Cyclosporine pharmacokinetics and blood pressure responses after conversion to once-daily dosing in maintenance liver transplant patients

Abstract:  In this six-month randomized multicenter trial, we characterized cyclosporine pharmacokinetics and blood pressure profiles in maintenance liver transplant patients converting from twice-daily to once-daily cyclosporine dosing. A total of 60 patients were randomized as follows: group A (n = 14) maintained twice-daily dosing; group B (n = 24) converted to once-daily dosing at the same total daily dose as pre-conversion; and group C (n = 22) was treated the same as group B but with a 25% reduction in dose and C2 at two to three wk post-conversion. After conversion to once-daily dosing in groups B and C, trough blood levels (C0) did not change; whereas, C2 nearly doubled. The total daily area under the concentration–time curve AUC(0–24) increased by 29%. After the dose reduction in group C, the AUC(0–24) was similar to the pre-conversion value. Hence, a 25–30% dose reduction can be considered after conversion to once-daily dosing. In the study observation period in weeks 4–15, the median (25–75 percentile) C2 was 568 (469–750) ng/mL for group A; 1055 (840–1224) ng/mL for group B; and 764 (575–959) ng/mL for group C. Conversion to once-daily dosing was associated with a decrease in nighttime mean arterial blood pressure.     

Residual fraction as a parameter to predict bladder outlet obstruction in men with lower urinary tract symptoms

Objectives:   To determine whether noninvasive tests including the residual fraction are reliable for the diagnosis of bladder outlet obstruction (BOO).
Methods:   A total of 212 men (median age 68, range 44–89 years) were included in the present study. The median serum prostate-specific antigen level and prostate volume were 1.3 ng/mL (range 0.2 to 9.4) and 37.9 mL (range 11.3 to 148.0), respectively.
Results:   Among the variables analyzed in the multivariate model, the likelihood of BOO varied by the total prostate volume, with a 3.6-fold higher odds for ≥40 mL than for <40 mL (odds ratio [OR], 3.616; 95% confidence interval [CI], 1.217–10.749; P  = 0.021). In the same model, a low maximal flow rate (Qmax) (OR, 2.840; 95% CI, 1.260–6.401; P  = 0.012) and high residual fraction (OR, 7.103; 95% CI, 1.924–26.225; P  = 0.003) were associated with an increased likelihood of BOO. The sensitivity and specificity for predicting BOO using a total prostate volume of 40 mL or greater were 73.7% and 65.2%, respectively. Using a Qmax cut-off of 12 mL/s or less for predicting BOO, the sensitivity and specificity were 77.2% and 54.2%, respectively. Prediction of the BOO by the residual fraction only had a sensitivity and specificity, for a residual fraction of less than 20%, of 75.4% and 67.7%, respectively.
Conclusions:   The presence or absence of BOO might be predicted using non-invasive methods. The residual fraction may help with patient management by better predicting the likely patient classification from pressure-flow studies.     

Efficacy and safety of bleselumab in kidney transplant recipients: A phase 2, randomized,open‐label,noninferiority study

This study assessed the efficacy and safety of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate‐release tacrolimus [IR‐TAC]; target minimum blood concentration [C_trough] 4‐11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR‐TAC (0.1 mg/kg per day; target C_trough 4‐11 ng/mL days 0‐30, then 2‐5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3‐5 posttransplant) and corticosteroids. One hundred thirty‐eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR‐TAC [n = 44]). For the primary endpoint (incidence of biopsy‐proven acute rejection [BPAR] at 6 months), bleselumab + IR‐TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] ?8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%‐46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR‐TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit–risk ratio. Most treatment‐emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).     

Expanding the donor pool: use of renal transplants from non-heart-beating donors supported with extracorporeal membrane oxygenation

