24-hour immunologic assessment of CD4+ and CD8+ lymphocytes in renal transplant recipients receiving chronic methylprednisolone

Glucocorticoids are commonly prescribed in the post-transplant period as a component of combination immunosuppressive regimens. However, the daily 24-hour pattern of helper lymphocytes (CD4+) and suppressor cells (CD8+) during chronic methylprednisolone therapy has not been examined in renal transplant recipients in relation to glucocorticoid exposure and time post-transplant. The response of total lymphocytes, CD4+ and CD8+ lymphocytes was examined in 23 stable renal transplant recipients who received methylprednisolone for at least 8 months post-transplant. The patient's prescribed oral methylprednisolone dose (mean daily dose = 9.7 ± 2.6 mg) was given intravenously and whole blood was sampled periodically over 24 h for lymphocyte counts and methylprednisolone concentrations. A complete blood count with differential was determined via an automated hemocytometer with CD4+ and CD8+ lymphocytes determined using flow cytometry. Methylprednisolone area under the concentration versus time curve (AUC) was determined and normalized for each patient's respective dose. A general lymphopenia resulted in all patients with a mean decrease of 61 ± 15% and an average nadir time occurring at 6 h. The decline from baseline was 76 ± 17% for absolute number of CD4+ and 59 ± 18% for CD8+ lymphocytes with an average nadir time at 6 h. Twelve patients exhibited a baseline CD4+ count to be less than 688 cells/mm³ (the low end of the reference range) and the lymphocyte count of all of the patients fell below this value at the nadir. Six patients had a CD8+ lymphocyte count below 380 cells/mm³ (low end of the reference range) at baseline with 21 of the 23 patients exhibiting less than 380 cells/mm³ at the nadir time. At the time of nadir, the mean CD4+ and CD8+ counts were 156 ± 105 cells/mm³ and 256 ± 270 cells/mm³, respectively. In 17 of the 23 patients, the CD4+ count was below 200 cells/mm³ at the time of nadir. The dose-normalized AUC of methylprednisolone ranged from 22.6 to 113.5 ng·h/ml with 48% of patients exhibiting morning cortisol concentrations greater than 60 ng/ml. No correlation was noted between daily methylprednisolone exposure and the extent of lymphocyte decline. Lymphocyte response patterns are not clinically recognized in renal transplant recipients, as a means of monitoring immunosuppression. The absolute CD4+ and CD8+ lymphocyte count and the timing of these sample collections post-steroid administration, may have clinical relevance when serially assessed as is done in other immunologic diseases. Prospective evaluation of lymphocyte subset patterns and correlation with susceptibility to overimmunosuppressive (i.e. opportunistic infections) is necessary to help determine if these complications can be minimized by more individualized steroid dose modification.