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  • Stumpf J
  • Budde K
  • Witzke O
  • Sommerer C
  • Vogel T
  • et al.
E Clinical Medicine. 2023 Dec 22;67:102381 doi: 10.1016/j.eclinm.2023.102381.
BACKGROUND:

Optimal initial tacrolimus dosing and early exposure of tacrolimus after renal transplantation is not well studied.

METHODS:

In this open-label, 6 months, multicenter, randomized controlled, non-inferiority study, we randomly assigned 432 renal allograft recipients to receive basiliximab induction, mycophenolate and steroids and either standard prolonged-release tacrolimus (trough levels: 7-9 ng/ml; Standard Care arm), or an initial 7-day fixed 5 mg/day dose of prolonged-release tacrolimus followed by lower tacrolimus predose levels (trough levels: 5-7 ng/ml; Slow & Low arm). The primary end point was the combined incidence rate of biopsy-proven acute rejections (BPAR; including borderline), graft failure, or death at 6 months with a non-inferiority margin of 12.5%. (EudraCT-Nr: 2013-001770-19.

FINDINGS:

The combined primary endpoint in the Slow & Low arm was non-inferior compared to the Standard Care arm (22.1% versus 20.7%; difference: 1.4%, 90% CI -5.5% to 8.3%). The overall rate of BPAR including borderlines was similar (Slow & Low 17.4% versus Standard Care 16.6%). Safety parameters such as delayed graft function, kidney function, donor specific HLA-antibodies, infections, or post-transplantation diabetes mellitus did not differ.

INTERPRETATION:

This is the first study to show that an initial fixed dose of 5 mg per day followed by lower tacrolimus exposure is non-inferior compared to standard tacrolimus therapy and equally efficient and safe within 6 months after renal transplantation. These data suggest that therapeutic drug monitoring for prolonged release tacrolimus can be abandoned until start of the second week after transplantation.

FUNDING:

Investigator-initiated trial, financial support by Astellas Pharma GmbH.

  • Ramachandran G
  • Pottakkat B
  • Basu S
  • Mohan P
Clin Nutr ESPEN. 2023 Oct;57:703-710 doi: 10.1016/j.clnesp.2023.08.021.
CET Conclusion
Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This is a very interesting and well conducted RCT in patients on the liver transplant waiting list. The study was double-blinded, so patients and clinicians were not aware whether each patient was receiving the probiotic treatment or placebo, available in identical capsules. Treatment was given for 6 weeks. Malnutrition is an important complication of cirrhosis and is related to patient outcome with or without transplantation. A sample size was calculated in advance assuming a relatively large dropout proportion, 215 patients were recruited. The assumption on dropout rate was actually quite accurate, and importantly intention to treat analysis was done. Overall patient compliance was very good. The proportion of patients who were well-nourished significantly increased after probiotic therapy, and no change was seen in the placebo group (subjective global assessment). The proportion of overweight and obese patients increased in the treatment group, but not in the placebo group. The proportion of underweight patients did not change in either group. Probiotic use was associated with significant improvement in CTP (Child Turcotte Pugh) score, and reduction in ascites. There was no change in MELD scores. There was no significant difference in survival over the observation period. When compared to baseline biochemical parameters, probiotic treatment was associated with decreased direct bilirubin levels, whilst other parameters remained unchanged. In the placebo group, there was a significant increase in the levels of urea from baseline, and other parameters did not show any significant changes. Overall, the study has shown significant beneficial impacts of probiotic therapy in this patient population without any negative impact of a simple therapy. It is possible that more convincing clinical outcomes would be seen with a longer duration of probiotic therapy, and in a population with more severe liver disease.
Aims: This study aimed to investigate how nutritional status, biochemical parameters, and the severity of liver disease are influenced by the administration of probiotics in patients with cirrhosis referred for liver transplantation.
Interventions: Participants were randomised to receive probiotics or placebo.
Participants: 215 cirrhotic patients referred for liver transplantation
Outcomes: The main outcomes were assessment of nutritional status using subjective global assessment (SGA) and anthropometric measurements like weight, height, body mass index (BMI), mid upper arm circumference (MUAC), triceps skin fold thickness (TSF), mid-arm muscle circumference (MAMC) and hand grip strength (HGS); liver function parameters including bilirubin, alanine transferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and international normalized ratio (INR); and severity of liver disease using the Child Turcotte Pugh classification (CTP) and Model for end-stage liver disea
Follow Up: 6 weeks
INTRODUCTION:

Probiotics have been shown to be effective in many diseases. However, their effects on the nutritional status in patients with cirrhosis is uncertain.