Abstract:  In response to organ shortage, we used the renal grafts from non-heart-beating donors (NHBDs). Extracorporeal membrane oxygenation (ECMO) was used to maintain NHBDs before organ procurement. We compared the results of renal transplantation from different donors, including heart-beating donors (HBDs), living-related donors (LDs), and NHBDs supported with ECMO. From February 1998 to June 2003, we recruited 219 patients receiving renal transplantation at National Taiwan University Hospital. Among them, 31 received kidneys from NHBDs supported with ECMO, 120 from HBDs, and 68 from LDs. Multiple organ transplant recipients were not included in this study. We compared the graft survival, serum creatinine levels, and estimated glomerular filtration rates of the three groups. The rate of delayed graft function was higher in NHBD recipients (41.9%) than in HBD recipients (27.0%) and LD recipients (10.9%) (p = 0.003). In the NHBD group, the recipients of grafts with delayed function had significantly longer ECMO runs (63.1 ± 3.0 min) than those without delayed function (53.7 ± 2.5 min) (p = 0.024). Estimated glomerular filtration rate (p = 0.472) and mean serum creatinine level (p = 0.286) were not significantly different between the three groups using a longitudinal approach. The 5-yr graft survival rates for NHBD (88.4%, 95% CI: 0.680–0.962), HBD (83.2%, 95% CI: 0.728–0.899), and LD transplant recipients (89.3%, 95% CI: 0.619–0.974) were not significantly different (p = 0.239). The 5-yr patient survival rates for NHBD, HBD, and LD transplant recipients were 100, 93.0 (95% CI: 0.859–0.966) and 100% respectively. The long-term allograft survival and function of kidneys from NHBDs supported by ECMO, HBD, and LD did not differ significantly. Long ECMO running time tended to delay graft function.     

Microalbuminuria post-renal transplantation: relation to cardiovascular risk factors and C-reactive protein

Abstract:  Microalbuminuria predicts graft loss and all-cause mortality in renal transplant recipients. In the general population, it clusters with both traditional cardiovascular risk factors and elevated C-reactive protein (CRP). Our objective was to define the relationship between microalbuminuria and these risk factors in stable renal transplant recipients. We identified 222 stable recipients who were minimum two months post-transplant and provided three urine albumin-to-creatinine ratio (ACR) measurements, excluding those with recent illness and proteinuria. Microalbuminuria was defined as averaged ACR ≥ 2.0 in men and 2.8 mg/mmol in women (Canadian Diabetes Association 2003). Risk factors associated with microalbuminuria were determined by multivariate logistic regression analysis. Averaged ACR correlated to CRP (R = 0.21, p = 0.001). Prevalence of microalbuminuria was 48% (108/222). Patients with microalbuminuria had higher CRP (7.01 ± 8 vs. 3.21 ± 3 mg/L, p < 0.0001) and systolic BP (129 ± 17 vs. 123 ± 12 mmHg, p = 0.004). Microalbuminuria was associated with increasing CRP [odds ratio 1.129 per 1 mg/L (95% CI 1.058–1.204), p = 0.0002], SBP [1.248 per 10 mmHg (1.023–1.522), p = 0.029] and smoking [1.938 (1.023–3.672), p = 0.042]. Post-transplant microalbuminuria is prevalent and is associated with elevated CRP, elevated BP, and smoking. Its relationship to these factors suggests it may be an indicator of graft and patient health.     

Pre-operative forced-air warming as a method of anxiolysis

We tested the hypothesis that pre-operative forced-air warming is as effective for anxiolysis as intravenous midazolam, using a blinded, placebo controlled factorial design. One hundred and twenty patients were randomly assigned to cotton blanket and saline injection ( n  =   30), forced-air warmer and saline injection ( n  =   30), midazolam 30 μg.kg⁻¹ and cotton blanket ( n  =   30), and forced-air warmer and midazolam 30 μg.kg⁻¹ ( n  =   30). Patients completed visual analogue scales for anxiety and thermal comfort, and the State-Trait Anxiety Inventory, at baseline and after 20 min. The estimated effect of midazolam on visual analogue scores for anxiety was −10 (95% CI −3 to −18; p = 0.007) and on state anxiety was −5 (95% CI −7 to −4; p = 0.03). Warming had no influence on visual analogue scores for anxiety (p = 0.50) or state anxiety (p = 0.33), but its estimated effect on thermal comfort was +23 (95% CI 19–27; p < 0.0001). There was no interaction between midazolam and warming. Pre-operative warming was not equivalent to midazolam for anxiolysis and cannot be recommended solely for this purpose.     

