Abstract
Background
Resistance to recombinant human erythropoietin (rhEPO) occurs in some chronic kidney disease (CKD) patients, which may be due to enhanced systemic inflammatory response and to the erythropoiesis-suppressing effect of pro-inflammatory cytokines, some of which are produced by T cells.
Aim of study
The aim of this study was to investigate the relationship between resistance to rhEPO therapy in hemodialysis CKD patients and inflammatory markers [C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (sIL2R), and serum albumin levels], blood cell counts, T-cell phenotype, cytokine production by T cells, and serum cytokine levels.
Materials and Methods
We studied 50 hemodialysis CKD patients, 25 responders and 25 nonresponders to rhEPO, and compared them to each other and with 25 healthy controls. When compared to controls, CKD patients showed increased serum levels of CRP, IL-6, and sIL2R and a T-cell lymphopenia, due to decreased numbers of both CD4+ and CD8+ T cells. T cells from CKD patients had an immunophenotype compatible with chronic T-cell stimulation as shown by the increased percentage of CD28−, CD57+, HLA-DR+, CD28−HLA-DR+, and CD57+ HLA-DR+ T cells and produce higher levels of IL-2, INF-γ, and TNF-α after short-term in vitro stimulation, although Th1 cytokines were not detectable in serum. Statistically significant differences were found between responders and nonresponders to rhEPO therapy for total lymphocyte and CD4+ T-lymphocyte counts, albumin (lower in nonresponders) and CRP (higher in nonresponders) levels.
Conclusion
CKD patients under hemodialysis present with raised inflammatory markers and decrease of total lymphocyte and CD4+ T-lymphocyte counts when compared with controls. Some of those markers are even further enhanced in nonresponders to rhEPO therapy patients, but resistance to this therapy cannot be justified by a Th1 polarized T-cell response.
Similar content being viewed by others
References
Kerr PG. Renal anaemia: recent developments, innovative approaches and future directions for improved management. Nephrology. 2006;11:542–8.
Macdougall IC. Present and future strategies in the treatment of renal anaemia. Nephrol Dial Transpl. 2001;16(suppl 5):50–5.
Macdougall IC, Cooper AC. Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant. 2002;17(Suppl 11):39–43.
Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal failure. Am J Kidney Dis. 1998;32(suppl 3):S112–9.
Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy morbidity and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28:53–61.
Smrzova J, Balla J, Bárány P. Inflammation and resistance to erythropoiesis-stimulting agents—what do we know and what needs to be clarified. Nephrol Dial Transpant. 2005;20(Suppl 8):viii2–7.
Cooper AC, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Increased expression of erythropoiesis inhibiting cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy. J Am Soc Nephrol. 2003;14:1776–84.
Macdougal IC. Poor response to erythropoietin: practical guidelines on investigation and management. Nephrol Dial Transplant. 1995;10:607–14.
Drueke TB. R-HuEPO hyporesponsiveness: who and why. Nephrol Dial Transplant. 1995;10(suppl 2):S62–8.
Danielson B. R-HuEPO hyporesponsiveness: who and why. Nephol Dial Transplant. 1995;10(suppl 2):S69–73.
Fishbane S. Hyporesponsiveness to recombinant human erythropoietin in dialysis patients. Dial Transplant. 2000;29:545–8.
Schindler R, Senf R, Frei U. Influencing the inflammatory response of haemodialysis patients by cytokine elimination using large-pore membranes. Nephrol Dial Transplant. 2002;17:17–9.
Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 1999;33:63–72.
Cooper AC, Breen CP, Vyas B, Ochola J, Kemeny DM, Macdougall IC. Poor response to recombinant erythropoitin is associated with loss of T-lymphocyte CD28 expression and altered interleukin-10 production. Nephrol Dial Transplant. 2003;18:133–40.
Descamps-Latscha B, Herbelin A, Nguyen AT, Roux-Lombard P, Zingraff J, Moynot A, Verger C, Dahmane D, Groote D, Jungers P, Dayer JM. Balance between IL-1β, TNF-α, and their specific inhibitors in chronic renal failure and maintenance dialysis. J Immunology. 1995;154:882–92.
Means RT Jr, Krantz SB. Inhibition of human erythroid colony forming units by interferons α and β: differing mechanisms despite shared receptor. Exp Haematol. 1996;24:204–8.
Allen DA, Breen C, Yaqoob MM, Macdougall IC. Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of INF-γ and TNF-α. J Invest Med. 1999;47:204–11.
Meier P, Dayer E, Blanc E, Wauters JP. Early T cell activation correlates with expression of apoptosis markers in patients with end-stage renal disease. J Am Soc Nephol. 2002;13:204–12.
