Tacrolimus dosing requirements and concentrations in adult living donor liver transplant recipients

Living donor liver transplantation in adult recipients is becoming increasingly common. The liver metabolizes most drugs, including immunosuppressive agents. Right-lobe grafts used in adult living donor liver transplantation consist of only 50% to 60% of the total liver. The purpose of this study is to determine whether there is a difference between tacrolimus doses and concentrations in patients who received a partial liver transplant from a living donor (LRD) versus those who received a whole-liver transplant from a cadaveric donor (CAD). Thirteen LRD recipients and 13 CAD recipients who underwent transplantation between April 1998 and July 2000 were included in this analysis. A CAD control group matched for age, sex, and race was used for comparison. Tacrolimus doses and concentrations were analyzed weekly for the first 4 weeks, then monthly for 6 months posttransplantation. There was no difference in acute rejection rates, renal and liver function test results, or number of potentially interacting medications administered between groups. LRD recipients required significantly lower doses of tacrolimus compared with CAD recipients at 2 weeks (0.058 v 0.110 mg/kg/d; P [lt ] .01), 3 weeks (0.068 v 0.123 mg/kg/d; P [lt ] .02), 4 weeks (0.086 v 0.141 mg/kg/d; P [lt ] .02), 2 months (0.097 v 0.141 mg/kg/d; P [lt ] .03), and 3 months (0.099 v 0.138 mg/kg/d; P [lt ] .03). Tacrolimus 12-hour trough concentrations were similar between groups at all times except for 2 weeks posttransplantation, when LRD recipients' concentrations were significantly greater than those of CAD recipients (12.4 v 9.5 ng/mL; P [lt ] .03). In addition, in the first month posttransplantation, LRD recipients were more likely to have greater concentrations of tacrolimus ([gt ]15 ng/mL; 22.1% v 9.2%; P [lt ] .01). In conclusion, LRD recipients have significantly decreased tacrolimus dosing requirements compared with CAD recipients during the first 3 months posttransplantation despite having similar tacrolimus concentrations. (Liver Transpl 2002;8:219-223.)     

Postoperative Course of Serum Albumin Levels and Organ Dysfunction After Liver Transplantation

Background and aimsPostoperative hypoalbuminemia, especially following liver transplantation, can lead to adverse multisystem effects and even death. We investigated the relationship between postoperative albumin levels and organ failure (assessed using Sequential Organ Failure Assessment [SOFA] scores).MethodsSixty liver transplant recipients admitted to the intensive care unit (ICU) from 2012 to 2015 were retrospectively divided into 2 groups: lower albumin (LA) (n=28) and higher albumin (HA) (n=32), using whether serum albumin level fell below 3.0 g/dL during the first postoperative week as the stratifying factor. The SOFA scores (primary endpoint) and associated complications (ascites amount, rejection, re-intubation, abdominal re-operation, thrombosis), additional treatment (dialysis, pleural effusion drainage), and duration of ICU stay (secondary endpoints) of the 2 groups were compared.ResultsAverage serum albumin levels were significantly different between HA and LA groups (3.6 [3.4–3.8] vs 3.1 [2.9–3.3], respectively, P < .05), although the amounts of albumin infused in the 2 groups during the first postoperative week were not different (HA vs LA: 42 [30–71] vs 40 [30–58], respectively, P = .37). Mean daily SOFA scores were not significantly different between the HA and LA groups (8.3 [6.6–9.0] vs 7.2 [6.3–8.6], P = .73), although the HA group had lower mean cardiovascular SOFA sub-scores than the LA group (0.1 [0–0.4] vs 0.4 [0–1.3], P = .032). There were no significant differences between the groups with regard to complication rates and duration of ICU and hospital stays.ConclusionsSerum albumin level might not influence cumulative organ function, but it decreases the amount of hemodynamic support required in liver transplant recipients.     

