Glucocorticoid-resistance in peripheral-blood lymphocytes does not correlate with number of affinity of glucocorticoid-receptors in chronic renal failure patients.
Glucocorticoid (GC) resistance in patients with chronic renal failure (CRF) seriously impairs successive GC therapy after renal transplantation. We examined the relationship between GC-receptor (GC-R) parameters in peripheral-blood mononuclear cells (PBMC) and PBMC resistance to GC in 21 CRF patients and 18 healthy subjects. Each subject group was divided into two subgroups according to PBMC sensitivity to prednisolone in a mitogen assay procedure; i.e., sensitive (IC50 < 381 ng/mL) and resistant (IC50 > 381 ng/mL) groups. In healthy subjects, the mean GC-R Bmax and Kd in quiescent PBMC of the GC-sensitive group were 2.89 +/- 1.23 fmol/10(6) cells and 4.00 +/- 2.24 nM, respectively. The Bmax in these subjects significantly increased to 6.61 +/- 2.02 (257.7 +/- 107.8%) after 24 h stimulation with concanavalin A (p < 0.01), while the Kd change was not significant. The GC-R Bmax and Kd in quiescent PBMC of the GC-resistant group were 5.33 +/- 1.37 fmol/10(6) cells and 3.20 +/- 1.39 nM, respectively. Both of these parameters, however, did not change significantly after mitogen stimulation. There was a significant negative correlation between IC50S of prednisolone and increase-ratios (post/pre ratio) of Bmax after mitogen stimulation (p < 0.05). In CRF patients, Bmax and Kd in quiescent PBMC of the GC-sensitive group were 6.04 +/- 2.35 fmol/10(6) cells and 3.49 +/- 1.72 nM, respectively, while those in PBMC of the GC-resistant group were 5.13 +/- 2.31 fmol/10(6) cells and 4.04 +/- 1.62 nM, respectively. The Bmax and Kd were not significantly changed after mitogen stimulation in both subgroups of CRF. Moreover, in contrast to healthy subjects, there was no correlation between IC50 and GC-R parameters in CRF. We concluded that, in healthy subjects, decreased PBMC capacity to amplify GC-R numbers in response to mitogen is correlated with GC resistance, whereas in CRF patients the resistant mechanism is not correlated with GC-R parameters. An unknown event might be involved in GC-resistance of CRF.
Hirano
T
T
Department of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.
Horigome
A
A
Oka
K
K
Takeuchi
H
H
Yoshida
M
M
Sakurai
E
E
Kozaki
K
K
Matsuno
N
N
Nagao
T
T
Kozaki
M
M
D000328:Adult; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure*; D008297:Male; D011239:Prednisolone / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000097:blood*
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011239:Prednisolone