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Biomarker Assessment of the Immunomodulator Effect of Atorvastatin in Stable Renal Transplant Recipients and Hypercholesterolemic Patients

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Abstract

Background: HMG-CoA reductase inhibitors (statins) have effects beyond lipid lowering, including immunomodulatory and anti-inflammatory properties. Statins are frequently combined with immunosuppressive agents in transplant recipients to modulate the hyperlipidemic side effects of the immunosuppressants. However, the role of statins in the immunosuppressive response that is achieved in individual patients remains to be assessed.

Objective: The aim of this study was to evaluate the immunomodulatory effect of atorvastatin given alone and in combined treatment with tacrolimus and mycophenolate mofetil.

Study Design: Two patient groups were studied: renal transplant recipients receiving tacrolimus and mycophenolate mofetil therapy, and hypercholesterolemic patients (the control group). Fasting blood samples were taken from participants before and 1 month after atorvastatin treatment was started to study a small battery of biomarkers that are able to reflect the range of the effects of immunosuppressive therapy and atorvastatin.

Setting: All patients in the study were enrolled at the Hospital Clinic of Barcelona.

Patients: All patients enrolled in the study were candidates for treatment with atorvastatin because of high cholesterol levels. One group consisted of 25 stable renal transplant recipients with low-density lipoprotein (LDL) cholesterol levels above 100mg/dL after 3 months of therapeutic lifestyle changes, according to the guidelines of the National Kidney Foundation —Kidney Disease Outcomes Quality Initiative. The other group included 25 hypercholesterolemic patients with LDL cholesterol levels above target values for the patients’ overall risk, as derived from the National Cholesterol Education Program Adult Treatment Panel III criteria.

Intervention: Atorvastatin (Lipitor®) treatment was started at a fixed dose of 20 mg daily.

Main Outcome Measure: The studied biomarkers were lymphocyte proliferation, intracellular adenosine triphosphate (ATP) synthesis in CD4+ T cells, intralymphocytary cytokine expression (interleukin [IL]-2, interferon [IFN]-γ), soluble cytokine production (IL-2, IFN-γ, IL-10, IL-17, and transforming growth factor-β) and regulatory T (Treg) cells.

Results: Atorvastatin proved to be an immunomodulatory agent, significantly decreasing lymphocyte proliferation by 15% (p = 0.001), increasing ATP levels by 16% (p = 0.0004), and showing a trend toward increasing Treg cells in hypercholesterolemic patients (p = 0.09). In the renal transplant recipients, atorvastatin therapy did not modify any of the biomarkers of immunosuppression that were studied.

Conclusion: Atorvastatin showed immunoregulatory effects on T cells in hypercholesterolemic patients. These effects were absent in renal transplant recipients, suggesting that the beneficial effects of atorvastatin in this patient group do not relate to immunoregulation. Therefore, statin treatment cannot be considered as a means to reduce the dose of immunosuppressive agents.

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Acknowledgments

This study was partially supported by a grant from the “Institut d’Investigacions Biomièdiques August Pi i Sunyer” (IDIBAPS) awarded to David Guillén and by a grant from the “Fundación)n de Investigación Médica Mutua Madrilena” awarded to Olga Millán. The authors’ work was independent of the funders. CIBERehd and CIBERobn are initiatives of ISCIII, Spain. The authors declare no conflict of interest. Research design: Mercè Brunet. Writing of the paper: David Guillén, Federico Cofán, Emilio Ros, Mercè Brunet. Performance of the research: David Guillén, Federico Cofán, Emilio Ros, Olga Millám, Montse Cofán. Data collection: David Guillén, Federico Cofán, Emilio Ros, Montse Cofán. Data analysis: David Guillén, Olga Millán, Mercè Brunet.

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Authors and Affiliations

  1. Pharmacology Laboratory (Biomedical Diagnosis Center), Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    David Guillén, Olga Millán &  Mercè Brunet

  2. Departament de Salut Pública, Facultat de Medicina, University of Barcelona, Barcelona, Spain

    David Guillén &  Mercè Brunet

  3. Renal Transplant Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain

    Federico Cofán

  4. Lipid Clinic, Endocrinology and Nutrition Service, Hospital Clinic, IDIBAPS, Barcelona, Spain

    Emilio Ros & Montse Cofán

  5. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain

    Emilio Ros & Montse Cofán

  6. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), ISCIII, Barcelona, Spain

    Olga Millán &  Mercè Brunet

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  1. David Guillén
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  2. Federico Cofán
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  4. Olga Millán
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  6. Mercè Brunet
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Correspondence to Mercè Brunet.

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Guillén, D., Cofán, F., Ros, E. et al. Biomarker Assessment of the Immunomodulator Effect of Atorvastatin in Stable Renal Transplant Recipients and Hypercholesterolemic Patients. Mol Diag Ther 14, 357–366 (2010). https://doi.org/10.1007/BF03256393

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