A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C

Hepatitis C is the most common indication for liver transplantation (LT) in the United States. Recurrence of hepatitis C virus (HCV) infection post-LT remains a problem for which there is no completely satisfactory treatment. The aim of the present study is to evaluate mycophenolate mofetil (MMF), which has both immunosuppressive and antiviral properties, to determine whether it is associated with a difference in the rate of HCV recurrence and also examine its impact on patient and graft survival. Between August 1995 and May 1998, a total of 106 patients who were HCV positive before LT were randomized to tacrolimus (TAC) and prednisone versus TAC, prednisone, and MMF therapy. The rate of recurrence of HCV, patient and graft survival, incidences of rejection, and histological findings were examined. Fifty six patients were randomized to TAC and steroid therapy (double [D] drug; group D), and 50 patients were randomized to TAC, steroid, and MMF therapy (triple [T] drug; group T). Liver biopsies were performed when liver function was abnormal; protocol liver biopsies were not performed. Mean follow-up was 4.3 [plusmn] 0.8 years. Actuarial patient survivals at 4 years were 72.6% in group D and 73.8% in group T (P = not significant). Actuarial graft survivals at 4 years were 65.6% in group D and 65.4% in group T. One patient in group D and 2 patients in group T underwent a second LT for recurrent HCV. One patient in each group died of recurrent HCV without re-LT. Twenty-six patients in group D (46.4%) and 23 patients in group T (46.0%) showed signs of recurrent HCV. Mean hepatitis activity index (HAI) scores were 7.4 [plusmn] 2.7 in group D and 7.0 [plusmn] 3.4 in group T, and mean fibrosis scores were 2.9 [plusmn] 1.7 in group D and 2.6 [plusmn] 1.1 in group T. The rate of rejection was 0.57/patient in each group for the entire follow-up period. None of these values reached statistical significance. Rates of HCV recurrence, graft loss or death from recurrent HCV, and 4-year actuarial patient and graft survival were not different between the groups. In liver transplant recipients with HCV, MMF has no impact on patient survival, graft survival, rejection, or rate of HCV recurrence based on biochemical changes and histological findings. In addition, there was no difference in HAI or fibrosis score between the two groups. Either MMF has no anti-HCV effect or its immunosuppressive properties overwhelm its antiviral effect in the clinical setting. (Liver Transpl 2002;8:40-46.)     

Clinical Effect of Preoperative 25-OH-Vitamin D3 Level in Liver Transplant Recipients

BackgroundVitamin D deficiency is common in patients with chronic liver disease and is associated with increased risk of infection and mortality. This study evaluated the effects of preoperative vitamin D levels on clinical outcomes after liver transplant.MethodsThis single-center retrospective study included liver transplant recipients from June to November 2017 who had preoperative 25-OH-vitamin D3 (25-OH-D3) data. Severe vitamin D deficiency, insufficiency, and normal levels were defined as serum 25-OH-D3 concentrations of < 10 ng/mL, 10 to 20 ng/mL, and ≥ 20 ng/mL, respectively. The primary outcome was length of hospital stay; secondary outcomes included the duration of normalization of inflammatory markers after liver transplant, new infection rates, rejection rates, length of intensive care unit stay, and mortality according to preoperative 25-OH-D3 levels.ResultsAmong 219 liver transplant recipients, 67.6% were vitamin D-deficient. The mean (standard deviation) 25-OH-D3 concentration was 17.8 (13.2) ng/mL, and 65 (29.7%) patients had levels < 10 ng/mL. Patients with lower mean 25-OH-D3 levels had significantly longer intensive care unit (13.8 [21.9] days vs 5.9 [12.3] days vs 2.7 [4.6] days, P < .001) and hospital (59.0 [66.0] days vs 42.0 [67.4] days vs 27.2 [17.1] days, P = .001) stays. The incidence of new infections was higher in the vitamin D deficiency group. (46.2% vs 28.9% vs 14.1%, P < .001). A higher Nutritional Risk Screening 2002 score (adjusted odds ratio, 1.77; 95% confidence interval [CI], 1.24-2.56; P = .002) and severe vitamin D deficiency (adjusted odds ratio, 3.43; 95% CI, 1.57-7.57; P = .002) were significant risk factors for poor outcome among patients who had been in the hospital for more than 43 days.ConclusionsVitamin D deficiency before liver transplant was associated with increased intensive care unit and hospital lengths of stay. Although several factors may influence the clinical outcomes of patients with liver transplant, low vitamin D3 was an independent risk factor.     

Do patient characteristics influence efficacy and renal outcomes in liver transplant patients receiving everolimus?

