Tacrolimus with mycophenolate mofetil or sirolimus compared with calcineurin inhibitor-free immunosuppression (sirolimus/mycophenolate mofetil) after heart transplantation: 5-year results

Kaczmarek, Ingo; Zaruba, Marc-Michael; Beiras-Fernández, Andrés; Reimann, R.; Nickel, Thomas; Grinninger, Carola; Sadoni, Sebastian; Hagl, Christian; Meiser, Bruno

doi:10.1016/j.healun.2012.11.028

Cited by 51 publications

(32 citation statements)

References 14 publications

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“…AKI in the first days after transplantation may be due to shock, systemic inflammation, and/or nephrotoxic drugs [4–6]. One such nephrotoxic drug is tacrolimus, a very effective immunosuppressant belonging to the calcineurin inhibitor class and ubiquitously used in lung transplant patients [7–11]. …”

Section: Introductionmentioning

confidence: 99%

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

Sikma

Hunault

Graaf

et al. 2017

Eur J Clin Pharmacol

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PurposeLung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury.MethodsWe retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions.ResultsAKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06–2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02–3.77), infection (OR 2.48; 95% CI 1.31–4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16–4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%.ConclusionsAfter lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation.What is known about this subject?• Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality.• To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated.• The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic.What this study adds:• For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation.• Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation.• AKI after lung transplantation shows low recovery rates. Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-017-2204-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

Sikma

Hunault

Graaf

et al. 2017

Eur J Clin Pharmacol

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“…It should be emphasized that we tested isolated effects of single drugs used in transplantation medicine, but in clinical practice regular transplantation therapy regimens involve two or more simultaneously administered drugs (Favi et al, 2013;Guethoff et al, 2013;Kaczmarek et al, 2013). Some of the drugs tested (RAP, EVE, MYC) displayed stimulating effect on AhR activation by TCDD in human cancer cell lines, which is a novel finding not described before.…”

Section: Discussionmentioning

confidence: 72%

The effects of drugs with immunosuppressive or immunomodulatory activities on xenobiotics-metabolizing enzymes expression in primary human hepatocytes

Vrzal

Ženata

Bachleda

et al. 2015

Toxicology in Vitro

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“…Freedom from BPAR decreased but was statistically not significant in the SRL/MMF group (73.3%) compared to the TAC/MMF (82.4%) and TAC/SRL groups (85.2%). After 5 years, the renal function remained normal in the SRL/MMF group, which was better by comparison with CNI‐containing regimens (Table ) …”

Section: De Novo Cni‐free Immunosuppressionmentioning

confidence: 97%

Renal protection strategies after heart transplantation

Reichart¹,

Reichenspurner²,

Barten³

2018

Clinical Transplantation

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Renal dysfunction caused by calcineurin inhibitor (CNI) nephrotoxicity occurs often and contributes significantly to late mortality after heart transplantation (HTx). Over the last decades, this has prompted many clinical studies in an effort to develop kidney-protecting immunosuppressive strategies including delayed CNI start, minimization, withdrawal, or even de novo CNI avoidance. In the past, these strategies often failed due to the lack of efficacy. Since 2009, novel CNI-reducing strategies have been under investigation. These strategies minimize renal damage using induction agents such as antithymocyte globulin and alternative immunosuppressive agents such as the mechanistic target of rapamycin inhibitors (sirolimus or everolimus) or mycophenolate.This review outlines the recent results of using these renal protection strategies including their drawbacks. We also discuss alternative approaches to optimize individual immunosuppressive therapies after HTx. K E Y W O R D Scalcineurin inhibitors, heart transplantation, immunosuppression, mechanistic target of rapamycin inhibitors, nephrotoxicity, renal protecting strategies

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Tacrolimus with mycophenolate mofetil or sirolimus compared with calcineurin inhibitor-free immunosuppression (sirolimus/mycophenolate mofetil) after heart transplantation: 5-year results

Cited by 51 publications

References 14 publications

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury

The effects of drugs with immunosuppressive or immunomodulatory activities on xenobiotics-metabolizing enzymes expression in primary human hepatocytes

Renal protection strategies after heart transplantation

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