Belatacept for maintenance immunosuppression in cardiothoracic transplantation: The potential frontier.

Current immunosuppressive regimens with calcineurin inhibitors have improved the management of patients after transplantation. However, their adverse effects are linked to increased morbidity and limit the long-term survival of heart and lung transplant recipients. Belatacept, a costimulation inhibitor interfering with the interaction between CD28 on T cells and the B7 ligands on antigen presenting cells, has shown success and is currently approved for use in renal transplant recipients. Furthermore, it lacks many of the cardiovascular, metabolic, neurologic, and renal adverse of effects of calcineurin inhibitors that have the largest impact on long-term survival in cardiothoracic transplant. Additionally, it requires no therapeutic drug monitoring and is only administered once a month. Limitations to belatacept use have been observed that must be considered when comparing immunosuppression options. Despite this, maintenance immunosuppression with belatacept has the potential to improve outcomes in cardiothoracic transplant recipients, as it has with kidney transplant recipients. However, no large clinical trials investigating belatacept for maintenance immunosuppression in heart and lung transplant recipients exist. There is a large need for focused research of belatacept in cardiothoracic transplantation. Belatacept is a viable treatment option for maintenance immunosuppression, and it is reasonable to pursue more evidence in cardiothoracic transplant recipients.

Long-term dosing patterns of enteric-coated mycophenolate sodium or mycophenolate mofetil with tacrolimus after renal transplantation.

MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events.

Tacrolimus exposure in the real world: an analysis from the Mycophenolic acid Observational REnal transplant study.

Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (≥60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL.

A longitudinal assessment of adherence with immunosuppressive therapy following kidney transplantation from the Mycophenolic Acid Observational REnal Transplant (MORE) study.

BACKGROUND: Nonadherence with immunosuppressive therapy after renal transplantation is a major clinical concern, but longitudinal data are sparse. Adherence data were recorded during the Mycophenolic Acid Observational REnal Transplant (MORE) study to help inform compliance management decisions. MATERIAL AND METHODS: Prospective data were analyzed from the four-year, observational MORE study of de novo adult renal transplant recipients receiving mycophenolic acid (MPA) as enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at 40 US sites under routine management. Adherence was assessed using the Immunosuppressant Therapy Adherence Scale (ITAS): total score 0-12 (12, adherence; <12, nonadherence). A logistic regression model was used to identify factors associated with nonadherence. RESULTS: In total, 808/946 recipients (85.4%) provided ≥1 ITAS score. Nonadherence was reported by 24.8%, 31.5%, 33.0%, 39.8%, 35.4% and 26.4% at months 3, 6, 12, 24, 36 and 48, respectively. Mean ITAS score was higher with EC-MPS vs. MMF at months 24 (11.3[1.0] vs. 10.9[1.4], p=0.001) and 36 (11.4[1.0] vs. 11.1[11.3], p=0.024). The odds ratio for nonadherence was 1.60 (95% CI 1.17, 2.19; p=0.003) for African Americans vs. non-African Americans. The rate of biopsy-proven acute rejection was 12.7% (51/401) in nonadherent recipients vs. 11.3% (46/406) in adherent recipients (p=0.59); graft loss was 4.7% (19/402) vs. 3.0% (12/406) (p=0.20); death was 1.5% (6/402) vs. 4.7% (19/406) (p=0.013). CONCLUSIONS: Adherence to the immunosuppressive regimen decreases over time, highlighting the need to monitor and encourage adherence even in long-term maintenance kidney transplant patients. Other than African American race, demographic factors may be of limited value in predicting nonadherence.

Early corticosteroid withdrawal in the real world: a long-term analysis of kidney transplant recipients from the Mycophenolic Acid Observational Renal Transplant Registry.