Data from the 24‐month randomized, multicenter, open‐label H2304 study in 719 de novo liver transplant recipients were analyzed to evaluate the influence of variables potentially affecting immunological or renal response: recipient age, gender, end‐stage disease, hepatitis C virus (HCV) status, and Model for End‐stage Liver Disease score and estimated glomerular filtration rate (eGFR) at randomization (day 30). Treated BPAR was similar between everolimus with reduced tacrolimus (EVR + Reduced TAC) vs. conventional tacrolimus‐based therapy (TAC Control) in all subpopulations, with a trend to lower risk under everolimus with reduced tacrolimus (EVR + Reduced TAC) in patients <60 yrs and HCV‐negative recipients. Risk of graft loss or death was similar in both treatment groups for all subpopulations. The change in eGFR to month 24 showed a benefit for EVR + Reduced TAC vs. TAC Control in all subpopulations other than those with the lowest baseline eGFR (30 to <55 mL/min/1.73m²), with a significant difference in favor of EVR + Reduced TAC for younger recipients (<60 yr), female patients, HCV‐negative patients and those with baseline eGFR of 55 to <70 mL/min/1.73 m². Everolimus with reduced tacrolimus maintains efficacy to at least two yr after liver transplantation even in patients with risk factors for rejection, with particular renal benefits in specific patient subpopulations.     

Prophylactic fluconazole in liver transplant recipients: A randomized,double-blind,placebo-controlled trial

Background:Among persons who receive solid organ 0842 transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective.Objective:To evaluate the efficacy and safety of prophylactic0842 fluconazole in liver transplant recipients.Design:Randomized, double-blind, placebo-controlled trial. 0842Setting:University-affiliated transplantation center.0842Patients:212 liver transplant recipients who received fluconazole0842 (400 mg/d) or placebo until 10 weeks after transplantation.Measurements:Fungal colonization, proven superficial 0842 or invasive fungal infection, drug-related side effects, and death.Results:Fungal colonization increased in 0842 patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003).Conclusions:Prophylactic 0842 fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

Acute Rejection of Hepatic Allografts From HLA-DR13 (Allele DRB1*1301)-Positive Donors

Acute rejection of hepatic allografts does not show consistent association with the number of mismatches of HLA classes I and II. Therefore, we investigated the relation between specific donor or recipient HLA antigens and the occurrence of acute rejection. HLA typing of 35 liver transplant recipients and donors was performed by serological standard technique, with confirmation and subtyping by polymerase chain reaction with sequence-specific primers. HLA class I antigens were not associated with the occurrence of acute rejection. The graft was positive for HLA-DR13 in 8 of 13 transplant recipients (62%) with acute rejection, but only 4 of 22 recipients (18%; P = .024;P_{Bonferroni-corrected} = .33, not significant) without rejection. The graft was positive for DRB1*1301 in 7 of 13 recipients (54%) with acute rejection, but only 1 of 22 recipients (5%) without rejection (P = .002; P_{Bonferroni-corrected} = .028). This patient had experienced long-lasting bacterial sepsis, which markedly reduced the risk for acute rejection. We speculate that the expression of donor DRB1*1301 (if mismatched) may increase the risk for acute hepatic allograft rejection. (Liver Transpl 2000;6:728-733.)     

Different Effect of Cyclosporine and Tacrolimus on Renal Expression of P-Glycoprotein in Human Kidney Transplantation

Objective

To investigate the differential effects of cyclosporine (CsA) and tacrolimus (TAC) on renal expression of P-glycoprotein (P-gp) in a cohort of kidney transplant recipients.

Methods

We enrolled 78 cadaveric kidney transplant recipients recuring basal immunosuppressive protocol with prednisone + mycophenolate mofetil + calcineurin inhibitor (CsA or TAC).

Results

We performed a 3-year analysis of 60 patients. There was no difference in age, gender, or cold ischemic time between two groups, Serum creatinine, urine protein, and blood fat levels of the CsA group were significantly higher than the TAC group (P < .05), while the creatinine clearance was remarkably lower than the TAC group (P < .05). The incidence of tubular atrophy, arteriohyalinosis, and interstitial fibrosis and nephrotoxic lesions among the CsA group were higher than the TAC group, as well as the chronic allograft nephropathy (CAN) Banff score (P < .05).^® P-gp was predominantly present in the a tubular apical membrane, basal membrane, and cytoplasm. The intensity and extent of tubular staining score in the CsA group were lower compared with the TAC group (P < .01 and P < .05, respectively).

