Clinical Significance of Peripheral Blood Lymphocyte Sensitivity to Glucocorticoids for the Differentiation of High-risk Patients With Decreased Allograft Function After Glucocorticoid Withdrawal in Renal Transplantation

• Published in: Clinical therapeutics 2014-08, Vol.36 (8), p.1264-1272
• Main Authors: Muhetaer, Gulimire, MD, Takeuchi, Hironori, PhD, Unezaki, Sakae, PhD, Kawachi, Shigeyuki, MD, Iwamoto, Hitoshi, MD, Nakamura, Yuki, MD, Shimazu, Motohide, MD, Sugiyama, Kentaro, PhD, Hirano, Toshihiko, PhD
• Format: Article
• Language: English
• Subjects: Adult; Allografts - physiopathology; Area Under Curve; Biomarkers; Blood; Cell Proliferation - drug effects; Cells, Cultured; Cyclosporine - pharmacology; Drug dosages; Female; glucocorticoid withdrawal; Glucocorticoids - adverse effects; Glucocorticoids - pharmacology; Humans; Hydrocortisone - blood; Hydrocortisone - pharmacology; Immunosuppressive Agents - pharmacology; immunosuppressive drugs; Inhibitory Concentration 50; Internal Medicine; Kidney - physiopathology; Kidney Transplantation; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Male; Medical Education; Methylprednisolone - pharmacology; Middle Aged; Patients; peripheral-blood mononuclear cells; pharmacodynamics; Renal Insufficiency - chemically induced; Renal Insufficiency - physiopathology; renal transplantation; Retrospective Studies; Risk Assessment - methods; ROC Curve; T-cell mitogen; Tacrolimus - pharmacology; Transplants & implants; Withholding Treatment
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2014.06.019

Abstract Purpose A reliable biomarker to differentiate high-risk recipients who will experience a decrease in allograft function after glucocorticoid withdrawal has not been established in renal transplantation. We examined the clinical significance of peripheral blood lymphocyte sensitivity to glucocorticoids in vitro for the differentiation of the high-risk patients after glucocorticoid reduction/withdrawal in renal transplant recipients. Methods The study included 44 renal transplant recipients with stable allograft function. Peripheral lymphocyte responses to suppressive effects of cortisol, methylprednisolone, cyclosporine, and tacrolimus in mitogen assay procedures in vitro were examined. Clinical outcome after glucocorticoid reduction/withdrawal was retrospectively compared between recipients with lymphocytes normally sensitive to the drugs and those with hyposensitivity. The receiver-operating characteristic (ROC) curve analysis was undertaken for setting the cutoff IC50 values of the drugs against the T cell mitogen–induced lymphocyte proliferation to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal. Findings The median (range) IC50 value for cortisol in the recipients who showed decreased renal function due to glucocorticoid withdrawal was 10,000 (570.9–72,279.3) ng/mL (n = 9), which was significantly higher than the value of 351.6 (2.0–10,000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 35) ( P < 0.001). Similarly, the median (range) IC50 value for methylprednisolone in the recipients who showed decreased renal function after glucocorticoid withdrawal was 69.1 (21.5–1442.7) ng/mL (n = 9), which was significantly higher than the value of 13.8 (0.7–1000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 30) ( P < 0.003). In contrast, there was no significant difference in the median IC50 values of cyclosporine and tacrolimus between the 2 recipient subgroups. The ROC curve analyses for the IC50 values of the immunosuppressive drugs estimated the cutoff value of cortisol and methylprednisolone to be 3580.0 and 21.5 ng/mL, respectively. The ROC AUCs for cortisol and methylprednisolone were 0.83 and 0.84, respectively. According to the cutoff IC50 value, the incidence of decreased allograft function in the low cortisol sensitivity (IC50 >3580.0 ng/mL) subgroup was 7 of 13 patients, which was significantly higher th