Effects of two immunosuppression regimens on T-lymphocyte subsets in elderly kidney transplant recipients

Abstract

Background: Despite the growing number of elderly kidney transplant (Ktx) recipients, few studies have examined the effects of immunosuppression on their lymphocyte profiles.

Methods: We evaluated the early conversion from mycophenolate sodium (MPS) to everolimus (EVL) after rabbit antithymocyte globulin (rATG) 2 mg/kg induction in elderly kidney recipients. Three groups of KTx patients were compared: (a) Young (n=20, 36 ± 7 y) receiving standard immunosuppression (Group A1) (prednisone, tacrolimus, and MPS), (b) Elderly (n=35, 65 ± 3 y) receiving standard immunosuppression (Group B1), and (c) Elderly (n=16, 65 ± 3 y) with early (mean 30 d) conversion from MPS to EVL (Group B2). Naive, memory, and regulatory peripheral blood TCD4⁺ lymphocytes were quantified at 0, 30, and 365 d.

Results: Results are reported as [mean(p25-p75)]. Young recipients had higher lymphocyte counts at baseline [2,100(1,630-2,400) vs. 1,310 (1,000-1,600)/mm³, p<0.0001] maintained higher counts within 365 d [1,850(1,590-2,120) vs. 1,130(460-1,325)/mm³, p=0.018 and vs. 1,410(805-1,895)/mm³, p=0.268]. Elderly recipients showed a decrease in lymphocytes within 30 d [1,310(1,000-1,600) vs. 910(700-1,198)/mm³, p=0.0012] with recovery within 365 d. The same pattern was observed in total lymphocytes and TCD4⁺ counts. Rabbit antithymocyte globulin induced a reduction in central memory T-cell percentages at 30 d in both young recipients [6.2(3.77-10.8) vs. 5.32(2.49-7.28)% of CD4⁺, p=0.036] and in elderly recipients [8.17(5.28-12.88) vs. 6.74(4.36-11)% of CD4⁺, p=0.05] on standard immunosuppression, returning to baseline at 365 d in elderly recipients but not in young recipients. Regulatory T CD39⁺ cells (Treg) percentages decreased at 30 d in elderly recipients [2.1(1.23-3.51) vs. 1.69(0.8-2.66)% of CD4⁺, p=0.0028] and in young recipients [1.29(0.45-1.85) vs. 0.84(0.18-1.82)% of CD4⁺, p=0.0038], returning to baseline at 365 d in elderly recipients [2.1(1.23-3.51) vs. 2.042(0.88-2.42)% of CD4⁺], but not in young recipients [1.29(0.45-1.85) vs. 0.86(0.7-1.34) % of CD4⁺]. The elderly everolimus conversion group did not show significant changes in cell profile over time or compared to elderly recipients with standard immunosuppression.

Conclusion: Aging favored the maintenance of Treg during the late transplantation period despite ongoing immunosuppression. Lymphocyte depletion due to rATG was more prominent in elderly recipients and affected memory subsets with a temporary reduction in central memory T cells. However, conversion to everolimus did not impact Treg profile. Reducing the dose of rATG in elderly recipients seems necessary for the expected lymphocyte changes with EVL to occur.

Clinical trial registration: nEverOld Trial, identifier NTC01631058.

Keywords: elderly; everolimus; kidney tranplantation; memory T CD4+ cells; regulatory (Treg) cell.

Figure 1

Flow cytometry characterization of peripheral blood T- cell subsets. Fluorescence minus one (FMO) controls were set up for CD127, FoxP3, CD39, CCR7 (CD197), and CD45RA. TCM, T central memory; TEM, T effector memory; TEMRA, terminally differentiated effector memory; Treg, regulatory T cells.

Figure 2

Total lymphocyte absolute counts over 365 days observation time for young standard immunosuppression (Group A1) (•), elderly standard immunosuppression (Group B1), (▪) and elderly everolimus conversion (Group B2) (▴) groups. *p<0.05 for comparison between Group A1 vs. Group B1 groups in a given time point. Horizontal bar p<0.05 for comparison between day 30 and pre-transplantation samples of Group B1.

Figure 3

Percentages of T CD4⁺naïve (A), T CD4⁺ effector memory (B), T CD4⁺central memory (C) and T CD4⁺ TCD4 terminally differentiated effector memory (D) lymphocytes over 365 days observation time for young standard immunosuppression (Group A1) (•), elderly standard immunosuppression (Group B1) (▪) and elderly everolimus conversion (Group B2) (▴) groups. *p<0.05 for comparison between Group A1 vs. Group B1 groups in a given time point after transplantation. Dotted, solid, and dashed horizontal bars p<0.05 for comparisons between a given time point and the pre-transplantation samples of Group A1, Group B1, and Group B2, respectively.

Figure 4

Percentages of regulatory (A) and CD39⁺regulatory (B) T cells over 365 days observation time for young standard immunosuppression (Group A1) (•), elderly standard immunosuppression (Group B1) (▪), and elderly everolimus conversion (Group B2) (▴) groups. *p<0.05 for comparison between Group A1 vs. Group B1 groups in a given time point after transplantation. Dotted, solid, and dashed horizontal bars p<0.05 for comparisons between a given time point and the baseline percentages of Group A1, Group B1, and Group B2, respectively.