Conclusion

Less P-gp expression in the CsA group than the TAC group may be the molecular action pathway of the high incidence of CsA nephrotoxicity and CsA-induced CAN. This study perhaps unraveled a novel interpretation that the differences of CsA and TAC on long-term allograft survival were due to increases dynamic effects of CsA at the exposures employed in this study.     

Mast cell hyperplasia in chronic rejection after liver transplantation

The pathogenesis of chronic hepatic allograft rejection is poorly understood. Recent studies suggested that hepatic mast cells may be involved in the pathogenesis of chronic cholestatic liver disease. Because chronic rejection after liver transplantation is predominantly a cholestatic process, the aim of this study is to determine whether hepatic mast cells are involved in its pathogenesis. Biopsy specimens from (1) normal livers (n = 5), (2) transplanted livers with end-stage chronic rejection (n = 8), and (3) transplanted livers with acute cellular rejection (mild, n = 7; moderate, n = 5; severe, n = 7) were studied. Biopsy specimens were stained immunohistochemically for mast cells with human antitryptase antibody. Mast cell density was significantly increased in the chronic-rejection group (4.9 [plusmn] 0.6/mm²) compared with controls (2.9 [plusmn] 0.5/mm²; P [lt ] .05). The percentage of portal tracts containing mast cells was significantly greater in chronic-rejection (89% [plusmn] 8%) than control biopsy specimens (69% [plusmn] 5%; P [lt ] .05), as was the average number of mast cells per portal tract (5.4 [plusmn] 0.9 v 1.9 [plusmn] 0.4 cells; P [lt ] .01). In chronic rejection, tissue mast cells frequently were seen surrounding damaged bile ducts in inflamed portal tracts. Neither mast cell density nor distribution was significantly different from controls in posttransplantation biopsy specimens with acute cellular rejection of mild, moderate, or severe degree. The finding of mast cells infiltrating portal tracts and surrounding damaged bile ducts in chronic rejection suggests that hepatic mast cells may be important effector cells in the pathogenesis of chronic rejection. (Liver Transpl 2002;8:50-57.)     

Granulocyte Colony-Stimulating Factor Therapy Is Associated With a Reduced Incidence of Acute Rejection Episodes or Allograft Vasculopathy in Heart Transplant Recipients

BackgroundWe evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients.MethodsOf 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10⁹cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence.ResultsAt baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67–37.2] and OR = 0.09 [0.02–0.52], respectively).ConclusionsG-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.     

Living donor liver transplant recipients achieve relatively higher immunosuppressant blood levels than cadaveric recipients

Two recent brief reports suggest that recipients of living donor liver transplants achieve higher levels of immunosuppressive agents than cadaveric (CAD) liver transplant recipients administered the same dose. These results could have important implications regarding the dosing of immunosuppressives in living donor liver transplant recipients. We report our findings relative to immunosuppressive doses and levels in a cohort of 46 living donor liver transplant recipients. Immunosuppressive blood levels and doses were recorded weeks 1, 2, 3, and 4 and months 2, 3, 4, 5, and 6 for 46 living donor liver transplant recipients and 66 matched CAD liver transplant recipients who underwent transplantation between August 1997 and May 2001. The ratio of level to dose also was recorded at each interval. The mean overall cyclosporine A dose was similar in living donor liver transplant recipients (323 mg/d) compared with CAD recipients (344 mg/d; P = not significant [NS]). The mean overall tacrolimus dose was 15% lower in patients who underwent living donor liver transplantation (LDLT; 5.7 mg/d) than CAD transplantation (6.7 mg/d), although statistical significance was not achieved (P = .08). The mean overall cyclosporine A level was 18% higher in those undergoing LDLT (275 ng/mL) than CAD transplantation (234 ng/mL; P = .015). The mean overall tacrolimus level was the same in living donor liver transplant recipients (10.8 ng/mL) and CAD recipients (10.2 ng/mL; P = NS). The overall cyclosporine A level-dose ratio was 26% higher for those undergoing LDLT (0.83) than CAD transplantation (0.66; P = .01). The overall tacrolimus level-dose ratio was 26% higher for those undergoing LDLT (1.82) than CAD transplantation (1.44; P = .01). In conclusion, (1) living donor liver transplant recipients achieve higher blood levels of tacrolimus and cyclosporine A for a given dose compared with CAD recipients, and (2) this difference is observed up to 6 months after transplantation, when hepatic regeneration is completed. (Liver Transpl 2002;8:212-218.)     

