Elevated serum soluble interleukin-2 receptor levels increase malignancy-related risk in patients on chronic hemodialysis

  • Chen XiaoHong
  • Shen Bo
  • Xiang FangFang
  • Guo Man
  • Zou JianZhou
  • Liu ZhongHua
  • Lv WenLv
  • Cao XueSen
  • Ding XiaoQiangEmail author
  • Zhang Boheng
Original Article



Patients on chronic hemodialysis (HD) have an increased incidence of malignancy due to decreased immunity. Soluble interleukin-2 receptor (sIL-2R), as an immunomodulator, seemed to have an effect in the process of malignancy. In this study, we aimed to evaluate the clinical significance of increased sIL-2R in the course of malignancy among HD patients.


Patients who undergoing chronic hemodialysis were followed for 24 months. Risk factors for malignancy events and malignancy-related mortality during the 2-year follow-up period were investigated among various clinicopathological variables.


Of the 363 patients included in this research, 47 patients (12.95%) had a prior history of treated malignancy. During the 2-year follow-up period, malignancy events were detected in 15 (4.12%) patients. Sixty-seven patients died during the study period, of which nine patients (13.43%) were died of malignancy. Malignancy events reduced 2-year mortality significantly (log-rank = 23.02, P < 0.0001). Both high sIL-2R levels ( ≥ 2-fold upper limit of the normal value) (OR 6.6, P = 0.006) and a prior history of treated malignancy (OR 4.12, P = 0.018)were identified by multivariate logistic analysis as independent determinants for malignancy events. However, only the levels of sIL-2R (used as a continuous variable) had the significantly predictive effect on malignancy events and malignancy-related mortality in the following 2 years.


Elevated sIL-2R levels was commonly seen in serum of HD patients. And this elevated level increased the risk of malignancy. Aside from its role as a biomarker, sIL-2R may also exert biological effects in the course of malignancy.


Soluble interleukin-2 receptor Hemodialysis Malignancy event Malignancy-related mortality 





Interleukin-2 receptor


Soluble interleukin-2 receptor




End-stage renal disease


Cardiovascular disease


Body-mass index


Erythropoietin-stimulating agent


Single-pooled Kt/V


Tumor necrosis Factor α


Red blood cell distribution width


High-sensitivity C-reactive protein


Alkaline phosphatase


γ-Glutamyl transferase


Lactate dehydrogenase


Serum creatinine


Uric acid




Intact parathyroid hormone


Glycosylated hemoglobin


Standard deviation


Interquartile range


Receiver operating characteristic


Odds ratio


Confidence interval



This study was founded by Shanghai Clinical Medical Center for Kidney Disease Project support by Shanghai Municipal Health Commission (no. 2017ZZ01015) and Shanghai Municipal Hospital Frontier Technology Project supported by Shanghai ShenKang Hospital Development Center (no. SHDC12018127).

Compliance with ethical standards

Conflict of interest

We declare no conflict of interest.

Informed consent

Informed consents were obtained from all individual participants included in the study.