BACKGROUND: Prospective, long-term data on corticosteroid withdrawal (CSW) versus corticosteroid continuation (CSC) following kidney transplantation are scarce. MATERIAL/METHODS: The Mycophenolic Renal Transplant (MORE) Registry was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA) and standard of care. Adult patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at time of transplant were analyzed to 4 years according to CSW by month 3 (n=363) or CSC (n=509). RESULTS: In the CSW and CSC groups, 3.3% and 13.0% had undergone retransplantation (p<0.001), 89.9% and 77.0% had panel reactive antibodies <30% (p<0.001), and 72.5% and 87.2% received pretransplant dialysis (p<0.001), respectively. Rabbit antithymocyte induction was used in 62.3% of CSW patients and 58.6% of CSC patients (p=0.015), and alemtuzumab in 23.7% and 4.7%, respectively (p=0.002). At all time points to 3 years post-transplant, significantly fewer CSW patients were maintained on the full recommended dose of MPA versus CSC patients. Biopsy-proven acute rejection occurred in 10.1% and 14.3% of CSW and CSC patients (p=0.12), graft survival was 96.9% versus 93.7% (p=0.030), and patient survival was 95.6% versus 95.0% (p=0.65), respectively. Adverse events were similar except for leukopenia (CSW 60.6%, CSC 29.9%; p<0.001) and neutropenia (CSW 17.4%, CSC 11.4%; p=0.013), with infections in 24.8% and 30.8% of CSW and CSC patients, respectively (p=0.057). CONCLUSIONS: CSW patients were less likely to receive the full dose of MPA than CSC patients, possibly due to induction-related hematological toxicity. Graft survival to 4 years post-transplant was superior in CSW patients.

Long-term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four-yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study.

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four-yr data on 904 patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non-AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non-AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC-MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non-AA patients. Biopsy-proven acute rejection was higher in AA vs. non-AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non-AA patients. Kidney allograft survival remains lower for AA vs. non-AA recipients even under the current standard of care.

Outcomes in ethnic minority renal transplant recipients receiving everolimus versus mycophenolate: comparative risk assessment results from a pooled analysis.

BACKGROUND: Everolimus (EVR) has demonstrated good efficacy after renal transplantation. Racial disparities in clinical outcomes after de novo renal transplantation are well documented; whether the efficacy of EVR varies based on recipient ethnicity is unknown. We conducted a comparative risk assessment of EVR by ethnicity. METHODS: Data on 2004 renal transplant recipients from three EVR studies were pooled to identify the impact of ethnicity on efficacy outcomes across EVR dosing groups and control groups. Ethnic groups compared were African Americans, non-U.S. blacks, Asians, Hispanics, and Caucasians. EVR groups received either 1.5 or 3 mg per day, with either standard-dose cyclosporine or reduced-dose cyclosporine. Control groups received mycophenolic acid (MPA) with standard-dose cyclosporine. Composite efficacy failure endpoint was graft loss, death, biopsy-proven acute rejection, or lost to follow-up. Adjusted odds ratios were calculated using a logistic regression model. RESULTS: The proportion of renal transplant recipients who met the composite endpoint was African Americans (46%), non-U.S. black (35%), Caucasian (31%), Hispanic (28%), and Asian (25%). The odds of meeting the composite endpoint were significantly (P=0.0001) greater for African Americans versus Caucasians but did not differ among the other ethnic groups (ethnic groups were only compared with Caucasians). EVR and MPA were associated with similar efficacy among each of the ethnic groups. CONCLUSION: In this pooled data analysis in more than 2000 renal transplant recipients, EVR versus MPA resulted in similar composite endpoint incidence events across ethnicities. Consistent with previously published data, African Americans had poorer clinical outcomes. EVR is efficacious regardless of ethnicity.

Outcomes in African American kidney transplant patients receiving tacrolimus and mycophenolic acid immunosuppression.

BACKGROUND: Prospective data regarding immunosuppression and rejection in African American patients receiving modern immunosuppressive regimens are sparse. METHODS: One-year data were analyzed from 901 tacrolimus-treated de novo kidney transplant patients in the prospective Mycophenolic Acid Observational Renal Transplant registry. RESULTS: Mean tacrolimus dose was significantly higher in African Americans (n=217) versus non-African Americans (n=684), but mean tacrolimus trough concentrations were similar. The proportion of patients receiving mycophenolic acid dose equal to or more than 2000 mg per day (mycophenolate mofetil equivalents) was significantly higher with enteric-coated mycophenolate sodium versus mycophenolate mofetil at month 6 among African Americans and at month 3 in non-African Americans, but rates of acute rejection and adverse events (including gastrointestinal events) were similar. The 1-year incidence of biopsy-proven acute rejection (BPAR) was 14.1% in African Americans versus 7.5% in non-African Americans. On multivariate analysis, African American ethnicity was associated with a higher risk of BPAR (hazard ratio, 1.93; 95% confidence interval, 1.19-3.09; P=0.007). Mean (standard deviation) glomerular filtration rate at month 12 estimated by the Chronic Kidney Disease Epidemiology Collaboration formula was 59.2 (22.2) mL/min/1.73 m in African Americans versus 58.8 (19.9) mL/min/1.73 m in non-African Americans (confidence interval of the difference, -3.4 to 4.3; P=0.83). CONCLUSION: This observational study confirms that African Americans require higher doses of tacrolimus to achieve target trough concentrations and are more likely to experience BPAR during the first year after kidney transplantation despite modern immunosuppression regimens. In our 1-year study, this was not associated with significantly inferior graft survival.

