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Role of cytokine gene polymorphisms in acute and chronic kidney disease following liver transplantation

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Abstract

Purpose

Development of renal dysfunction, including acute kidney injury (AKI) and chronic kidney disease (CKD), after liver transplantation (LT) remains a critical issue adversely affecting patient survival in both the short and long term. Previous reports have suggested that inflammatory and antiinflammatory cytokines and their functionally relevant gene polymorphisms may play critical roles in the development of AKI and CKD. However, the involvement of these cytokines and their gene polymorphisms in renal deterioration following LT remains unclear.

Methods

We examined 62 recipients who underwent LT at Nagoya University between 2004 and 2009 and who had survived for at least 1 year. The following gene polymorphisms in recipients were analyzed: tumor necrosis factor-A (TNFA) T-1031C, interleukin-2 (IL2) T-330G, IL10 C-819T, IL13 C-1111T, transforming growth factor-B (TGFB) T29C, and IL4 T-33C.

Results

Thirteen patients (21 %) developed AKI within 4 weeks after LT. Of the investigated gene polymorphisms, the IL4 -33 T/T genotype was significantly associated with higher incidence of AKI compared with the other two genotypes [hazard ratio (HR) = 5.48, 95 % confidence interval (CI) 1.18–25.52, p = 0.03]. On the other hand, 16 patients (26 %) had developed CKD at median follow-up of 9.2 years after LT. We showed the lack of association between investigated gene polymorphisms in recipients and CKD development.

Conclusions

The IL4 -33 T/T genotype might be a risk factor for AKI in LT, and this might contribute to earlier withdrawal of immunosuppressive agents to minimize renal toxicity. In contrast, none of the investigated cytokine gene polymorphisms were associated with CKD.

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Abbreviations

AKI:

Acute kidney injury

CKD:

Chronic kidney disease

CNI:

Calcineurin inhibitor

eGFR:

Estimated glomerular filtration rate

ESRD:

End-stage renal disease

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

IL:

Interleukin

LT:

Liver transplantation

PCR:

Polymerase chain reaction

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

References

  1. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a single-center experience. Ann Surg 2005;241:905–916; discussion 16–8

  2. Barri YM, Sanchez EQ, Jennings LW, et al. Acute kidney injury following liver transplantation: definition and outcome. Liver Transpl 2009;15:475–483

  3. Bilbao I, Charco R, Balsells J, et al. Risk factors for acute renal failure requiring dialysis after liver transplantation. Clin Transplant 1998;12:123–129

  4. O’Riordan A, Wong V, McQuillan R, McCormick PA, Hegarty JE, Watson AJ. Acute renal disease, as defined by the RIFLE criteria, post-liver transplantation. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg 2007;7:168–176

  5. Paramesh AS, Roayaie S, Doan Y, et al. Post-liver transplant acute renal failure: factors predicting development of end-stage renal disease. Clin Transplant 2004;18:94–99

  6. Barreto AG, Daher EF, Silva Junior GB, et al. Risk factors for acute kidney injury and 30-day mortality after liver transplantation. Ann Hepatol 2015;14:688–694

  7. Cywinski JB, Mascha EJ, You J, et al. Pre-transplant MELD and sodium MELD scores are poor predictors of graft failure and mortality after liver transplantation. Hepatol Int 2011;5:841–849

  8. Zhu M, Li Y, Xia Q, et al. Strong impact of acute kidney injury on survival after liver transplantation. Transplant Proc 2010;42:3634–3638

  9. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931–940

  10. Belopolskaya OB, Smelaya TV, Moroz VV, Golubev AM, Salnikova LE. Clinical associations of host genetic variations in the genes of cytokines in critically ill patients. Clin Exp Immunol 2015;180:531–541

  11. McBride WT, Prasad PS, Armstrong M, et al. Cytokine phenotype, genotype, and renal outcomes at cardiac surgery. Cytokine 2013;61:275–284

  12. Susantitaphong P, Perianayagam MC, Tighiouart H, Liangos O, Bonventre JV, Jaber BL. Tumor necrosis factor alpha promoter polymorphism and severity of acute kidney injury. Nephron Clin Pract 2013;123:67–73

  13. Carrero JJ, Park SH, Axelsson J, Lindholm B, Stenvinkel P. Cytokines, atherogenesis, and hypercatabolism in chronic kidney disease: a dreadful triad. Semin Dial 2009;22:381–386

  14. Okada R, Wakai K, Naito M, et al. Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study. BMC Nephrol 2012;13:2

  15. Silverstein DM. Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease. Pediatr Nephrol 2009;24:1445–1452

  16. Kamei H, Masuda S, Nakamura T, et al. Cytokine gene polymorphisms in acute cellular rejection following living donor liver transplantation: analysis of 155 donor–recipient pairs. Hepatol Int 2013;7:916–922