Waltzer WC, Bachvaroff RJ, Raisbeck AP, Egelandsdal B, Pullis C, Shen L, Rapaport FT. Immunological monitoring in patients with end-stage renal disease. J Clin Immunol. 1984;4:364–8.
Litjens NHR, van Druninger CJ, Betjes MGH. Progressive loss of renal function is associated with activation and depletion of naïve T lymphocytes. Clinical Immunology. 2006;118:83–91.
Locatelli F, Aljama P, Barany P, European Best Practice Guidelines Working Group, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2):ii1–47.
d’Angeac AD, Monier S, Pilling D, Travaglio-Encinoza A, Reme T, Salmon M. CD57+ T lymphocytes are derived from CD57-precursors by differentiation occurring in late immune responses. Eur J Immunol. 1997;24:1503–11.
Lima M, Teixeira Mdos A, Queiros ML, Santos AH, Goncalves C, Correia J, Farinha F, Mendonca F, Soares JM, Almeida J, Orfao A, Justica B. Immunophenotype and TCR-Vbeta repertoire of peripheral blood T-cells in acute infectious mononucleosis. Blood Cells Mol Dis. 2003;30:1–12.
Lima M, Almeida J, Teixeira MA, Santos AH, Queiros ML, Fonseca S, Moura J, Goncalves M, Orfao A, Pinto Ribeiro AC. Reactive phenotypes after acute and chronic NK-cell activation. J Biol Regul Homeost Agents. 2004;18:331–4.
Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, Corthesy P, Devevre E, Speiser DE, Rufer N. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol. 2007;178:4112–9.
Bárány P. Inflammation, serum C-reactive protein, and erythropoietin resistance. Nephrol Dial Transplant. 2001;16:224–7.
Spittle MA, Hoenich NA, Handelman GJ, Adhikarla R, Homel P, Levin NW. Oxidative stress and inflammation in hemodialysis patients. Am J Kidney Dis. 2001;38:1408–13.
Reddan DN, Klassen PS, Szczech LA, Coladonato JA, O’Shea S, Owen WF Jr, Lowrie EG. White blood cells as a novel mortality predictor in haemodialysis patients. Nephrol Dial Transplant. 2003;18:1167–73.
Fernandez-Fresnedo G, Ramos MA, Gonzalez-Pardo MC, de Francisco AL, Lopez-Hoyos M, Aris M. B lymphopenia in uremia is related to an accelerated in vitro apoptosis and dysregulation of Bcl-2. Nephrol Dial Transplant. 2000;15:502–10.
Kurz P, Kohler H, Meuer S, Hutteroth T, Meyer zum Buschenfelde KH. Impaired cellular immune response in chronic renal failure: evidence for a T cell defect. Kidney Int. 1986;29:1209–14.
Litjens NHR, van Druningen CJ, Betjes MGH. Progressive loss of renal function is associated with activation and depletion of naïve T lymphocytes. Clinical Immunology. 2006;118:83–91.
Kang I, Hong MS, Nolasco H, Park SH, Dan JM, Choi JY, Craft J. Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine. J Immunol. 2004;173:673–81.
Napolitano LA, Grant RM, Dreeks SG, Schmidt D, De Rosa SC, Herzenberg LA, Herndier BG, Andersson J, McCune JM. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001;7:73–9.
Moser B, Roth G, Brunner M, Lilaj T, Deicher R, Wolner E, Kovarik J, Boltz-Nitulescu G, Vychytil A, Ankersmit HJ. Aberrant T cell activation and heightened apoptotic turnover in end-stage renal failure patients: a comparative evaluation between non-dialysis, haemodialysis, and peritoneal dialysis. Biochem Biophys Res Commun. 2003;308:581–5.
Jiang Q, Li WQ, Aiello FB, Mazzucchelli B, Asefa B, Khaled AR, Durum SK. Cell biology of IL-7, a key lymphotrophim. Cytokine Growth Factor Rev. 2005;16:513–33.
Acknowledgments
The authors are grateful to Amgen for financial support and to the nurses of Fresenius Medical Center, Dinefro-Diálises e Nefrologia, SA and Uninefro-Sociedade Prestadora de Cuidados Médicos e de Diálise, SA, for technical support. This study was supported by a PhD grant (SFRH/BD/27688/2006) attributed to E. Costa by Fundação para a Ciencia e Tecnologia (FCT) and Fundo Social Europeu.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Costa, E., Lima, M., Alves, J.M. et al. Inflammation, T-Cell Phenotype, and Inflammatory Cytokines in Chronic Kidney Disease Patients Under Hemodialysis and its Relationship to Resistance to Recombinant Human Erythropoietin Therapy. J Clin Immunol 28, 268–275 (2008). https://doi.org/10.1007/s10875-007-9168-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-007-9168-x