Association of mycophenolic acid dose with efficacy and safety events in kidney transplant patients receiving tacrolimus: an analysis of the Mycophenolic acid Observational REnal transplant registry.

BACKGROUND: Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking. METHODS: Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg). RESULTS: The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p=0.02]; month 12, 47.3% vs. 39.4% [p=0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose>2000 mg (p=0.029) vs. 2000 mg. CONCLUSIONS: These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined.

Mycophenolic acid in kidney transplant patients with diabetes mellitus: does the formulation matter?

Diabetes mellitus is frequent in kidney transplant recipients and is commonly associated with gastrointestinal (GI) complications. Delayed gastric emptying affects 30% to 50% of patients with type 1 or 2 diabetes and can influence oral drug absorption. Time-to-peak concentration of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) is longer in diabetic kidney transplant patients than patients without diabetes. By retaining gut contents in the stomach for longer, this could increase local GI toxicity in diabetic recipients due to an extended duration of exposure to MPA in the stomach. The enteric-coated mycophenolate sodium (EC-MPS) formulation delays the release of MPA until pH is higher than 5.5, such that absorption takes place more distally compared with MMF. Patient-reported outcomes data have been used to assess the effect of conversion to EC-MPS in maintenance kidney transplant patients with diabetes who were experiencing MMF-related GI symptoms. Results indicated that conversion leads to improved GI symptom burden despite higher MPA exposure under the EC-MPS regimen. Improved GI tolerance using EC-MPS has permitted maintenance of optimal MPA exposure in nondiabetic populations. Comparative trials to evaluate the GI symptom burden and maximum achieved MPA dosing using the EC-MPS and MMF formulations in de novo and maintenance diabetic kidney transplant recipients are merited.

Early steroid withdrawal in solitary pancreas transplantation results in equivalent graft and patient survival compared with maintenance steroid therapy.

Although steroid withdrawal in simultaneous kidney pancreas transplantation has been shown to be feasible, the results of early steroid withdrawal in immunologically solitary pancreas transplantation are not well known. This study evaluated an early steroid withdrawal protocol in this group. The results of steroid withdrawal at 21 d post-transplant in solitary pancreas transplant recipients was compared with a control group consisting of solitary pancreas transplant recipients maintained on steroids (MG). Additional immunosuppression consisted of rabbit anti-thymocyte globulin induction followed by tacrolimus and mycophenolate mofetil in both groups. The withdrawal group (WG, n = 22) consisted of 11 pancreas transplant alone (PTA), six pancreas after kidney (PAK), and five simultaneous cadaveric pancreas living kidney (SPLK) recipients. The steroid maintenance group (MG, n = 32) consisted of 8 PTA, 11 PAK, and 13 SPLK recipients. Recipient and donor demographic characteristics were similar. Seventy eight percent of MG patients had infection-related complications in the first year compared with 50% of the WG patients (p = 0.04). The one-yr rejection, pancreas graft, and patient survival rates were 27.3% 95.5%, and 100% in the WG, and 37.5%, 81.3%, and 93.8% in the MG respectively and not significantly different. We conclude that early corticosteroid withdrawal in isolated pancreas transplantation results in fewer infections and can be achieved without an increased risk of rejection or graft loss over the first year.

Daclizumab induction in solid organ transplantation.