  1. 1.
    Chien CC, Han MM, Chiu YH et al (2017) Epidemiology of cancer in end-stage renal disease dialysis patients: a national cohort study in Taiwan. J Cancer 8(1):9–18. Google Scholar
  2. 2.
    Cheung CY, Chan GC, Chan SK et al (2016) Cancer incidence and mortality in chronic dialysis population: a multicenter cohort study. Am J Nephrol 43(3):153–159. Google Scholar
  3. 3.
    Butler AM, Olshan AF, Kshirsagar AV et al (2015) Cancer incidence among US Medicare ESRD patients receiving hemodialysis, 1996–2009. Am J Kidney Dis 65(5):763–772. Google Scholar
  4. 4.
    Maisonneuve P, Agodoa L, Gellert R et al (1999) Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet (London, England) 354(9173):93–99Google Scholar
  5. 5.
    Vamvakas S, Bahner U, Heidland A (1998) Cancer in end-stage renal disease: potential factors involved—editorial. Am J Nephrol 18(2):89–95. Google Scholar
  6. 6.
    Bayer AL, Pugliese A, Malek TR (2013) The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res 57(1–3):197–209. Google Scholar
  7. 7.
    Bien E, Balcerska A (2008) Serum soluble interleukin 2 receptor alpha in human cancer of adults and children: a review. Biomarkers Biochem Indic Expo Response Susceptibility Chem 13(1):1–26. Google Scholar
  8. 8.
    Rubin LA, Kurman CC, Fritz ME et al (1985) Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol (Baltimore, Md: 1950) 135(5):3172–3177Google Scholar
  9. 9.
    Memoli B, Libetta C, De Nicola L et al (1996) Hemodialysis related interleukin-2 receptor release by peripheral blood mononuclear cells. ASAIO J (Am Soc Artif Intern Org: 1992) 42(1):60–63Google Scholar
  10. 10.
    Daichou Y, Kurashige S, Hashimoto S et al (1999) Characteristic cytokine products of Th1 and Th2 cells in hemodialysis patients. Nephron 83(3):237–245Google Scholar
  11. 11.
    Beaurain G, Naret C, Marcon L et al (1989) In vivo T cell preactivation in chronic uremic hemodialyzed and non-hemodialyzed patients. Kidney Int 36(4):636–644Google Scholar
  12. 12.
    Sennesael JJ, Demanet CG, Verbeelen DL (1995) Serum soluble interleukin 2 receptor in hemodialysis patients treated with recombinant human erythropoietin. Blood Purif 13(6):347–356. Google Scholar
  13. 13.
    Mehta R, Shah G, Adler W et al (2004) Soluble interleukin 2 receptor (sIL-2R) levels in renal transplant recipients. Clin Transpl 18(Suppl 12):67–71. Google Scholar
  14. 14.
    Shu KH, Lu YS, Cheng CH et al (1998) Soluble interleukin 2 receptor in dialyzed patients. Artif Org 22(2):142–144Google Scholar
  15. 15.
    Holtkamp W, Brodersen HP, Stollberg T et al (1993) Zinc supplementation stimulates tetanus antibody formation and soluble interleukin-2 receptor levels in chronic hemodialysis patients. Clin Investig 71(7):537–541Google Scholar
  16. 16.
    Ding X (2016) SIKD is on the road. Blood Purif 42(1):I–vi. Google Scholar
  17. 17.
    Cao XS, Chen J, Zou JZ et al (2015) Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clin J Am Soc Nephrol 10(1):111–119. Google Scholar
  18. 18.
    Daugirdas JT (1993) Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol JASN 4(5):1205–1213Google Scholar
  19. 19.
    Chen W, Zheng R, Baade PD et al (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132. Google Scholar
  20. 20.
    Chen WQ, Zheng RS, Zeng HM et al (2012) Trend analysis and prediction of cancer incidence in China. Zhonghua yu fang yi xue za zhi [Chin J Prev Med] 46(7):581–586Google Scholar
  21. 21.
    Matas A, Simmons R, Kjellstrand C et al (1975) Increased incidence of malignancy during chronic renal failure. Lancet (London, England) 1(7912):883–886Google Scholar
  22. 22.
    Cengiz K (2002) Increased incidence of neoplasia in chronic renal failure (20-year experience). Int Urol Nephrol 33(1):121–126Google Scholar
  23. 23.
    Lin HF, Li YH, Wang CH et al (2012) Increased risk of cancer in chronic dialysis patients: a population-based cohort study in Taiwan. Nephrol Dial Transpl 27(4):1585–1590. Google Scholar
