Biomarker assessment of the immunomodulator effect of atorvastatin in stable renal transplant recipients and hypercholesterolemic patients.
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.


METHODS
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.


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


METHODS
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 100 mg/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.


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


METHODS
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 (T(reg)) 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 T(reg) 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.


CONCLUSIONS
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.
Pharmacology Laboratory (Biomedical Diagnosis Center), Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
David
D
Guillén
Federico
F
Cofán
Emilio
E
Ros
Olga
O
Millán
Montse
M
Cofán
Mercè
M
Brunet
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000032:analysis; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use; D014180:Transplantation
D015415:Biomarkers; D017077:Culture Media, Conditioned; D016207:Cytokines; D006538:Heptanoic Acids; D007166:Immunosuppressive Agents; D011758:Pyrroles; D000255:Adenosine Triphosphate; D000069059:Atorvastatin; D009173:Mycophenolic Acid; D016559:Tacrolimus