Mycophenolate mofetil vs. sirolimus in kidney transplant recipients receiving tacrolimus-based immunosuppressive regimen

Abstract:  Mycophenolate mofetil (MMF) and sirolimus (SRL) are effective immunosuppressive drugs with distinct safety profile.
Methods:  Kidney transplant recipients receiving tacrolimus (TAC)-based immunosuppressive regimen were randomized to receive fixed daily doses of MMF (2 g/d, n = 50) or SRL (one loading dose of 15 mg, 5 mg/d till day 7 and 2 mg/d thereafter, n = 50) without induction therapy.
Results:  No differences were observed in the incidence of the composite (biopsy-confirmed acute rejection, graft loss or death) end-point (18% vs. 16%, p = 1.000), biopsy confirmed acute rejection (12% vs. 14%, p = 1.000), one-yr patient (94% vs. 98%, p = 0.308), graft (92% vs. 98%, p = 0.168), and death-censored graft survival (98% vs. 100%, p = 0.317) comparing patients receiving MMF or SRL respectively. Patients receiving SRL showed worse safety outcomes, higher mean creatinine (1.6 ± 0.5 mg/dL vs. 1.4 ± 0.3 mg/dL, p = 0.007), higher proportion of patients with proteinuria (52.0% vs. 10.7%, p = 0.041), higher mean urinary protein concentrations (0.3 ± 0.5 g/L vs. 0.1 ± 0.2 g/L, p = 0.012), higher mean cholesterol concentration (217 mg/dL vs. 190 mg/dL, p = 0.030), and higher proportion of patients prematurely discontinued from randomized therapy (26% vs. 8%, p = 0.031).
Conclusion:  In patients receiving TAC, MMF produced similar efficacy but superior safety profile compared with SRL.     

A randomized trial of basiliximab with three different patterns of cyclosporin A initiation in renal transplant from expanded criteria donors and at high risk of delayed graft function

Abstract:  This study assays therapy with basiliximab and different patterns of cyclosporin A (CsA) initiation in renal transplant (RT) recipients from expanded criteria donors (ECD) and at high risk of delayed graft function (DGF). A multicentre six-month open-label randomized trial with three parallel groups treated with basiliximab plus steroids, mycophenolate mofetil and different patterns of CsA initiation: early within 24 h post-RT at 3 mg/kg/d (Group 1; n = 38), and at 5 mg/kg/d (Group 2; n = 40), or delayed after 7–10 d at 5 mg/kg/d (Group 3; n = 36). There were no differences among groups in six months GFR (43.1 ± 12, 48.0 ± 14 and 47.2 ± 17 mL/min, respectively), DGF (Group 1: 31%, Group 2: 37%, Group 3: 42%), nor biopsy-proven acute rejection, although clinically treated and biopsy-proven acute rejection was significantly higher in Group 3 (25%) vs. Group 1 (5.3%, p < 0.05). At six months no differences were observed in death-censored graft survival or patient survival. Induction therapy with basiliximab and three CsA-ME initiation patterns in RT recipients from ECD and at high risk of DGF presented good renal function and graft survival at six months. Late onset group did not achieve improvement in DGF rate and showed a higher incidence of clinically treated and biopsy-proven acute rejection.     

A meta-analysis of the utility of C-reactive protein in predicting early, intermediate-term and long term mortality and major adverse cardiac events in vascular surgical patients

We conducted a meta-analysis of the utility of pre-operative C reactive protein (CRP) in predicting early (< 30 days), intermediate (30–180 days) and long term (> 180 days) mortality and major adverse cardiac events (MACE; cardiac mortality and nonfatal myocardial infarction (MI) combined) following vascular surgery. Of 291 studies identified, ten prospective patient cohorts were identified. A pre-operative CRP > 3 mg.l⁻¹ was not associated with 30-day all-cause mortality, cardiac mortality, nonfatal myocardial infarction or MACE. Intermediate-term all-cause mortality, cardiac death and MACE showed a trend to a worse outcome (odds ratio (OR) 9.07, 95% confidence interval (CI) 0.86–96.28, p = 0.07; OR 8.71, 95% CI 0.5–153.1, p = 0.14 and OR 2.81, 95% CI 0.78–5.18, p = 0.15 respectively). Long term all cause mortality (OR 2.40, 95% CI 1.15–5.02, p = 0.02), cardiac death (OR 5.66, 95% CI 1.71–18.73, p = 0.005) and MACE (OR 2.76, 95% CI 1.38–5.55, p = 0.004) were significantly increased.     

