Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial.

BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial.

Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept-based CNIA/ESW regimens with a tacrolimus-based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti-thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease-calculated eGFR of <45 mL/min/1.73 m2 at 12 months. Results are reported by treatment group (alemtuzumab/belatacept, rATG/belatacept, and rATG/tacrolimus). Superiority was not observed at 1 year for the primary endpoint (9/107 [8.4%], 15/104 [14.4%], and 14/105 [13.3%], respectively; P = NS) for either belatacept-based regimen. Differences were not observed for secondary endpoints (death, death-censored graft loss, or estimated glomerular filtration rates < 45 mL/min/1.73 m2 ). Differences were observed in biopsy-proved acute cellular rejection (10.3%, 18.3%, and 1.9%, respectively) (P < .001), but not in antibody-mediated rejection, mixed acute rejection, or de novo donor-specific anti-HLA antibodies. Neurologic and electrolyte abnormality adverse events were less frequent under belatacept. Belatacept-based CNIA/ESW regimens did not prove to be superior for the primary or secondary endpoints. Belatacept-treated patients demonstrated an increase in biopsy-proved acute cellular rejection and reduced neurologic and metabolic adverse events. These results demonstrate that simultaneous CNIA/ESW is feasible without excessive acute rejection.

Effective arteriovenous fistula alternative for hemodialysis access.

BACKGROUND: The use of autologous arteriovenous fistulae (AVF) for hemodialysis (HD) is the gold standard; however, for many patients at tertiary referral centers, this is not an option. METHODS: We conducted a four year retrospective cohort study to evaluate HD access outcomes with AVF, bovine carotid artery (BCA), and polytetrafluoroethylene arteriovenous graft (PTFE). RESULTS: The study contained 416 AVF, 175 BCA, and 58 PTFE, N = 649. There was statistical difference between rates of infection (AVF 3.4%, BCA 2.9%, PTFE 11.9%), P = 0.02. Maturation failed in 7.5% of AVF but in none of the BCA or PTFE (P = 0.001). Accesses were abandoned with AVF (1.9%), BCA (1.5%), and PTFE (9.5%), P = 0.01. CONCLUSION: Bovine carotid artery can be an effective alternative form of HD access with lower infection, abandonment, and failure to maturation rates when autologous arteriovenous fistula is not an option.

Videoscopic basilic vein harvest for creation of transposed brachiobasilic arteriovenous fistulae.

INTRODUCTION: Due to the extensive dissection required during the standard transposed brachiobasilic arterial venous fistula (BB-AVF) procedure and the potential for postoperative complications, many surgeons are reluctant to construct BB-AVFs. Less invasive vein harvest has been performed for this procedure with good results, but this procedure remains rarely used. METHODS: We began to perform videoscopic-assisted BB-AVF creation in selected patients at our institution in 2006. Vein harvesting from the antecubital fossa to the level of the axilla is performed by an experienced surgical technician under the guidance of the dialysis access surgeon. Perioperative data and postoperative outcomes were retrospectively reviewed with institutional review board approval. RESULTS: From 2006 to 2010, we performed videoscopic-assisted BB-AVF in 21 patients. Median age was 59 years and median body mass index was 30; women comprised 52% of the cohort. Previous vascular access procedures had been performed on 81% of patients. Of the 21 attempts with the video-assisted approach, only 1 required conversion to a standard open procedure. Of the remaining cases, there were no significant intraoperative or postoperative surgical complications with a median operative time of 159 minutes and maximum length of stay of 1 night. Maturation of the fistula sufficient for cannulation and use occurred in 80% of patients, with the median time to first access in patients who matured being 60 days. At 3 years follow-up, 47% of fistulas that matured were still functional, with 33% lost to death or successful renal transplantation. CONCLUSION: Videoscopic-assisted transposition of the basilic vein is a reasonable option for BB-AVF placement. The procedure can be performed in an acceptable expeditious fashion with near elimination of infection, wound breakdown, lymph drainage, nerve injury, and satisfactory maturation (80%) and patency rates. Technicians experienced in lower extremity vein harvest can perform this procedure successfully under the supervision of an experienced access surgeon.

Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation.

Nonalcoholic steatohepatitis (NASH) is increasingly recognized as the most common chronic liver disease worldwide. The aim of this study is to investigate the transplantation trends of liver transplant (LT) recipients with NASH. Using the United Network for Organ Sharing database, we found a steady increase in LT rate especially in those more than 65 years old. We identified differences across ethnic groups and United Network for Organ Sharing regions. This study highlights the impact of the rising prevalence of NASH on the demand for LT and provides invaluable information to healthcare policymakers and the transplant community about the target groups and geographic location for focused and early intervention.

Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma.