Coadministration of Erythromycin to Increase Tacrolimus Concentrations in Liver Transplant Recipients

BackgroundWe evaluated the effects of using erythromycin (ERY) in liver transplant recipients to improve the early postoperative control of tacrolimus (TAC) concentration.MethodsThis study adopts a retrospective medical record analysis method from January 2015 to December 2017. Assessment items include TAC daily dose (D), TAC whole blood trough level (Co), rejection episodes, and adverse effects. The magnitude of ERY inhibition on TAC metabolism was decided by analyzing dose-corrected trough concentration (Co/D). Oral 250 mg ERY every day to every other day was prescribed when patients needed to swallow more than 10 capsules of TAC per day, TAC trough levels rose too slowly, and/or acute rejection occurred. TAC trough levels were obtained daily. ERY was stopped when the TAC trough level was above 10 ng/mL or rejection episode relieved.ResultsA total of 8 liver transplant recipients was collected. Oral ERY was administered at 6 to 13 days after transplantation. The duration of ERY regimen was 2 to 7 days. The average initial and maximum Co/D was 0.6 ± 0.0 and 1.8 ± 1.0. After ERY was deleted, Co/D was back to the value without ERY at about 2 to 20 days. The magnitude of interaction between tacrolimus and erythromycin is 1.4- to 4.6-fold. The highest dose of TAC was 10 to 12 mg/d. There were no drug-related complications during this period. Acute rejection relapsed in 1 patient after we stopped ERY.ConclusionCoadministration of ERY and TAC is a strategic choice for liver transplant recipients whose TAC blood concentration was difficult in approaching therapeutic levels.     

Intra-Liver Allograft C3d-Binding Donor-Specific Anti-HLA Antibodies Predict Rejection After Liver Transplantation

BackgroundThere is no doubt that antibody-mediated rejection (AMR) due to donor-specific anti-HLA antibodies (DSA) brings a poor outcome for liver transplant recipients. However, the relationship between intragraft DSA (g-DSA), complement-binding abilities, and AMR remains unknown.Materials and MethodsWe enrolled a total of 20 liver transplant recipients who underwent protocol or episode graft biopsies in the mid to long term after liver transplant (median 48.5, range 6-198 months), and their status of g-DSA and complement 3d (C3d)-binding abilities was assessed with the graft immunocomplex capture fluorescence analysis (ICFA) technique.ResultsThe prevalence of g-DSA was 15.0 % in liver transplant recipients (3/20), and serum DSA (s-DSA) also existed in 15.0% of recipients. The number of g-DSA+/s-DSA+, g-DSA+/s–DSA–, g-DSA–/s-DSA+, and g-DSA–/s-DSA– cases are 1, 2, 2, and 15, respectively. The g-DSA+ group demonstrated a significant high rejection activity index: 3.67 ± 1.53, compared with the g-DSA– group: 1.24 ± 1.15 (P = .0045). Moreover, C3d-binding reaction was notably higher in the g-DSA+ group (C3d index: 1.87 ± 0.38 vs 0.76 ± 0.35) (P < .0001). Overall, the g-DSA+ group was more associated with liver allograft rejection—not only AMR, but also T cell–mediated rejection (P = .031).ConclusionsThese results suggest that the existence of g-DSA and intragraft C3d-binding reaction had a negative impact on the liver allografts, but in contrast s-DSA did not have any significant impact.     

Risk factors for acute rejection in liver transplantation and its impact on the outcomes of recipients