  17. Williams JR. The Declaration of Helsinki and public health. Bull World Health Organ 2008;86:650–652

  18. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–R212

  19. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013;158:825–830

  20. Abdiev S, Ahn KS, Khadjibaev A, et al. Helicobacter pylori infection and cytokine gene polymorphisms in Uzbeks. Nagoya J Med Sci 2010;72:167–172

  21. Hamajima N, Saito T, Matsuo K, Kozaki K, Takahashi T, Tajima K. Polymerase chain reaction with confronting two-pair primers for polymorphism genotyping. Jpn J Cancer Res 2000;91:865–868

  22. Togawa S, Joh T, Itoh M, et al. Interleukin-2 gene polymorphisms associated with increased risk of gastric atrophy from Helicobacter pylori infection. Helicobacter 2005;10:172–178

  23. Chang CF, Lu TM, Yang WC, Lin SJ, Lin CC, Chung MY. Gene polymorphisms of interleukin-10 and tumor necrosis factor-alpha are associated with contrast-induced nephropathy. Am J Nephrol 2013;37:110–117

  24. Jaber BL, Rao M, Guo D, et al. Cytokine gene promoter polymorphisms and mortality in acute renal failure. Cytokine 2004;25:212–219

  25. Cuenca AB, Citores MJ, de la Fuente S, et al. TT genotype of transforming growth factor beta1 +869C/T is associated with the development of chronic kidney disease after liver transplantation. Transplant Proc 2014;46:3108–3110

  26. Bijlsma FJ, van Kuik J, van Hoffen E, et al. Acute cardiac transplant rejection is associated with low frequencies of interleukin-4 producing helper T-lymphocytes rather than with interleukin-4 promoter or splice variants. Hum Immunol 2002;63:317–323

  27. Bijlsma FJ, vanKuik J, Tilanus MG, et al. Donor interleukin-4 promoter gene polymorphism influences allograft rejection after heart transplantation. J Heart Lung Transplant 2002;21:340–346

  28. Essner R, Rhoades K, McBride WH, Morton DL, Economou JS. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol 1989;142:3857–3861

  29. Bozzi A, Reis BS, Pereira PP, Pedroso EP, Goes AM. Interferon-gamma and interleukin-4 single nucleotide gene polymorphisms in paracoccidioidomycosis. Cytokine 2009;48:212–217

  30. Tindall EA, Severi G, Hoang HN, et al. Comprehensive analysis of the cytokine-rich chromosome 5q31.1 region suggests a role for IL-4 gene variants in prostate cancer risk. Carcinogenesis 2010;31:1748–1754

  31. Mittal RD, Manchanda PK. Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease. Immunogenetics 2007;59:159–165

  32. Yao Q, Lindholm B, Stenvinkel P. Inflammation as a cause of malnutrition, atherosclerotic cardiovascular disease, and poor outcome in hemodialysis patients. Hemodial Int 2004;8:118–129

  33. Hiromura K, Kurosawa M, Yano S, Naruse T. Tubulointerstitial mast cell infiltration in glomerulonephritis. Am J Kidney Dis 1998;32:593–599

  34. Tsuda K, Yamanaka K, Kitagawa H, et al. Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naive T cells into cytokine-producing mature T cells. PLoS ONE 2012;7:e31465

  35. Kim JY, Akalin E, Dikman S, et al. The variable pathology of kidney disease after liver transplantation. Transplantation 2010;89:215–221

  36. Fussner LA, Charlton MR, Heimbach JK, et al. The impact of gender and NASH on chronic kidney disease before and after liver transplantation. Liver Int 2014;34:1259–1266

  37. O’Riordan A, Dutt N, Cairns H, et al. Renal biopsy in liver transplant recipients. Nephrol Dial Transplant 2009;24:2276–2282

  38. Weber ML, Ibrahim HN, Lake JR. Renal dysfunction in liver transplant recipients: evaluation of the critical issues. Liver Transpl 2012;18:1290–1301

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Authors and Affiliations

  1. Department of Transplantation Surgery, Nagoya University Hospital, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan

    Hideya Kamei, Yasuharu Onishi & Taro Nakamura

  2. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan

    Masatoshi Ishigami

  3. Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya, 466-8550, Japan

    Nobuyuki Hamajima

Authors
  1. Hideya Kamei
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  2. Yasuharu Onishi
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Correspondence to Hideya Kamei.

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We have no funding sources or personal acknowledgments to be listed. We have no disclosures or financial support.

Conflicts of interest

The authors H. Kamei, Y. Onishi, T. Nakamura, M. Ishigami, and N. Hamajima declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee. This study was approved by the ethics committees of Nagoya University School of Medicine (approval no. 290). All procedures were carried out in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

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Signed informed consent was obtained from all participants.

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Kamei, H., Onishi, Y., Nakamura, T. et al. Role of cytokine gene polymorphisms in acute and chronic kidney disease following liver transplantation. Hepatol Int 10, 665–672 (2016). https://doi.org/10.1007/s12072-016-9721-x

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  • DOI: https://doi.org/10.1007/s12072-016-9721-x

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