BACKGROUND: Obesity has been associated with poor oncologic outcomes following pancreatoduodenectomy for pancreatic cancer. However, there is a paucity of evidence on the impact of obesity on postoperative complications, oncologic outcome and survival in patients with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT). METHODS: From a database of over 1000 patients who underwent OLT during 1996-2008, 159 patients with a diagnosis of HCC were identified. Demographic data, body mass index (BMI), perioperative parameters, recurrence and survival were obtained. Complications were grouped according to Clavien-Dindo grading (Grades I-V). RESULTS: There were increased incidences of life-threatening complications in overweight (58%) and obese (70%) patients compared with the non-obese patient group (41%) (P < 0.05). Furthermore, the incidence of recurrence of HCC was doubled in the presence of overweight (15%) and obesity (15%) compared with non-obesity (7%) (P < 0.05). Time to recurrence also decreased significantly. Differences in mean ± standard deviation survival in the overweight (45 ± 3 months) and obese (41 ± 4 months) groups compared with the non-obese group (58 ± 6 months) did not reach statistical significance. CONCLUSIONS: These findings indicate that BMI is an important surrogate marker for obesity and portends an increased risk for complications and a poorer oncologic outcome following OLT for HCC.

The acceptable reactive crossmatch (ARC), post-transplant monitoring, and their impact on kidney transplantation: a single center experience.

Although the adverse allograft outcomes associated with HLA antibodies are well documented, some controversy exists regarding the importance of low-level donor specific anti-HLA antibodies (DSA). To provide further detail on this controversy, we prospectively looked at low-level DSA in negative T- and B-cell flow cytometric crossmatch (FCXM) or acceptable reactive crossmatch (ARC) patients who each underwent protocol based post-transplant antibody monitoring. HLA Class I and II antibody screening and specificity determination was conducted via a solid phase assay (SPA) and FCXM versus donor and autologous T and B cells. Post-transplant patients were immunosuppressed with quadruple maintained immunosuppressive therapy, rabbit anti-thymocyte globulin induction, and HLA antibody monitoring. Out of 31 ARC patients transplanted, 65% had a PRA > 50% and 26% showed increased DSA at 7-14 days post-transplant. Antibody mediated rejection (AMR) was treated with pharmacological and/or plasmapheresis (PP) therapy. DSA were lowered and remained at low-levels (MFI 1000- 3000) or below FCXM cutoffs. None of the 31 patients transplanted developed de-novo antibodies. Two patients lost their allografts, one to polyoma (BK) virus, and one to antibody mediated rejection (AMR). In conclusion, our experience demonstrates that patients deemed higher risk for an immunological event due to low-level DSA should be transplanted with an ARC and followed post-transplant according to an established alloantibody monitoring protocol. With close monitoring, 5-year outcomes can be expected to approach that of low-immunologic risk transplant patients.

Outcome of liver transplantation in a Hispanic population: 100 liver transplants in Puerto Ricans.

BACKGROUND: The residents of Puerto Rico (PR) had limited access to liver transplantation (LTx) prior to 1996. LTx remains locally unavailable and success rates for LTx for patients from PR have never been published. The outcome of the first 100 LTx recipients from PR transplanted at our center is analyzed. METHODS: 100 consecutive patients transplanted between 3/1997 and 1/2005 were evaluated. RESULTS: Hepatitis C was the indication for LTx in 44%. Overall patient survival at 1, 3 and 5 yrs was: 94.0%, 81.4% and 75.7%, respectively, while for hepatitis C, it was 90%, 73% and 73%, respectively. At mean follow up of 44 mo., 80% of patients were alive (66% HCV were alive vs 91% non HCV, p < 0.01). CONCLUSIONS: Access to LTx in Puerto Rico has dramatically improved since 1996. The government-sponsored fund has provided access to indigent patients. Decreased survival in this minority population was not observed at 1, 3 and 5 years. Long-term survival was most affected by recurrence of HCV.

12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients.

The proliferation signal inhibitor everolimus (Certican), has demonstrated efficacy with full-dose cyclosporine (CsA) (Neoral). Two multicenter randomized controlled studies were performed to compare 12-month efficacy and safety of everolimus 1.5 and 3.0 mg/day with reduced-dose CsA. Study 1 enrolled 237 de novo renal allograft recipients, randomizing 222 nonblack patients to either everolimus 1.5 or 3.0 mg/day, with the Neoral) dose guided by C(2) (monitoring of CsA concentration 2 h after dosing). Study 2 had a similar protocol, with basiliximab included, enrolling 256 recipients and randomizing 243 nonblack patients. In Study 1, there was a lower incidence of acute rejection in nonblack patients on 3 mg/day (16.4%) compared with 1.5 mg/day (25.9%), P = 0.08. In Study 2, the inclusion of basiliximab lowered the overall incidence of acute rejection; 14.3% of nonblack patients (3 mg/day) and 13.6% of nonblack patients (1.5 mg/day) had acute rejection by 12 months (P =0.891). Renal function was preserved throughout the study, with no differences observed between groups within studies. Everolimus was well tolerated with no significant differences between doses. Everolimus, in combination with reduced-dose Neoral), demonstrated efficacy and was well tolerated. Basiliximab allows for utilization of lower doses of everolimus with reduced dosing of Neoral).

Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies.

Two prospective, randomized studies evaluated everolimus 1.5 vs. 3 mg/day with steroids and low-exposure cyclosporine (CsA) (C2 monitoring) in de novo renal transplant patients. Everolimus dosing was adjusted to maintain a minimum trough level of 3 ng/mL. Study 1 (A2306; n=237) had no induction therapy; in Study 2 (A2307; n=256) basiliximab was administered (Days 0 and 4). The primary endpoint was renal function at 6 months. CsA C2 target levels, initially 1200 ng/mL in Study 1 and 600 ng/mL in Study 2, were tapered over time post-transplant. Median creatinine levels in Study 1 were 133 and 132 micromol/L at 6 months in the 1.5 and 3 mg/day groups, respectively, and 130 micromol/L in both groups in Study 2. Biopsy-proven acute rejection (BPAR) occurred in 25.0% and 15.2% of patients in the 1.5 and 3 mg/day groups in Study 1, and 13.7% and 15.1% in Study 2. Incidence of BPAR was significantly higher in patients with an everolimus trough <3 ng/mL. There were no significant between-group differences in the composite endpoint of BPAR, graft loss or death, nor any significant between-group differences in adverse events in either study. Concentration-controlled everolimus with low-exposure CsA provided effective protection against rejection with good renal function.

Prospective, randomized, multi-center trial of antibody induction therapy in simultaneous pancreas-kidney transplantation.

A randomized, multicenter, prospective study was conducted at 18 pancreas transplant centers in the United States to determine the role of induction therapy in simultaneous pancreas-kidney (SPK) transplantation. One hundred and 74 recipients were enrolled: 87 recipients each in the induction and noninduction treatment arms. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. There were no statistically significant differences between treatment groups for patient, kidney, and pancreas graft survival at 1-year. The 1-year cumulative incidence of any treated biopsy-confirmed or presumptive rejection episodes (kidney or pancreas) in the induction and noninduction treatment arms was 24.6% and 31.2% (p = 0.28), respectively. The 1-year cumulative incidence of biopsy-confirmed, treated, acute kidney allograft rejection in the induction and noninduction treatment arms was 13.1% and 23.0% (p = 0.08), respectively. Biopsy-confirmed kidney allograft rejection occurred later post-transplant and appeared to be less severe among recipients that received induction therapy. The highest rate of Cytomegalovirus (CMV) viremia/syndrome was observed in the subgroup of recipients who received T-cell depleting antibody induction and received organs from CMV serologically positive donors. Decisions regarding the routine use of induction therapy in SPK transplantation must take into consideration its differential effects on risk of rejection and infection.

Carotid intima media thickness decreases after pancreas transplantation.

BACKGROUND: Pancreas transplantation (PTX) improves diabetic microvascular complications, but it is unknown whether PTX alters macrovascular disease. Carotid intima media thickness (IMT) has been shown to correlate with cardiovascular events, so this study was designed to evaluate changes in carotid IMT after PTX. METHODS: Four groups were studied: PTX candidates (n=60); successful PTX recipients (n=89; mean time since PTX=4.0+/-0.3 years); patients with type 1 diabetes but without nephropathy (n=20); and normal controls (n=32). Mean IMT and mean of maximum carotid IMT measurements (mean-max IMT), hemoglobin A1C, serum creatinine, body mass index (BMI), blood pressure, smoking status, use of hypolipidemic medications, and fasting lipids were determined in all groups. RESULTS: Age, gender distribution, and BMI were not different among the groups. Duration of diabetes was also equal between pre- and post-PTX groups. Mean and mean-max IMT were greatest pre-PTX and decreased after PTX (P<0.05) to a value that was not different from controls. Hemoglobin A1C and creatinine decreased, and high density lipoprotein (HDL) increased after PTX (P<0.05), but there were no significant differences in other lipids, BMI, use of lipid lowering agents, blood pressure, or smoking status. CONCLUSIONS: Carotid IMT is lower after PTX, suggesting a reduction in overall cardiovascular risk independent of changes in use of hypolipidemic agents, smoking, blood pressure, BMI, or lipids, except HDL. Improved carotid IMT after successful PTX predicts a reduction in future vascular disease events and suggests that the macrovascular disease of type 1 diabetes is at least partially reversible with improved glucose control.