  24. 24.
    Wong G, Staplin N, Emberson J et al (2016) Chronic kidney disease and the risk of cancer: an individual patient data meta-analysis of 32,057 participants from six prospective studies. BMC Cancer 16:488. Google Scholar
  25. 25.
    Yoo KD, Lee JP, Lee SM et al (2017) Cancer in Korean patients with end-stage renal disease: a 7-year follow-up. PLoS ONE 12(7):e0178649. Google Scholar
  26. 26.
    Igney FH, Krammer PH (2002) Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol 71(6):907–920Google Scholar
  27. 27.
    Poggi A, Zocchi MR (2006) Mechanisms of tumor escape: role of tumor microenvironment in inducing apoptosis of cytolytic effector cells. Arch Immunol Ther Exp 54(5):323–333. Google Scholar
  28. 28.
    Chouaib S, Thiery J, Gati A et al (2002) Tumor escape from killing: role of killer inhibitory receptors and acquisition of tumor resistance to cell death. Tissue Antigens 60(4):273–281Google Scholar
  29. 29.
    Xiang FF, Zhu JM, Cao XS et al (2016) Lymphocyte depletion and subset alteration correlate to renal function in chronic kidney disease patients. Ren Fail 38(1):7–14. Google Scholar
  30. 30.
    Xiang F, Chen R, Cao X et al (2018) Monocyte/lymphocyte ratio as a better predictor of cardiovascular and all-cause mortality in hemodialysis patients: a prospective cohort study. Hemodial Int Int Symp Home Hemodial 22(1):82–92. Google Scholar
  31. 31.
    Guo M, Chen R, Xiang F et al (2018) Decreased percentage of memory B cells is independently associated with increased susceptibility to infection in patients on maintenance hemodialysis. Int Urol Nephrol. Google Scholar
  32. 32.
    Chen R, Xiang F, Hu J et al (2017) Factors associated with the elevated percentage of CD4CD69 T cells in maintained hemodialysis patients. Ren Fail 39(1):547–554. Google Scholar
  33. 33.
    Descamps-Latscha B, Herbelin A, Nguyen AT et al (1995) Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis Relationships with activation markers of T cells, B cells, and monocytes. J Immunol (Baltimore, Md: 1950) 154(2):882–892Google Scholar
  34. 34.
    Chatenoud L, Dugas B, Beaurain G et al (1986) Presence of preactivated T cells in hemodialyzed patients: their possible role in altered immunity. Proc Natl Acad Sci USA 83(19):7457–7461Google Scholar
  35. 35.
    Schiffl H, Lang SM, Stratakis D et al (2001) Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters. Nephrol Dial Transpl 16(9):1863–1869Google Scholar
  36. 36.
    Debeljak N, Solar P, Sytkowski AJ (2014) Erythropoietin and cancer: the unintended consequences of anemia correction. Front Immunol 5:563. Google Scholar
  37. 37.
    Fentiman IS (2012) Gamma-glutamyl transferase: risk and prognosis of cancer. Br J Cancer 106(9):1467–1468. Google Scholar
  38. 38.
    Nakase K, Tsuji K, Tamaki S et al (2005) Elevated levels of soluble interleukin-2 receptor in serum of patients with hematological or non-hematological malignancies. Cancer Detect Prev 29(3):256–259. Google Scholar
  39. 39.
    Nakase K, Kita K, Nasu K et al (1994) Differential expression of interleukin-2 receptors (alpha and beta chain) in mature lymphoid neoplasms. Am J Hematol 46(3):179–183Google Scholar
  40. 40.
    Nakase K, Kita K, Shirakawa S et al (1994) Induction of cell surface interleukin 2 receptor alpha chain expression on non-T lymphoid leukemia cells. Leuk Res 18(11):855–859Google Scholar
  41. 41.
    Rimoldi D, Salvi S, Hartmann F et al (1993) Expression of IL-2 receptors in human melanoma cells. Anticancer Res 13(3):555–564Google Scholar
  42. 42.
    Yano T, Fukuyama Y, Yokoyama H et al (1996) Interleukin-2 receptors in pulmonary adenocarcinoma tissue. Lung Cancer (Amst, Neth) 16(1):13–19Google Scholar
  43. 43.
    Wang LS, Chow KC, Li WY et al (2000) Clinical significance of serum soluble interleukin 2 receptor-alpha in esophageal squamous cell carcinoma. Clin Cancer Res 6(4):1445–1451Google Scholar
