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Aging and disease    2019, Vol. 10 Issue (1) : 49-61     DOI: 10.14336/AD.2018.0318
Orginal Article |
Aging and End Stage Renal Disease Cause A Decrease in Absolute Circulating Lymphocyte Counts with A Shift to A Memory Profile and Diverge in Treg Population
Geraldo Rubens Ramos Freitas1,2, Maria da Luz Fernandes2, Fabiana Agena2, Omar Jaluul3, Sérgio Colenci Silva3, Francine Brambate Carvalhinho Lemos2, Verônica Coelho4, David-Neto Elias2, Nelson Zocoler Galante2,*
1Division of Nephrology, and
2Renal Transplant Service, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
3Division of Geriatrics, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
4Laboratory of Immunology, Heart Institute, University of Sao Paulo School of Medicine. Institute for Investigation in Immunology, Sao Paulo, Brazil.
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Abstract  

There is a growing number of elderly kidney transplant (Ktx) recipients. Elderly recipients present lower acute rejection rates but higher incidence of infection and malignancies. Aging per se seems to result in a shift to memory profile and chronic kidney disease (CKD) in premature immunological aging. Understanding aging and CKD effects on the immune system can improve elderly Ktx immunosuppression. We analyzed the effects of aging and CKD in the immune system, comparing healthy adults (HAd) (n=14, 26±2y), healthy elderly (HEld) (n=15, 79±7y), end stage renal disease (ESRD) adults (EnAd) (n=18, 36±7y) and ESRD elderly (EnEld) (n=31, 65±3y) prior to Ktx regarding their naïve, memory and regulatory T and B peripheral lymphocytes. Aging and ESRD presented additive effect decreasing absolute numbers of B and T-lymphocytes, affecting memory, naive and regulatory subsets without synergic effect. Both resulted in higher percentages of T memory subsets and opposing effects on regulatory T (TREG) subsets, higher percentage in aging and lower in ESRD. Combined effect of aging and ESRD also resulted in higher regulatory B cell percentages. In addition to global lymphopenia and TCD4+ memory shift in both aging and ESRD, aging shifts to an immunoregulatory profile, inducing a increase in TREG percentages, contrasting with ESRD that decreases TREGs. Differential immunosuppression regimens for elderly Ktx may be required. (ClinicalTrials.gov number: NTC01631058).

Keywords T lymphocytes      B lymphocytes      Chronic Kidney Disease      Kidney transplantation      Immune senescence     
Corresponding Authors: Galante Nelson Zocoler   
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These authors contributed equally to work

