title: 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.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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 than that of the higher sensitivity subgroup of 2 of 31 (P = 0.0012). A similar case was observed using the cutoff IC50 value of methylprednisolone (P = 0.0012), whereas recipient grouping according to the cutoff IC50 values of cyclosporine and tacrolimus failed to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal.
  
  
  CONCLUSIONS
  Glucocorticoid pharmacodynamics in lymphocytes of individual patient origin is a reliable biomarker for differentiation of renal transplant recipients who will experience a safe reduction/withdrawal of glucocorticoid.
authors.affiliation: Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan; Department of Surgery, Uygur Autonomous Region People׳s Hospital, Xinjiang Uyghur Autonomous Region, China.
authors.forename: Gulimire
authors.initials: G
authors.lastname: Muhetaer
authors.affiliation: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Unezaki
authors.affiliation: Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kawachi
authors.affiliation: Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Fifth Department of Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
authors.forename: Motohide
authors.initials: M
authors.lastname: Shimazu
authors.affiliation: Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Clinical Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Electronic address: hiranot@toyaku.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000328:Adult; D064591:Allografts / Q000503:physiopathology; D019540:Area Under Curve; D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000503:physiopathology; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D012372:ROC Curve; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D016559:Tacrolimus / Q000494:pharmacology; D028761:Withholding Treatment
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D006854:Hydrocortisone; D016559:Tacrolimus; D008775:Methylprednisolone
keywords: T-cell mitogen; glucocorticoid withdrawal; immunosuppressive drugs; peripheral-blood mononuclear cells; pharmacodynamics; renal transplantation