AIM:

We aimed to study the effect of probiotics on nutritional status, biochemical parameters, and liver disease severity in patients with cirrhosis referred for liver transplantation.

METHODS:

A randomised, double-blind, placebo-controlled study was conducted from July 2021-October 2022. A total of 215 patients with cirrhosis referred for liver transplantation were enrolled and randomised to two groups to receive either probiotics (VSL#3, Sun Pharma, India, 112.5 billion colony-forming units (cfu) containing eight strains of bacteria) or placebo (corn starch filled capsules), two capsules/day for six weeks. Nutritional assessment was done, and biochemical parameters were measured before and after the intervention.

RESULTS:

Nutritional assessment parameters like body mass index (p = 0.001), triceps skin fold thickness (p = 0.011), muscle strength (p = 0.007) and subjective global assessment scores (p < 0.000) showed a positive trend in the probiotic group. Probiotic intake also significantly downregulated direct bilirubin levels (p = 0.043) and increased albumin levels compared to baseline, but other biochemical parameters remained unchanged. Child Turcotte Pugh score also decreased significantly compared to pre therapy (p = 0.0001). These changes were not observed in the placebo group. Moreover, probiotic VSL#3 supplementation was safe and well-tolerable without any adverse events in patients with cirrhosis.

CONCLUSION:

Probiotic VSL#3 supplementation improved the nutritional status, reduced the severity of liver disease and was safe and tolerable in patients with cirrhosis.

TRIAL REGISTRATION:

www.ctri.nic.in (CTRI/2021/07/034917).

  • Lloberas N
  • Grinyó JM
  • Colom H
  • Vidal-Alabró A
  • Fontova P
  • et al.
Kidney Int. 2023 Oct;104(4):840-850 doi: 10.1016/j.kint.2023.06.021.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This single-centre randomised study compared initial tacrolimus dosing by body weight (control), or by Bayesian prediction (study), following renal transplantation. Patients in the study group had their tacrolimus dosing guided by a Bayesian model incorporating age, haematocrit and CYP3A genotype. The authors demonstrate that a significantly higher proportion of patients in the study arm achieved therapeutic target, with lower interpatient variability, shorter time to target trough concentrations and fewer dose modifications. Whilst no differences in clinical outcomes were seen, there was a trend towards lower incidence and shorter duration of DGF in the study group. These results are very promising and appear to demonstrate the benefit of personalised dosing using the Bayesian model. The population in this study are from a single centre, and predominantly male and Caucasian. Future studies should confirm these findings in populations with a greater mix of ethnicity, and confirm potential clinical benefit in a larger sample.
Aims: The aim of this study was to evaluate the clinical applicability of a Population pharmacokinetic (PPK) model for achieving Tac Co (therapeutic trough Tac concentration) versus the manufacturer’s labelling dosage.
Interventions: Participants were randomised to either the PPK group or the control group with patients receiving Tac adjustment according to the manufacturer’s labeling.
Participants: 96 adult renal transplant recipients
Outcomes: The primary outcome was the percentage of patients reaching the Tac Co target (6 and 10 ng/ml) after the first steady state. The secondary outcomes were the timing needed to reach the therapeutic target, the number of dose modifications needed to reach the target, and the clinical outcome.
Follow Up: 90 days posttransplantation