Issue Date: 10 January 2018
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Freitas Geraldo Rubens Ramos
da Luz Fernandes Maria
Agena Fabiana
Jaluul Omar
Silva Sérgio Colenci
Lemos Francine Brambate Carvalhinho
Coelho Verônica
Elias David-Neto
Galante Nelson Zocoler
Cite this article:   
Freitas Geraldo Rubens Ramos,da Luz Fernandes Maria,Agena Fabiana, et al. Aging and End Stage Renal Disease Cause A Decrease in Absolute Circulating Lymphocyte Counts with A Shift to A Memory Profile and Diverge in Treg Population[J]. Aging and disease, 2019, 10(1): 49-61.
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http://www.aginganddisease.org/EN/10.14336/AD.2018.0318     OR     http://www.aginganddisease.org/EN/Y2019/V10/I1/49
Figure 1.  Flow cytometry characterization of peripheral blood T and B cell subsets. Fluorescence minus one (FMO) controls were set up for CD127, FoxP3, CD39, CCR7 (CD197) and CD45RA. Panel A represents the strategy for T cell subsets characterization and panel B for B cell subsets characterization. TCM - T central memory, TEM - T effector memory, TEMRA - T effector memory with RA reexpression, TREG - regulatory T cells, BM - B memory, BREG - regulatory B cells.
HAd (n=14)HEld (n=15)EnAd (n=18)EnEld (n=31)P
Age (years)26±279±7a36±7b,d65±3c,e,f<0.001
Gender (Male) n (%)5 (36)1 (7)7 (39)d18 (58)e0.01
BMI (Kg/m2)------24(22.4-25.6)25(22.8-27.2)0.206#
Comorbidities
SAH n (%)0016 (89)b,d31 (100)e<0.001
Diabetes mellitus n (%)003 (17)15 (48)c,e<0.001
Glomerulopathy n (%)003 (17)2 (7)0.107
ADPKD n (%)001 (6)2 (7)0.41
Renal replacement data
Time on RRT (months)------32 (14-45.5)36 (21-54)0.23#
RRT (HD) n (%)------17 (94)28 (90)1.0#
Laboratorial data
Albumin------4.4(4.17-4.62)4.3(3.6-4.7)0.4#
Hemoglobin------12.2(9.9-13.1)12.6(11-12.9)0.88#
PTH------236(80.5-608)237(130-574)0.868#
Table 1  Demographic data.
Figure 2.  Aging and end stage renal disease effects in absolute total lymphocytes, T-, TCD4-, TCD8- and B- cells (A) and in B-cells subsets percentages (B). Healthy adults (n=14) (), healthy elderly (n=15) (), end stage renal disease adult patients (n=18) () and end stage renal disease elderly patients (n=31) () absolute counts and percentages are shown in the same repeatedly order in each cell subset analysis. Lymp - total lymphocyte, T - T lymphocyte, TCD4 - T helper, TCD8 - T cytotoxic, B - B lymphocyte, BM - B memory, BREG -regulatory B cells. Bars represent median and interquartile ranges.
HAd (n=14)HEld (n=15)EnAd (n=17)EnEld (n=27)
Total Lymp2515 (2033-2688)2060 (1500-2200)a2100 (1605-2395)b1370 (1000-1600)c,e,f
T1737 (1446-1933)1172 (934.3-1360)a1238 (847.3-1599)b718 (483.7-992.8)c,e,f
TCD4997.2 (813.1-1205)670 (597.2-999.3)a724.9 (508-951)b470.2 (274.5-631.2)c,e,f
TCD8584 (403.2-761.8)322.5 (210.1-510.6)a380.5 (281.1-501.3)b213 (147.9-359.8)c,f
B243 (175.2-313.1)229 (127.7-321.4)165.1 (115.5-227.9)b82 (56.5-137.2)c,e,f
T naive228.5 (111.1-337.4)155.3 (86.2-246.9)106.1 (45.4-234.2)b89 (25.1-138)c,e
TCM66.9 (44.4-86.8)68.4 (39.6-85.6)59.1 (16.5-75.6)35 (19.6-62)c,e
TEM262.5 (156.1-421.4)201.2 (145.8-254.2)234.8 (162.3-338.8)164.4 (88.6-230.5)c,f
TEMRA354.1 (263.8-470.3)190.5 (104.3-315)a293.4 (107.4-323.3)b120 (64.6-179.2)c,e,f
TREG24 (10.6-29.2)24.1 (15.4-34.5)12.9 (3 -16.5)d8.9 (4.8-18.1)c,e
B naive106.5 (71.6-132.5)87.4 (34.7-116.2)49.7 (33-75.9)b23.4 (11.2-47.7)c,e,f
BM69.1 (42.6-85.1)43.9 (23.9-70.8)45.4 (26.5-52.5)b26.4 (7-32)c,e,f
BREG15.5 (8.9-22.3)18.5 (9.8-30.5)12.3 (7.1-17.3)7.5 (2.4-15.7)c,e
Table 2  Effects of aging and end stage renal disease in the absolute numbers (cells/mm3) of lymphocyte subpopulations among healthy adults, healthy elderly, adult ESRD patients and elderly ESRD patients.
Figure 3.  Aging and end stage renal disease effects in T - cells subsets percentages, T naïve, TCM, TEM, TEMRA (A) and TREG (B). Healthy adults (n=14) (), healthy elderly (n=15) (), end stage renal disease adult patients (n=18) () and end stage renal disease elderly patients (n=31) () subsets percentages are shown in the same repeatedly order in each cell subset analysis. TCM - T central memory, TEM - T effector memory, TEMRA - T effector memory with RA reexpression, TREG - regulatory T cells. Bars represent median and interquartile ranges.
Lymphocyte subsetsAbsolutePercentages
AgeaESRDAge x ESRDbAgeaESRDAge x ESRDb
Total<0.001<0.0010.20.180.460.06
T<0.001<0.0010.640.0090.170.51
TCD4+<0.001<0.0010.950.660.500.15
TCD8+<0.0010.0010.450.0070.410.41
B0.06<0.0010.380.650.020.53
T naive0.040.0030.960.950.340.95
T central memory0.410.0010.760.020.390.62
T effector memory0.0540.370.530.190.030.79
TEMRA<0.001<0.0010.550.020.260.56
Regulatory T cells0.52<0.0010.350.040.020.54
B naive0.06<0.0010.690.120.110.64
B memory0.001<0.0010.610.380.960.94
Regulatory B cells0.980.040.790.070.320.94
Table 3  Two-way Analysis of variance for ESRD, age and Age x ESRD interaction.
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