Relationship between Lymphocyte and Clinical Steroid Responsiveness in Focal Segmental Glomerulosclerosis

Abstract

A remission in nephrotic proteinuria with steroid treatment appears to favorably alter the natural history of focal segmental glomerulosclerosis (FSGS). It is not known why some patients have a favorable response to steroid treatment whereas others do not. Considering the possibility that differences in the pharmacodynamic responsiveness to steroids among patients might be one factor, the authors examined the relationship between the pretreatment suppressive effect of steroids on lymphocyte proliferation (% inhibition) in vitro and the short- and intermediate-term responses of creatinine clearance (Clcr) and/or nephrotic proteinuria (urine protein/creatinine ratio = Up/c) in 13 patients with FSGS. There were significant correlations between % inhibition and the changes in Clcr at 3 (r = 0.92, p < 0.001) and 6 (r = 0.86, p < 0.01) months and the changes in Up/c at 3 months (r = -0.74, p = 0.02). Thus, the greater the pretreatment lymphocyte steroid sensitivity, the greater the increase in Clcr or decrease in Up/c. The changes in these parameters could not be accounted for on the basis of steroid dose or histopathology. The in vitro sensitivity of FSGS patients' lymphocytes to steroids may be of value in anticipating their clinical response to treatment.

Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine

“…Such a PBMC culture system can simulate the in vivo immune network closer than cultures with separated cells such as T cells, B cells, or monocytes, since PBMCs include various kinds of immune cells, many of which may participate in immune network responses in vivo. Thus, most studies so far have used PBMCs without specific cellseparation [13,16,17,19,[21][22][23][24]. Furthermore, as biopsy specimens, PBMCs are relatively easy to be prepared from 10-20 ml of venous blood.…”

“…Furthermore, as biopsy specimens, PBMCs are relatively easy to be prepared from 10-20 ml of venous blood. Separation and culture procedures of PBMCs in several reports are similar and have been generalized [13,[16][17][18][19][20][21][22], except when a variety of proliferation stimuli, which include concanavalin A and phytohemagglutinin as T cell mitogens [13,16,17,[19][20][21][22][23], interleukins (ILs) [25], or genetically heterogeneous lymphocytes [18,26], have been used. PBMCs are cultured for 3-4 days in vitro in the presence of any one of these stimuli and serial concentrations of immunosuppressive drugs.…”

“…PBMCs are cultured for 3-4 days in vitro in the presence of any one of these stimuli and serial concentrations of immunosuppressive drugs. Radioisotope-labeled thymidine has been used in most cases for estimation of the blastogenesis of lymphocytes [16,17,19,22,26]. After PBMCs were cultured as described above, the cells were incubated for longer periods (generally 16-20 h) in the presence of 3 Hthymidine, and then cell blastogenesis is determined by measuring the amount of 3 H-thymidine incorporated into the cells.…”

“…This deviation might be caused by variations in pharmacological responses to the therapeutic efficacy of immunosuppressive drugs between patients. To evaluate the individual therapeutic potential for these drugs on each patient before the administration of the drug, pharmacodynamic approaches using peripheral-blood mononuclear cells (PBMCs) in vitro could be an attractive and efficient strategy [16][17][18][19][20][21][22].…”

Can We Personalize Treatment for Kidney Diseases?

“…For example, in minimal-change disease, eight patients with high sensitivity to CsA in vitro experienced complete remission significantly sooner than six low-sensitivity patients (40). Similarly, in patients who had FSGS and were treated with corticosteroids, there was a significant correlation between improvement in creatinine clearance and proteinuria at 3 and 6 mo (n ϭ 13) and percentage inhibition of lymphocyte proliferation by corticosteroids in vitro (41). Finally, in a group of 51 renal allograft recipients who were treated with corticosteroids, AZA, and CsA, allograft survival was highest in patients whose lymphocytes were highly sensitive to CsA in vitro (42).…”