For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer's labeling based on a patient's body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer's labelling dosage. A prospective two-arm, randomized, clinical trial was conducted to determine Tac starting and subsequent dose adjustments in 90 kidney transplant recipients. Patients were randomized to a control group with Tac adjustment according to the manufacturer's labeling or the PPK group adjusted to reach target Co (6-10 ng/ml) after the first steady state (primary endpoint) using a Bayesian prediction model (NONMEM). A significantly higher percentage of patients from the PPK group (54.8%) compared with the control group (20.8%) achieved the therapeutic target fulfilling 30% of the established superiority margin defined. Patients receiving PPK showed significantly less intra-patient variability compared to the control group, reached the Tac Co target sooner (5 days vs 10 days), and required significantly fewer Tac dose modifications compared to the control group within 90 days following kidney transplant. No statistically significant differences occurred in clinical outcomes. Thus, PPK-based Tac dosing offers significant superiority for starting Tac prescription over classical labeling-based dosing according to the body weight, which may optimize Tac-based therapy in the first days following transplantation.

  • Arends EJ
  • Meziyerh S
  • Moes DJAR
  • Kamerling SWA
  • van der Kooy S
  • et al.
Kidney Int Rep. 2023 Sep 7;8(12):2654-2664 doi: 10.1016/j.ekir.2023.09.003.
INTRODUCTION:

Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus in vitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunocompromised patients.

METHODS:

First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a post hoc analysis on SARS-CoV-2 infections in 216 patients with lupus nephritis (LN) on standard immunosuppression who were randomly exposed to voclosporin or placebo as part of a clinical trial that was conducted during the worldwide COVID-19 pandemic.

RESULTS:

The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8-28) and tacrolimus-treated KTRs (median 12 days, IQR 4-16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (ΔCt 7.7 [3.4-10.7]) compared to tacrolimus-treated KTRs (ΔCt 2.7 [2.0-4.3]; P = 0.035). In voclosporin-exposed patients with LN, SARS-CoV-2 infection was detected in 6% (7/116) compared to 12% (12/100) in placebo-exposed patients (relative risk [RR] 1.4 [0.97-2.06]). Notably, no voclosporin-exposed patients with LN died from severe SARS-CoV-2 infection compared to 3% (3/100) in placebo-exposed patients (RR 2.2 [1.90-2.54]).

CONCLUSION:

This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.

  • Wöhl DS
  • James B
  • Götz M
  • Brennfleck F
  • Holub-Hayles I
  • et al.
Trials. 2023 May 11;24(1):325 doi: 10.1186/s13063-023-07344-7.
BACKGROUND:

Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients.

METHODS:

The EnGraft compares bioavailability and tests superiority of Envarsus® (test arm) versus Advagraf™ (comparator arm) in de novo LTx recipients. A total of 268 patients from 15 German transplant centres will be randomised 1:1 within 14 days post-LTx. The primary endpoint is dose-normalised trough level (C/D ratio) measured 12 weeks after randomisation. Secondary endpoints include the number of dose adjustments, time to reach first defined trough level and incidence of graft rejections. Additionally, clinical and laboratory parameters will be assessed over a 3-year period.

DISCUSSION:

C/D ratio is an estimate for tacrolimus bioavailability. Improving bioavailability and increasing C/D ratio using Envarsus could reduce renal dysfunction and other tacrolimus-related toxicities; previous trials have shown that a higher C/D ratio (i.e. slower tacrolimus metabolism) is not only associated with improved renal function but also linked to reduced neurotoxic side effects. A higher C/D ratio could improve clinical outcomes for LTx recipients; EnGraft has begun, with one third of patients recruited by January 2022.

TRIAL REGISTRATION:

This trial has been registered (4 May 2020) in the EU Clinical Trials Register, EudraCT-Nummer: 2020-000796-20. Additionally, this trial has been registered (22 January 2021) at ClinicalTrials.gov: NCT04720326. The trial received a favourable opinion from the concerned lead ethics committee at the University of Regensburg, under the reference 20-1842-112.

  • Vinke JS
  • Eisenga MF
  • Sanders JF
  • Berger SP
  • Spikman JM
  • et al.
BMJ Open. 2023 Mar 22;13(3):e065423 doi: 10.1136/bmjopen-2022-065423.
INTRODUCTION:

Iron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs.