ObjectiveTo determine the risk factors for acute rejection in liver transplantation and its impact on the outcomes of the recipients.MethodsClinicopathological data of 290 patients who underwent liver transplantation from January 2012 to December 2021 at our center were retrospectively evaluated. Patients were grouped into an acute rejection (AR) group and a normal (NM) group based on the confirmed histopathological diagnosis of acute rejection. Univariate and multivariate logistic regression were used to determine the risk factors for acute rejection.Results244 patients were included in the study. Acute rejection occurred in 27 (11.1%) of the patients. Warm ischemia time (P = 0.137), cold ischemia time (P = 0.064) and chronic liver failure (P = 0.001) were potential risk factors for acute rejection. Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47–27.32) was the independent risk factor. There was no significant difference in overall survival between recipients with acute rejection and those without it (P = 0.985). The 1-, 3- and 5-year overall survival in the NM group was 98.1%, 85.7% and 78.6% respectively vs 88.9%, 82.5% and 82.5% respectively in the AR group.ConclusionAcute rejection does not appear to affect the long-term survival of the recipients. Only chronic liver failure was an independent risk factor for acute rejection. Our findings further illustrate that contradictions still exist on which factors influence acute rejection in liver transplant recipients.SummaryClinicopathological data of 290 liver transplant recipients at our center between January 2012 and December 2021 were retrospectively evaluated to determine the risk factors for acute rejection and its impact on the outcomes of the recipients. 244 patients were included in the analysis. 27 of the 244 experienced acute rejection. Propensity score matching was performed to reduce the confounding effect. Patients were assigned to an acute rejection group (n = 27) and a normal group (n = 54). Chronic liver failure (P < 0.001, OR = 8.22, 95% CI = 2.47–27.32) was the determined to be independent risk factor for acute rejection. Acute rejection did not appear to affect the long-term survival of the recipients and there was no significant difference in overall survival between the patients with acute rejection and those without it.     

Assessing health-related quality of life pre[ndash ] and post[ndash ]liver transplantation: A prospective multicenter study

We report on a prospective multicenter study to assess pretransplantation and posttransplantation health-related quality of life (HRQL) of liver transplant recipients. HRQL was assessed at several timepoints using a self-completion questionnaire consisting of the EuroQol instrument (EQ-5D) and the 36-Item Short-Form Health Survey (SF-36) health status profile measure. All individuals selected to receive treatment as part of the UK NHS liver transplantation program at each of six liver transplantation centers in England and Wales during a 2-year period (n = 542) were eligible to be included on the study. An overall response rate of 84% (455 responses) was achieved. A paired comparison of HRQL at listing and 3 months posttransplantation showed statistically significant improvements (P [lt ] .05) in all dimensions of the SF-36 (with the exception of Bodily Pain [P = .686]) and the EQ-5D tariff and visual analogue scale (VAS) scores. An analysis of posttransplantation HRQL over time for patients who survived until the end of the study (24 months posttransplantation) showed a statistically significant improvement (P [lt ] .05) for all dimensions of the SF-36 (apart from Mental Health [P = .245] and Role[ndash ]Emotional dimensions [P = .265]) and the EQ-5D VAS and tariff scores. Adjusting for patients who died posttransplantation reduced mean EQ-5D tariff scores substantially, and the change over time in EQ-5D tariff scores was no longer statistically significant (P = .55). Results of regression analysis conducted to assess the importance of patient characteristics and center size on EQ-5D tariff and VAS scores generated posttransplantation indicated there was variation in scores according to patient age and center size. (Liver Transpl 2002;8:263-270.)     

Once-daily tacrolimus extended release formulation: experience at 2 years postconversion from a Prograf-based regimen in stable liver transplant recipients

Compliance with complex immunosuppressant drug therapies in transplant recipients might be improved with regimens that require less frequent dosing. A once-daily extended release (XL) formulation of tacrolimus has been developed that allows a 1:1 conversion from the twice-a-day tacrolimus (TAC) formulation and has a good exposure to trough concentration correlation. In an open-label, multicenter study, stable liver transplant recipients (n=69) were converted from twice-a-day TAC to XL once-daily in the morning, and were maintained for at least 2 years postconversion using the same therapeutic monitoring and patient care techniques employed with TAC. Two years after conversion, the incidence of biopsy-confirmed acute rejection was 5.8% (4 of 69); patient and graft survival was 98.6% (68 of 69). The safety profile of XL was consistent with that previously reported for TAC. Liver transplant recipients can be converted from twice-a-day TAC to once-daily XL and maintained for at least 2 years postconversion with neither unique efficacy nor safety concerns.     

Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience

BackgroundThis study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups.MethodsA total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients.ResultsBaseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040).ConclusionThis study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.     

Use of Tacrolimus and the Development of Posttransplant Diabetes Mellitus: A Brazilian Single-Center, Observational Study

Introduction

Posttransplant diabetes mellitus (PTDM) is considered to be a serious complication of kidney transplantation that may reduce patient and graft survival. The immunosuppressant tacrolimus (TAC) increases the risk of developing PTDM.

