CEN Case Reports

, Volume 6, Issue 2, pp 169–174 | Cite as

Tubulointerstitial nephritis as adverse effect of programmed cell death 1 inhibitor, nivolumab, showed distinct histological findings

  • Ai UchidaEmail author
  • Maho Watanabe
  • Aya Nawata
  • Yosuke Ikari
  • Masaru Sasaki
  • Kana Shigemoto
  • Satoshi Hisano
  • Hitoshi Nakashima
Case report


Immune-checkpoint inhibitor nivolumab (anti-PD-1 antibody) blocks T cell inhibition and stimulate immunologic response toward cancer cells. It was also revealed that PD-1/PD-L1 interaction crucially controls the effector differentiation of auto-reactive T cells to maintain self-tolerance. Therefore, potential autoimmunological side-effect can occur in any organ. Here, we report a case of 67-year-old Japanese male with lung adenocarcinoma treated with nivolumab who developed acute tubulointerstitial nephritis after the third infusion of nivolumab. Kidney biopsy showed distinct histological findings: Proliferation of CD38 positive and IgG positive plasma cells, and affluent infiltration of FoxP3+ regulatory T cells. Herein, we do pathological discussion concerning acute tubulointerstitial nephritis occurred in this case based on these histological findings.


Immune-checkpoint inhibitor Anti-programmed cell death-1 Nivolumab Tubulointerstitial nephritis FoxP3 



We thank Drs. Mamoru Tanaka and Yusuke Kashiwado (Kyushu University) for their generous help on immunofluorescent study.

Compliance with ethical standards

Ethics approval and consent to participate

This study was exempted from institutional review board approval because it was a case report.

Conflict of interest

All the authors have declared no competing interests.

Informed consent

Informed consent was obtained from the patient in this report.


  1. 1.
    Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–9.CrossRefGoogle Scholar
  2. 2.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.CrossRefGoogle Scholar
  3. 3.
    Luke JJ, Ott PA. PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. Oncotarget. 2015;6(6):3479–92.CrossRefGoogle Scholar
  4. 4.
    Barbee MS, Ogunniyi A, Horvat TZ, Dang TO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann Pharmacother. 2015;49(8):907–37.CrossRefGoogle Scholar
  5. 5.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, Investigators K. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.CrossRefGoogle Scholar
  6. 6.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.CrossRefGoogle Scholar
  7. 7.
    Martin-Orozco N, Wang YH, Yagita H, Dong C. Cutting Edge: programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. J Immunol. 2006;177(12):8291–5.CrossRefGoogle Scholar
  8. 8.
    Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005;6(3):280–6.CrossRefGoogle Scholar
  9. 9.
    Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.CrossRefGoogle Scholar
  10. 10.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.CrossRefGoogle Scholar
  11. 11.
    Cornell LD, Smith RN, Colvin RB. Kidney transplantation: mechanisms of rejection and acceptance. Annu Rev Pathol. 2008;3:189–220.CrossRefGoogle Scholar
  12. 12.
    Schoop R, Wahl P, Le Hir M, Heemann U, Wang M, Wuthrich RP. Suppressed T-cell activation by IFN-gamma-induced expression of PD-L1 on renal tubular epithelial cells. Nephrol Dial Transplant. 2004;19(11):2713–20.CrossRefGoogle Scholar
  13. 13.
    de Haij S, Woltman AM, Trouw LA, Bakker AC, Kamerling SW, van der Kooij SW, Chen L, Kroczek RA, Daha MR, van Kooten C. Renal tubular epithelial cells modulate T-cell responses via ICOS-L and B7-H1. Kidney Int. 2005;68(5):2091–102.CrossRefGoogle Scholar
  14. 14.
    Ding H, Wu X, Gao W. PD-L1 is expressed by human renal tubular epithelial cells and suppresses T cell cytokine synthesis. Clin Immunol. 2005;115(2):184–91.CrossRefGoogle Scholar
  15. 15.
    Shirali AC, Perazella MA, Gettinger S. Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients. Am J Kidney Dis. 2016;68(2):287–91.CrossRefGoogle Scholar
  16. 16.
    Kawamura E, Hisano S, Nakashima H, Takeshita M, Saito T. Immunohistological analysis for immunological response and mechanism of interstitial fibrosis in IgG4-related kidney disease. Mod Rheumatol. 2015;25(4):571–8.CrossRefGoogle Scholar
  17. 17.
    Killebrew JR, Perdue N, Kwan A, Thornton AM, Shevach EM, Campbell DJ. A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease. J Immunol. 2011;187(2):861–9.CrossRefGoogle Scholar
  18. 18.
    Levine AG, Arvey A, Jin W, Rudensky AY. Continuous requirement for the TCR in regulatory T cell function. Nat Immunol. 2014;15(11):1070–8.CrossRefGoogle Scholar
  19. 19.
    Zhang B, Chikuma S, Hori S, Fagarasan S, Honjo T. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci USA. 2016;113(30):8490–5.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2017

Authors and Affiliations

  • Ai Uchida
    • 1
    Email author
  • Maho Watanabe
    • 1
  • Aya Nawata
    • 2
  • Yosuke Ikari
    • 3
  • Masaru Sasaki
    • 1
  • Kana Shigemoto
    • 1
  • Satoshi Hisano
    • 2
  • Hitoshi Nakashima
    • 1
  1. 1.Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of MedicineFukuoka UniversityFukuokaJapan
  2. 2.Division of Pathology, Department of Internal Medicine, Faculty of MedicineFukuoka UniversityFukuokaJapan
  3. 3.Division of Medical Oncology, Hematology and Infectious Diseases, Department of Internal Medicine, Faculty of MedicineFukuoka UniversityFukuokaJapan

Personalised recommendations