METHODS AND ANALYSIS:

The Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin <100 µg/L or plasma ferritin 100-299 µg/L with transferrin saturation <20%. Patients are randomised to receive 10 mL of ferric carboxymaltose (50 mg Fe3+/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function.

ETHICS AND DISSEMINATION:

The protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations.

TRIAL REGISTRATION NUMBER:

NCT03769441.

  • Mohebbi N
  • Ritter A
  • Wiegand A
  • Graf N
  • Dahdal S
  • et al.
Lancet. 2023 Feb 18;401(10376):557-567 doi: 10.1016/S0140-6736(22)02606-X.
CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This multicentre study from Switzerland investigated the effect of using sodium bicarbonate to correct metabolic acidosis on the graft function of stable renal transplant recipients. Recipients with a serum bicarbonate level of <22 mmol/L were randomised to oral sodium bicarbonate or placebo for 2 years. Despite adequate correction of metabolic acidosis in the treatment group, there was no difference in eGFR decline between groups, leading the authors to conclude that sodium bicarbonate supplementation to preserve GFR in renal transplant recipients is not recommended. The methodology of the study is excellent, with centralised variable block randomisation and placebo-control. A modified ITT analysis is used including all patients who were randomised and attended a baseline visit. It should be noted that the mean serum bicarbonate level in both groups at baseline was only just below the lower limit of normal (~21 mmol/L), leaving the possibility that greater benefit may be seen in patients with a more profound acidosis. However, this was not supported by prespecified subgroup analysis (albeit with more limited statistical power).
Aims: The aim of this study was to examine the effects of sodium bicarbonate treatment on graft function in renal transplant patients with metabolic acidosis.
Interventions: Participants were randomised to receive either oral sodium bicarbonate or matching placebo.
Participants: 242 kidney transplant recipients with metabolic acidosis.
Outcomes: The primary outcome was the estimated glomerular filtration rate (GFR) slope over a treatment phase of 24 months. Secondary outcomes were serum bicarbonate and pH, albuminuria, and mean daytime systolic and diastolic blood pressure.
Follow Up: 24 months
BACKGROUND:

Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients.

METHODS:

The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996.

FINDINGS:

Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death.

INTERPRETATION:

In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis.

FUNDING:

Swiss National Science Foundation.

  • Meurisse N
  • Mertens M
  • Fieuws S
  • Gilbo N
  • Jochmans I
  • et al.
JAMA Netw Open. 2023 Feb 1;6(2):e230819 doi: 10.1001/jamanetworkopen.2023.0819.
CET Conclusion
Reviewer: Mr John Fallon, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: The investigators found no significant benefit of their CDA in the parameters they used for surrogates of IRI. The study design is sound, but there are some noteworthy limitations. The complex drug regimen was based on a proof-of-concept study done in a porcine transplant model in which they found substantial improvement in IRI. However, the drug regimen had to be altered, nearly all the compounds were altered and replaced with drugs that should have a similar biological effect, but many of which operate via different mechanisms. The level of control in an animal house model is unable to be recreated in real world transplantation, as well as the altered biology between our species. These limitations will have contributed to the inconclusive findings along with the study being powered for a 50% reduction in peak AST. This being said, the strategy did not seem to cause harm, with graft and overall survival being the same, and this sort of multiangled therapeutic approach being the likely strategy required to cause meaningful amelioration of IRI. The authors point out that they may have been more successful if the treatments could have been delivered during a normothermic preservation method rather than traditional static cold storage. The study design transplanted into a normothermic model may prove to be more fruitful.
Aims: The investigators aimed to use a combined drug approach (CDA) vs standard care to reduce the magnitude of ischaemia reperfusion injury (IRI) during liver transplant.
Interventions: Participants were randomised to either the CDA group or the standard of care only (control) group.
Participants: 74 adult primary full-size liver transplant recipients from donation after brain death (DBD) or Maastricht 3 donation after circulatory death (DCD) donors.
Outcomes: Primary outcome measure was peak aspartate aminotransferase (AST) at 72-hours post-transplant. Secondary outcome measures were: frequency of post-reperfusion syndrome, early allograft dysfunction (EAD), severe surgical complications, ischaemic cholangiopathy, acute kidney injury (AKI) and acute cellular rejection.
Follow Up: Participants were followed-up for 12 months.
IMPORTANCE:

In a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant.