  44. 44.
    Huang A, Quinn H, Glover C et al (2002) The presence of interleukin-2 receptor alpha in the serum of colorectal cancer patients is unlikely to result only from T cell up-regulation. Cancer Immunol Immunother CII 51(1):53–57. Google Scholar
  45. 45.
    De Paiva CS, Yoon KC, Pangelinan SB et al (2009) Cleavage of functional IL-2 receptor alpha chain (CD25) from murine corneal and conjunctival epithelia by MMP-9. J Inflamm (Lond, Engl) 6:31. Google Scholar
  46. 46.
    Berghella AM, Pellegrini P, Piancatelli D et al (1994) Progression mechanisms in colon cancer: soluble interleukin-2 (IL-2) receptor, IL-2 plus anti-CD3 proliferative response and tumour stage correlations. Cancer Immunol Immunother CII 38(3):160–166Google Scholar
  47. 47.
    Murakami S (2004) Soluble interleukin-2 receptor in cancer. Front Biosci J Virtual Libr 9:3085–3090Google Scholar
  48. 48.
    Kobayashi H, Tagaya Y, Han ES et al (1999) Use of an antibody against the soluble interleukin 2 receptor alpha subunit can modulate the stability and biodistribution of interleukin-2. Cytokine 11(12):1065–1075. Google Scholar
  49. 49.
    Wang X, Rickert M, Garcia KC (2005) Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science (New York, NY) 310(5751):1159–1163. Google Scholar
  50. 50.
    Yang ZZ, Grote DM, Ziesmer SC et al (2011) Soluble IL-2Ralpha facilitates IL-2-mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma. Blood 118(10):2809–2820. Google Scholar
  51. 51.
    Brivio F, Lissoni P, Fumagalli L et al (2008) Correlation between soluble IL-2 receptor serum levels and regulatory T lymphocytes in patients with solid tumors. Int J Biol Mark 23(2):121–122Google Scholar
  52. 52.
    Kasprzak A, Olejniczak K, Przybyszewska W et al (2007) Cellular expression of interleukin 2 (IL-2) and its receptor (IL-2R, CD25) in lung tumours. Folia Morphol 66(3):159–166Google Scholar
  53. 53.
    Kuhn DJ, Dou QP (2005) The role of interleukin-2 receptor alpha in cancer. Front Biosci J Virtual Libr 10:1462–1474Google Scholar
  54. 54.
    Nukui A, Masuda A, Abe H et al (2017) Increased serum level of soluble interleukin-2 receptor is associated with a worse response of metastatic clear cell renal cell carcinoma to interferon alpha and sequential VEGF-targeting therapy. BMC Cancer 17(1):372. Google Scholar
  55. 55.
    Zaoui P, Green W, Hakim RM (1991) Hemodialysis with cuprophane membrane modulates interleukin-2 receptor expression. Kidney Int 39(5):1020–1026Google Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Chen XiaoHong
    • 1
    • 2
    • 3
    • 4
    • 5
  • Shen Bo
    • 1
    • 2
    • 3
    • 4
    • 5
  • Xiang FangFang
    • 1
    • 2
    • 3
    • 4
    • 5
  • Guo Man
    • 1
    • 2
    • 3
    • 4
    • 5
  • Zou JianZhou
    • 1
    • 2
    • 3
    • 4
    • 5
  • Liu ZhongHua
    • 1
    • 2
    • 3
    • 4
    • 5
  • Lv WenLv
    • 1
    • 2
    • 3
    • 4
    • 5
  • Cao XueSen
    • 1
    • 2
    • 3
    • 4
    • 5
  • Ding XiaoQiang
    • 1
    • 2
    • 3
    • 4
    • 5
    • 8
    Email author
  • Zhang Boheng
    • 6
    • 7
  1. 1.Shanghai Institute of Kidney and DialysisShanghaiPeople’s Republic of China
  2. 2.Shanghai Key Laboratory of Kidney and Blood PurificationShanghaiPeople’s Republic of China
  3. 3.Hemodialysis Quality Control Center of ShanghaiShanghaiPeople’s Republic of China
  4. 4.Department of Nephrology, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China
  5. 5.Shanghai Medical Center of KidneyShanghaiPeople’s Republic of China
  6. 6.Liver Cancer Institute, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China
  7. 7.Center for Evidence Based MedicineFudan UniversityShanghaiPeople’s Republic of China
  8. 8.Blood Purification CenterZhongshan Hospital of Fudan UniversityShanghaiPeople’s Republic of China

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