Purpose

We sought to estimate the risk of PTDM among renal transplant recipients treated with TAC, to identify other risk factors for PTDM, and to describe its consequences.

Methods

We retrospectively analyzed 413 recipients of ages ≥18 years who were free of diabetes before kidney transplantation. They were treated with TAC, cyclosporine (CyA), or sirolimus (SIR) plus steroid therapy with a minimum follow-up posttransplant of 6 months. PTDM was diagnosed according to American Diabetes Association guidelines.

Results

The mean age was 42.3 years and 230 (55.7%) were male. The initial immunosuppression for 171 (41.4%) patients was TAC; 221 (53.5%), CyA; and 21 (5.1%), SIR. PTDM occurred in 85/413 (20.6%) of patients. The median time to PTDM development was 54 days posttransplant. The cumulative incidence of PTDM was 24.6% and 17.2% for TAC and CyA treatment groups, respectively. In the intention-to-treat analysis, the proportion of patients receiving TAC who developed PTDM was significantly higher than that of CyA (HR = 1.6 [1.01-2.42]; P = .04). The Kaplan-Meier method showed that 78.5% patients taking TAC were free of PTDM at 6 months compared with 88.8% taking CyA (P = .003). The other independent risk factors were body mass index (BMI; P < .0001); recipient age (P < .0001) and acute rejection episodes (AE; P = .01). Three-year actuarial graft survivals were 85.5% for PTDM patients compared with 93.3% for those without diabetes (P = .021); patient survivals, 88.9% and 96.7%, respectively (P = .017).

Conclusion

The incidence of PTDM is associated with TAC use, recipient age, BMI, and ARE. Therefore, PTDM is an important risk factor for graft loss and mortality.     

Clinical relevance of sHLA-G-mediated with better graft acceptance in early posttransplantation

The aim of this study was to measure the level of soluble human leukocyte antigen (sHLA-G) in renal transplant patients, to determine the relationship between these levels and the occurrence of acute rejection episodes, and to identify their influence on graft acceptance early posttransplantation. sHLA-G, as measured by an enzyme-linked immunosorbent assay, was significantly increased (P < .01) early posttransplantation (3 months); the other group maintained low levels throughout the study. The latter group displayed a high incidence of acute rejection episodes and a lower clearance of serum creatinine with a longer period for hemoglobin to recover to normal (P < .01). These results suggested that HLA-G participates in the induction of immunologic tolerance in these recipients.     

Immunoprophylaxis with basiliximab,a chimeric anti[ndash ]interleukin-2 receptor monoclonal antibody,in combination with azathioprine-containing triple therapy in liver transplant recipients

Acute graft rejection remains a major problem among additional sequelae in liver transplant recipients. Basiliximab, a chimeric monoclonal antibody with high affinity for the CD25 chain of the interleukin-2 receptor, has significantly reduced the incidence of acute rejection episodes in renal transplant recipients. This single-arm, open-label, multicenter study investigated the efficacy and tolerability of basiliximab immunoprophylaxis in adult patients undergoing first elective liver transplantation. One hundred one patients (70 hepatitis C virus [HCV]-negative patients, 31 HCV-positive patients) were administered basiliximab, 20 mg, by intravenous bolus injection the day of transplantation (day 0) and day 4. In addition, all patients were administered triple immunosuppressive therapy with cyclosporine, steroids, and azathioprine. The efficacy of basiliximab was assessed by conventional parameters, and tolerability was assessed by the incidence of adverse events, infections, and laboratory test result abnormalities. At 6 months, the incidence of first acute biopsy-confirmed rejection episodes was 22.8%. Rejections were more frequent in the HCV-positive (29.0%) than HCV-negative subgroup (20.0%; P = .441). No rejection episode was graded histologically as severe, and no patient required antibody therapy for the management of acute rejection. Ten patients (9.9%) required treatment with tacrolimus for acute rejection episodes. Patient and graft survival rates at 12 months were 90.1% and 88.1%, respectively. Basiliximab caused no injection-site reactions, anaphylaxis, or cytokine release syndrome. Five malignancies were reported at 12 months: of these, three malignancies predated transplantation surgery. Compared with earlier studies, the addition of basiliximab immunoprophylaxis to triple immunosuppressive therapy provides increased efficacy in reducing the incidence of acute rejection episodes, with no clinically significant increase in adverse events. (Liver Transpl 2002;8:123-131.)