Antibody induction therapy is used in solid organ transplantation to prevent rejection in the early postoperative period. It is especially useful in high-risk groups such as retransplants, patients with delayed graft function to delay the initiation of nephrotoxic calcineurin inhibitors (tacrolimus, cyclosporin), highly sensitised recipients and African-American recipients. Historically, antibody induction has been associated with a high incidence of adverse effects and a complicated administration regimen. Daclizumab is a monoclonal antibody that exerts its effect by binding to the alpha subunit (CD25) of the human interleukin (IL)-2 receptor on the surface of activated lymphocytes, thus preventing the binding of IL-2. It is used for induction therapy and is well-tolerated with easy administration. Although originally studied as a five-dose regimen, there is a growing accumulation of data that fewer doses (two or three) are efficacious and less costly for preventing rejection.

Should living-unrelated renal transplant recipients receive antibody induction? Results of a clinical experience trial.

BACKGROUND: Living-donor kidney transplant recipients generally do not receive antibody induction. Induction avoidance may not be appropriate, particularly for living-unrelated renal transplant (LURT) recipients, in whom matching may not be optimal. We compared the incidence of acute rejection and graft outcome of LURT recipients who were administered no induction and cadaveric renal transplant (CRT) recipients who were administered anti-CD25 antibody. These groups both had immediate graft function and similar maintenance immunosuppression. METHODS: This retrospective analysis included patients who received kidney transplants between 1999 and 2000. CRT recipients received basiliximab, corticosteroids, mycophenolate mofetil (MMF), and delayed tacrolimus (serum creatinine <3 mg/dL). LURT recipients received tacrolimus (initiated pretransplantation), MMF, and corticosteroids. RESULTS: The analysis included 136 LURT recipients and 126 CRT recipients. CRT recipients included more African Americans (52.4% vs. 30.9%, P<0.01). LURT recipients included more patients with at least one human leukocyte antigen mismatch (97.8% vs. 85.7%, P<0.01). A higher acute rejection rate was observed in LURT recipients at both 6 months (LURT recipients 19.1% vs. CRT recipients 3.2%, P<0.01) and 1 year (21.3% vs. 4.0%, P<0.0004); a higher rate also was observed in African American LURT recipients compared with African American CRT recipients (35.7% vs. 4.5%, P<0.0015) at 1 year. LURT recipients demonstrated a threefold greater rejection risk than CRT recipients who were administered basiliximab (relative risk: 3.6, P<0.002). Graft survival was similar at 1 year. CONCLUSION: The higher rejection rates in LURT recipients (no induction) compared with CRT recipients (basiliximab induction), despite similar chronic immunosuppression (tacrolimus, MMF, and steroids) and immediate graft function, indicate the potential advantage of anti-CD25 induction in LURT protocols to reduce the risk of acute rejection.

Clinical course of polyoma virus nephropathy in 67 renal transplant patients.

Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between June 1997 and March 2001, 67 patients with graft dysfunction were found to have biopsy-proven PVN. The diagnosis was made at a mean of 12.8 +/- 9.9 mo posttransplantation. The majority of patients were men (79%) with a mean age of 54 +/- 14 yr (range, 28 to 75). All patients received immunosuppression with a calcineurin inhibitor (tacrolimus in 89% of patients). All patients except two received mycophenolate mofetil and prednisone. After the diagnosis of PVN, maintenance immunosuppression was reduced in 52 patients and remained unchanged in 15 patients. After reduction of immunosuppression, eight patients (15.3%) developed acute rejection and six (11.5%) became negative for PV in biopsy and urine. After a mean observation period of 12.6 mo (mean of 26 mo posttransplantation), 16.4% of patients had lost their grafts (8 of 52 in the reduction group and 3 of 15 in the no change group). In comparison to a case-matched polyoma virus-negative control group, the PVN patients were older (P =.0004) and there was a predominance of men (P = 0.02). Kaplan-Meier analysis demonstrated that patients with PVN had reduced graft survival compared with negative controls (P =.0004). It is concluded that PVN is a serious hazard for renal transplant recipients and contributes directly to graft loss. Antiviral drugs are needed, as the reduction of immunosuppression alone may not significantly improve graft function in patients with already established PVN. Although multiple factors probably play a role in the development of PVN, judicious use of immunosuppressive agents is indicated to minimize the occurrence of this infection.