Interventional radiologic procedures in the treatment of complications after liver transplantation

The aim of this study is to report our interventional radiologic procedures (IRP) in liver transplant (LTX) patients. These include procedures for biliary, arterial, venous, and portal complications, as well as the treatment of infected and non-infected fluid collections.
This retrospective study covered 583 patients (mean age: 44 ± 14 yr) in whom a total of 685 LTX were performed from August 1987 to April 2005.
Overall, 182 LTX patients underwent a total of 428 IRP, including digital subtraction angiography (n = 152/35.51%), percutaneous transluminal angioplasty (PTA) (n = 4/0.93%) and PTA + stent (n = 7/1.63%) of arterial anastomosis, PTA + stent of the celiac trunk (n = 2/0.46%), transjugular intrahepatic portosystemic shunt (TIPS) (n = 2/0.46%), arterial lysis (n = 4/0.93%), venous lysis (n = 2/0.46%), inferior vena cava stenting (n = 2/0.46%), percutaneous biliary drainage (n = 34/7.94%), percutaneous transluminal dilatation (PTD) of the choledocho-enteric anastomosis (n = 16/3.73%), biliary stent (n = 5/1.16%), intrahepatic biliary flushing treatment, stone and cast biliary extraction (n = 27/6.30%), other interventions (e.g., embolization in other regions, transjugular liver biopsies, lymphangiographies) (n = 9/2.10%), and ultrasound- and computer tomography-guided biopsies and percutaneous drainage (n = 153/35.74%). The overall success rate was 85.7%.
Technical improvements in LTX and interventional radiology permit vascular and biliary complications to be treated successfully by interventional radiology.     

004Topical Zinc Oxide for Open Pilonidal Wounds

Extended healing time and lack of documented effective treatments of sacrococcygeal pilonidal disease create substantial problems. Locally applied zinc oxide has been reported to promote wound healing. We have compared topical zinc oxide (3%) with placebo meshes for pilonidal wounds healing by secondary intention in a randomized, double‐blind, placebo‐controlled multicenter trial. Sixty‐four consecutive patients, 53 males, aged between 18 and 60 years (median 26 years) with excised pilonidal wounds were centrally randomized to local zinc oxide (30 mg/g, n = 33) or to placebo (n = 31) mesh treatment. Patients were followed with strict recording of beneficial and harmful effects. The median healing times were 54 days (42–71 days, interquartile range, n = 33) for the zinc group and 62 days (55–82 days, n = 31) for the placebo group. This difference was not statistically different (p = 0.32). Based on Cox regression analysis initial wound volume influenced healing negatively (p = 0.016) while smoking (p = 0.011) was associated with faster wound healing. Significantly (p < 0.01) more placebo (n = 12) than zinc oxide‐treated patients (n = 3) needed antibiotics postoperatively. Although topical zinc oxide increased (p < 0.001) wound fluid zinc levels (1830 ± 405 μM, mean ± SEM) compared with placebo (3.1 ± 1.6 μM) serum‐zinc levels did not differ significantly between the zinc (13.5 ± 0.4 μM) and placebo (12.8 ± 0.4 μm) groups on postoperative day 7. No adverse events were recorded. Topical zinc oxide treatment did not accelerate time to closure of open pilonidal wounds but was associated with reduced antibiotic usage.     

The influence of CTLA‐4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients

Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is a cell surface protein, which down‐regulates the immune response at CTLA‐4/CD28/B7 pathway. We aimed to investigate the influence of the ?318C/T, +49A/G, ?1661A/G and CT60A/G, and CTLA‐4 gene polymorphisms on acute rejection of kidney allograft in Turkish patients. The study design was a case–control study that consists of three groups: Group 1 (n = 34) represented the kidney transplant (Ktx) recipients who experienced acute rejection, Group 2 (n = 47) was randomly assigned Ktx recipients without acute rejection, and Group 3 (n = 50) consisting of healthy volunteers to evaluate the normal genomic distribution. The polymerase chain reaction–restriction fragment length polymorphism technique was used to determine the polymorphisms. Genotype and allele frequencies among three groups denoted similar distributions for +49A/G, ?1661A/G, and CT60A/G. Conversely, ?318C/T genotype was three times more frequent in the acute rejection group than in the non‐rejection group (OR = 3.45; 95%CI = 1.18–10.1, p = 0.015) and two times more frequent than the healthy control group (OR = 2.45; 95% CI = 0.98 – 6.11, p = 0.047). Additionally, having a T allele at ?318 position was significantly associated with acute rejection (0.147 vs. 0.043, OR = 3.45; 95% CI = 1.13–10.56, p = 0.02). 318C/T gene polymorphism and T allelic variant were found to be associated with increased acute rejection risk in Turkish kidney allograft recipients.     

Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor‐specific antibodies in the first year of kidney transplantation

De novo donor‐specific antibodies (dnDSAs) have been associated with reduced graft survival. Tacrolimus (TAC)–based regimens are the most common among immunosuppressive approaches used in in clinical practice today, yet an optimal therapeutic dose to prevent dnDSAs has not been established. We evaluated mean TAC C₀ (tacrolimus trough concentration) and TAC time in therapeutic range for the risk of dnDSAs in a cohort of 538 patients in the first year after kidney transplantation. A mean TAC C₀ < 8 ng/mL was associated with dnDSAs by 6 months (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.32–4.79, P = .005) and by 12 months (OR 2.32, 95% CI 1.30–4.15, P = .004), and there was a graded increase in risk with lower mean TAC C₀. TAC time in the therapeutic range of <60% was associated with dnDSAs (OR 2.05, 95% CI 1.28‐3.30, P = .003) and acute rejection (hazard ratio [HR] 4.18, 95% CI 2.31–7.58, P < .001) by 12 months and death‐censored graft loss by 5 years (HR 3.12, 95% CI 1.53–6.37, P = .002). TAC minimization may come at a cost of higher rates of dnDSAs, and TAC time in therapeutic range may be a valuable strategy to stratify patients at increased risk of adverse outcomes.     

A randomized trial of alemtuzumab vs. anti-thymocyte globulin induction in renal and pancreas transplantation

Abstract:  The role of alemtuzumab as an immunosuppressive agent is evolving. We conducted a prospective randomized trial comparing alemtuzumab and rabbit anti-thymocyte globulin (rATG) induction in adult kidney and pancreas transplantation using similar maintenance immunosuppression. Between February 1, 2005 and June 15, 2006 (median follow-up six months), 98 patients were randomized either to alemtuzumab (n = 48) or to rATG (n = 50) induction; 77 (79%) underwent kidney alone (KA) transplant, 17 (17%) pancreas–kidney transplant, and four (4%) pancreas after kidney transplant. Of 77 KA transplants, 66 (86%) were from deceased donors and 31 (40%) from expanded criteria donors (ECD). Re-transplantation, HLA-match, antibody titer, ECD, race, cytomegalovirus status, steroid use, delayed graft function, preservation time, and immunological risk were similar between the two induction groups. Patient, kidney, and pancreas graft survival rates were 100%, 96%, and 95%, respectively. Survival, initial length of stay, delayed graft function, and overall acute rejection rates were similar between alemtuzumab and rATG groups, but acute rejection occurred in nine (20%) rATG patients compared with zero (0%) alemtuzumab patients who received KA transplants (p = 0.007). Mean induction costs differed in the alemtuzumab ($1474) and rATG ($4996, p < 0.001) groups. In the short term after kidney and pancreas transplantation, alemtuzumab and rATG induction therapies are similarly safe and effective.     

Adding Sirolimus to Tacrolimus-Based Immunosuppression in Pediatric Renal Transplant Recipients Reduces Tacrolimus Exposure

In adult renal recipients, coadministration of tacrolimus (TAC) and sirolimus (SIR) results in reduced exposure to TAC at SIR doses of 2 mg/day. Eight pediatric renal recipients (median age at transplant 2.0 years, range: 1.2-12.9 years) were converted to TAC- and SIR-based immunosuppression as a rescue therapy. All patients had biopsy-proven chronic allograft nephropathy. TAC levels were measured using a commercially available EMIT assay and SIR levels with a newly developed assay based on the LC-MS MS technology. SIR was started at 0.13+/-0.05 mg/kg/day (3.51+/-1.26 mg/m2/day) in two divided doses. TAC was given at 0.14+/-0.09 mg/kg/day, resulting in a trough level of 6.3+/-2.5 ng/mL. After the addition of SIR, the median dose required to keep TAC blood trough concentrations within the target range increased by 71.2% (range: 21.9-245.4%), dose-normalized TAC exposure (AUC) decreased to 67.1% and the dose-normalized C(max), a surrogate for absorption rate, to 53.8% (both geometric means) while terminal half-life (t1/2), a pharmacokinetic parameter characterizing systemic elimination, remained unchanged (p<0.93). Adding SIR to TAC-based immunosuppression in young pediatric renal transplant recipients results in a significant decrease of TAC exposure. TAC trough levels should be monitored frequently.     

