of Transplant Recipients data on all U.S. adult renal transplants performed between 1995 and 2002. Statistical analyses included Kaplan–Meier survival analysis, Cox multivariable regression and chi‐square tests. MMF patients had less AR compared with AZA‐treated patients (23.5% vs. 28.3%, p < 0.001) and less risk for LAR over 4 yr [hazard ratio (HR): 0.64, 95% CI 0.44, 0.92; p = 0.02]. While time to any‐cause death did not differ between the groups, MMF treatment was associated with a 20% decreased risk of CV death (HR: 0.80, 95% CI 0.67, 0.97; p = 0.020) compared with AZA treatment. MMF patients also had a lower incidence of malignancies than AZA patients (2.2% vs. 3.7%, p < 0.001). These results suggest treatment with MMF compared with treatment with AZA in diabetic transplant patients is associated with less AR, less risk of LAR, a decreased risk of CV death, and a lower incidence of malignancies.

Mycophenolate Mofetil Use Is Associated with Decreased Risk of Late Acute Rejection in Adult Liver Transplant Recipients

Mycophenolate mofetil (MMF) used in a triple‐drug regimen has been shown to decrease acute rejection rates, compared to a double‐drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described.

Addition of MMF to dual immunosuppression does not increase the risk of malignant short-term death after liver transplantation

Immunosuppression is often incriminated for the increased risk of post‐transplant malignancies. To examine whether triple‐ (MMF+Tacro+CS) versus dual‐drug therapy (Tacro+CS) is associated with an increased incidence of malignancy, or death due to malignancy, data from a large registry of liver transplant recipients were analyzed. Data from adult primary liver recipients reported to the Scientific Registry of Transplant Recipients between June 1, 1995, and April 30, 2004, and recorded at transplant on triple‐drug (n = 9180) or dual‐drug (n = 10 099) therapy were included. Kaplan‐Meier survival analysis showed no significant differences in death due to malignancy 4 years post‐transplantation between the treatment groups. Multivariable analysis using Cox proportional hazard models confirmed no differences in risk of death due to malignancy between the groups (HR: 0.83, p = 0.107). Incidence of any post‐transplant malignancy was also not significantly different. Older recipient age and cause of liver disease were significantly associated with an increased risk of malignancy‐related death. These data utilizing relatively short follow‐up suggest the addition of MMF to Tacro+CS at transplant is not associated with death due to malignancy, at least in the short term. Individual recipient factors appear to be important risk factors for malignancy‐related death; elucidating these risk factors can assist in identifying who should be monitored most aggressively for post‐transplant malignancies.

Daclizumab is associated with decreased rejection and improved patient survival in renal transplant recipients

Abstract:  The present study investigated the safety of induction therapy with daclizumab (compared with no induction treatment), in adult renal transplant patients reported to the Scientific Registry of Transplant Recipients (SRTR) database between January 1, 1998 and July 27, 2003. Patients who were discharged from the hospital on mycophenolate mofetil, azathioprine, or sirolimus were divided into two groups: induction treatment with daclizumab (n = 8203) and no induction treatment (n = 25,368). Patient survival, death due to infection and death due to malignancy were evaluated at 1 and 3 yr post‐transplantation. Rejection and graft survival were also examined. Kaplan–Meier and Cox regression models were used to evaluate outcomes. No significant differences were found between patients treated with daclizumab compared with patients who received no induction therapy for death due to infection or malignancy at 1 and 3 yr post‐transplantation. Patients treated with daclizumab (compared with no induction treatment) had statistically significantly better survival rates at 1 (96.9% vs. 96.2%, p = 0.003) and 3 yr (92.4% vs. 91.4%, p = 0.004) although absolute differences were minimal. This was confirmed in the multivariable Cox regression analysis for patient death at 1 (HR = 0.77, p < 0.001) and 3 yr (HR = 0.83, p = 0.001) post‐transplantation. Patients treated with daclizumab compared to no induction had lower rejection rates at 1 (13.1% vs. 17.3%, p < 0.001) and 3 yr post‐transplantation (16.7% vs. 21.3%, p < 0.001). Cox regression confirmed a decreased risk for rejection at 1 (HR = 0.74, p < 0.001) and 3 yr (HR = 0.75, p < 0.001). Treatment with daclizumab was associated with reduced risk for graft loss at 1 (HR = 0.82, p < 0.001) and 3 years (HR = 0.86, p < 0.001). In conclusion, daclizumab was associated with a significantly reduced risk for rejection and graft loss compared with no induction treatment, and improved patient survival. In addition, daclizumab was not associated with an increase in risk of death due to infection or malignancy, when compared with no induction therapy. These findings demonstrate the short and long‐term safety and efficacy of daclizumab in patients transplanted between January 1998 and July 2003.