OBJECTIVE:

To assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury.

DESIGN, SETTING, AND PARTICIPANTS:

This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020.

INTERVENTIONS:

Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival.

RESULTS:

Of 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; P = .49) (to convert AST to μkat/L, multiply by 0.0167). There also were no significant differences in the secondary end points between the groups.

CONCLUSIONS AND RELEVANCE:

In this randomized clinical trial, the combined drug approach targeting the post-cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT02251041.

  • Metz M
  • Beghini M
  • Wolf P
  • Pfleger L
  • Hackl M
  • et al.
Cell Metab. 2022 Nov 1;34(11):1719-1731.e5 doi: 10.1016/j.cmet.2022.09.020.

Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight patients with non-alcoholic fatty liver disease and relative hypoleptinemia independent of its anorexic action. In rodents, leptin signaling in the brain increases very-low-density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled crossover trial (EudraCT Nr. 2017-003014-22), we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. A single metreleptin injection stimulated hepatic VLDL-TG secretion (primary outcome) and reduced hepatic lipid content in fasted, lean men (n = 13, age range 20-38 years) but failed to do so in metabolically healthy liver transplant recipients (n = 9, age range 26-62 years) who represent a model for hepatic denervation. In an independent cohort of lean men (n = 10, age range 23-31 years), vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.

  • Darnaude-Ximénez I
  • Caballero-Bermejo AF
  • Ruiz-Antorán B
  • Aguilar-Pérez M
  • Gómez-López A
  • et al.
JMIR Res Protoc. 2022 Sep 14;11(9):e37275 doi: 10.2196/37275.
BACKGROUND:

Aspergillosis is the most frequently observed invasive fungal disease (IFD) in lung transplant recipients. Isavuconazole (ISA) has shown a better safety profile and noninferiority to voriconazole in the treatment of patients with IFD.

OBJECTIVE:

The aim of this study is to describe the bronchopulmonary pharmacokinetic profile of oral ISA by analyzing the degree of penetration in the epithelial lining fluid and alveolar macrophages in patients receiving lung transplantation with a diagnosis of IFD.

METHODS:

A total of 12 patients aged ≥18 years receiving a lung transplant with an IFD diagnosis and indication for ISA treatment and follow-up bronchoscopy will be included in the study. After 5 days of treatment with ISA and before the treatment is discontinued, the patients will be randomized (1:1:1:1) to perform the scheduled bronchoscopy at various times after the administration of ISA (2, 4, 8, and 12 hours). In total, 4 blood samples will be obtained per patient: at 72 hours after treatment initiation, on the day of the bronchoscopy, at the time of the bronchoalveolar lavage (simultaneously), and at 7 days after treatment initiation, to analyze tacrolimus and ISA plasma levels. ISA concentrations will be measured in plasma, epithelial lining fluid, and alveolar macrophages by a high-performance liquid chromatography/UV coupled to fluorescence method.

RESULTS:

Enrollment for the PBISA01 trial began in October 2020 and was completed in October 2021. All samples will be analyzed once recruitment is complete, and the results are expected to be published in October 2022.

CONCLUSIONS:

There are no clinical studies that analyze the bronchopulmonary penetration of ISA. Bronchoalveolar lavage performed routinely in the follow-up of lung transplant recipients constitutes an opportunity to analyze the bronchopulmonary penetration of ISA.

TRIAL REGISTRATION:

European Clinical Trials Register 2019-004240-30; www.clinicaltrialsregister.eu/ctr-search/trial/2019-004240-30/ES.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):

DERR1-10.2196/37275.