Daclizumab induction/tacrolimus sparing: a randomized prospective trial in renal transplantation

Abstract: Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL-2 receptor complex. We reasoned therefore that the absence of IL-2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty-eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12–17 ng/mL; n  = 13); Group 2, low dose (LD) tacrolimus (trough 5–10 ng/mL; n  = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD ( n  = 12) and LD ( n  = 6). All patients and grafts survived for the 6-month study period. There was one rejection episode in a non-compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.     

Delirium is associated with early postoperative cognitive dysfunction

The purpose of this analysis was to determine if postoperative delirium was associated with early postoperative cognitive dysfunction (at 7 days) and long-term postoperative cognitive dysfunction (at 3 months). The International Study of Postoperative Cognitive Dysfunction recruited 1218 subjects ≥ 60 years old undergoing elective, non-cardiac surgery. Postoperatively, subjects were evaluated for delirium using the criteria of the Diagnostic and Statistical Manual. Subjects underwent neuropsychological testing pre-operatively and postoperatively at 7 days ( n  = 1018) and 3 months ( n  = 946). Postoperative cognitive dysfunction was defined as a composite Z -score > 2 across tests or at least two individual test Z -scores > 2. Subjects with delirium were significantly less likely to participate in postoperative testing. Delirium was associated with an increased incidence of early postoperative cognitive dysfunction (adjusted risk ratio 1.6, 95% CI 1.1–2.1), but not long-term postoperative cognitive dysfunction (adjusted risk ratio 1.3, 95% CI 0.6–2.4). Delirium was associated with early postoperative cognitive dysfunction, but the relationship of delirium to long-term postoperative cognitive dysfunction remains unclear.     

Efficacy and safety of everolimus with reduced tacrolimus in living‐donor liver transplant recipients: 12‐month results of a randomized multicenter study

In a multicenter, open‐label, study, 284 living‐donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non‐inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference –0.7% (90% CI ?5.2%, 3.7%); P < .001 for non‐inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non‐inferiority (P < .001 for non‐inferiority), but not superiority and was similar between groups overall (mean ?8.0 vs. ?12.1 mL/min/1.73 m², P = .108), and in patients continuing randomized treatment (?8.0 vs. ?13.3 mL/min/1.73 m², P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria ≥1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC‐treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non‐inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432.     

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

SIMCER was a 6‐mo, multicenter, open‐label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low‐exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus‐based therapy (n = 95), both with basiliximab induction and enteric‐coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. ?13.3 mL/min per 1.73 m² for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m² for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy‐proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus‐treated patients (17.8%) and three tacrolimus‐treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI‐based immunosuppression but more frequent BPAR.     

No-load sirolimus with tacrolimus and steroids is safe and effective in renal transplantation

AIM: Basiliximab (BX) induction, tacrolimus (TAC), and steroids have sharply reduced acute cellular rejection at our institution. However, late graft loss has continued, for which sirolimus (SL) was introduced into the protocol. METHODS: From July 1, 2001 to December 31, 2003, 152 live donor (LD) renal transplant recipients received TAC (level 15 to 20 ng/mL) and steroids, with BX induction. One hundred twenty-two patients (Group 1) received SL (3 mg/d African-americans; 2 mg/d for others) starting on days 2 and 3. The SL level was adjusted to 8 to 10 ng/d, usually by weeks 3 to 4 posttransplant. The TAC doses were then progressively reduced. Records were reviewed for demographics, immunosuppressive drug levels, serum cholesterol and blood pressure, and complications. Graft and patient survival rates were calculated. Comparison was made to 53 LD recipients transplanted from July 1, 1998, to June 30, 2001 (Group 2) receiving BX, steroids and TAC, without SL. Recipients of deceased donor kidneys were excluded because of variability in kidney quality, ischemic time, and patient management. RESULTS: Demographics were similar between groups: African Americans, 25% to 35%; mean age 36 years; mean HLA mismatch 3.7. Wound problems and infection were minimal in both groups. Mean serum creatinine and cholesterol and systolic and diastolic blood pressure measured periodically up to 1 year were similar, as was the incidence of rejection. In 25% of patients, SL was discontinued. CONCLUSIONS: Gradual introduction of SL appears to be associated with minimal wound problems. With more aggressive reduction in TAC, better renal function, and better long-term graft survival may be attainable. We currently lower TAC levels to 5 ng/mL by 3 months.