Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 6, pp 1051–1059 | Cite as

Antiproteinuric effects of renin–angiotensin inhibitors in lung cancer patients receiving bevacizumab

  • Satoru Nihei
  • Junya Sato
  • Toshiyuki Harada
  • Shoichi Kuyama
  • Toshiro Suzuki
  • Nobutsugu Waga
  • Yoshitaka Saito
  • Shigeki Kisara
  • Atsuko Yokota
  • Kouji Okada
  • Masami Tsuchiya
  • Kazufumi Terui
  • Yumiko Tadokoro
  • Takeshi Chiba
  • Kenzo Kudo
  • Satoshi Oizumi
  • Akira Inoue
  • Naoto Morikawa
Original Article



The objective of this study was to investigate the effect of renin–angiotensin system inhibitors (RASIs) on bevacizumab (BV)-induced proteinuria in non-small cell lung cancer (NSCLC) patients.

Materials and methods

We retrospectively reviewed the medical records of NSCLC patients receiving BV between 2008 and 2014 at 11 hospitals. The patients were categorized into three groups according to their antihypertensive drug use: RASI user, non-RASI user, and non-user groups. The primary outcome was a proteinuria event of any grade during the first 6 cycles of BV treatment.


A total of 211 patients were included, 89 of whom received antihypertensive drugs. Of these 89 patients, 49 were in the RASI user group, and 40 were in the non-RASI user group. The non-user group comprised 122 patients. The occurrence of proteinuria in the RASI user group was significantly lower than that in the non-RASI user group (P = 0.037) but was not significantly lower than that in the non-user group (P = 0.287). Patients using RASIs had a lower rate of proteinuria than those who did not use RASIs according to multivariate analysis (odds ratio 0.32; 95% confidence interval 0.12–0.86; P = 0.024).


Our study suggests that RASI administration reduces the risk of proteinuria in patients receiving BV.


Bevacizumab Renin–angiotensin system inhibitor Non-small cell lung cancer Proteinuria 



This research study received no specific grant from any funding agency in the public, commercial, or not-for-profit sector. The following principal investigators and institutions contributed to the study: Y. Mori (Iwate Prefectural Central Hospital), H. Yokouchi (Fukushima Medical University Hospital), K. Taima (Hirosaki University Hospital), M. Maemondo (Miyagi Cancer Center), and H. Watanabe (Saka General Hospital).

Compliance with ethical standards

Conflict of interest

The authors have declared no conflicts of interest.

Research involving human participants and/or animals

Formal consent is not required for this type of study.

Informed consent

Informed consent is not required for this type of study.

Ethical approval

This study was approved by the institutional review board of each participating institution and was conducted according to institutional and ethical rules concerning research on tissue specimens and patients.


  1. 1.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550. CrossRefPubMedGoogle Scholar
  2. 2.
    Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019. CrossRefPubMedGoogle Scholar
  3. 3.
    Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722. CrossRefPubMedGoogle Scholar
  4. 4.
    Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMedGoogle Scholar
  5. 5.
    Lai XX, Xu RA, Yu-Ping L, Yang H (2016) Risk of adverse events with bevacizumab addition to therapy in advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. Onco Targets Ther 9:2421–2428. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wu S, Kim C, Baer L, Zhu X (2010) Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol 21:1381–1389. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    George BA, Zhou XJ, Toto R (2007) Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis 49:e23–ee29. CrossRefPubMedGoogle Scholar
  8. 8.
    Izzedine H, Ederhy S, Goldwasser F, Soria JC, Milano G, Cohen A, Khayat D, Spano JP (2009) Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol 20:807–815. CrossRefPubMedGoogle Scholar
  9. 9.
    Greka A, Mundel P (2012) Cell biology and pathology of podocytes. Annu Rev Physiol 74:299–323. CrossRefPubMedGoogle Scholar
  10. 10.
    Rüster C, Wolf G (2006) Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 17:2985–2991. CrossRefPubMedGoogle Scholar
  11. 11.
    Yu SY, Qi R, Zhao H (2013) Losartan reverses glomerular podocytes injury induced by Ang II via stabilizing the expression of GLUT1. Mol Biol 40:6295–6301Google Scholar
  12. 12.
    Shengyou Y, Li Y (2015) The effects of siRNA-silenced TRPC6 on podocyte autophagy and apoptosis induced by Ang II. J Renin Angiotensin Aldosterone Syst 16:1266–1273. CrossRefPubMedGoogle Scholar
  13. 13.
    US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, 2010 (2014) Accessed 31 Dec 2014
  14. 14.
    Crinò L, Dansin E, Garrido P, Griesinger F, Laskin J, Pavlakis N, Stroiakovski D, Thatcher N, Tsai CM, Wu YL, Zhou C (2010) Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol 11:733–740. CrossRefPubMedGoogle Scholar
  15. 15.
    Yoh K, Hosomi Y, Kasahara K, Yamada K, Takahashi T, Yamamoto N, Nishio M, Ohe Y, Koue T, Nakamura T, Enatsu S, Lee P, Ferry D, Tamura T, Nakagawa K (2016) A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy. Lung Cancer 99:186–193. CrossRefPubMedGoogle Scholar
  16. 16.
    Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE (2008) VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358:1129–1136. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Eremina V, Baelde HJ, Quaggin SE (2007) Role of the VEGF-a signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier. Nephron Physiol 106:32–37. CrossRefGoogle Scholar
  18. 18.
    Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC (2010) VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer 46:439–448. CrossRefPubMedGoogle Scholar
  19. 19.
    Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ (2013) Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 31:3004–3011. CrossRefPubMedGoogle Scholar
  20. 20.
    Yeh J, Frieze D, Martins R, Carr L (2010) Clinical utility of routine proteinuria evaluation in treatment decisions of patients receiving bevacizumab for metastatic solid tumors. Ann Pharmacother 44:1010–1015. CrossRefPubMedGoogle Scholar
  21. 21.
    Ramirez SP, McClellan W, Port FK, Hsu SI (2002) Risk factors for proteinuria in a large, multiracial, Southeast Asian population. J Am Soc Nephrol 13:1907–1917. CrossRefPubMedGoogle Scholar
  22. 22.
    Teramachi H, Shiga H, Komada N, Tamura K, Yasuda M, Umeda M, Tachi T, Goto C, Tsuchiya T (2013) Risk factors contributing to urinary protein expression resulting from bevacizumab combination chemotherapy. Pharmazie 68:217–220PubMedGoogle Scholar
  23. 23.
    Gansevoort RT, Sluiter WJ, Hemmelder MH, de Zeeuw D, de Jong PE (1995) Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of comparative trials. Nephrol Dial Transplant 10:1963–1974CrossRefPubMedGoogle Scholar
  24. 24.
    Maki DD, Ma JZ, Louis TA, Kasiske BL (1995) Long-term effects of antihypertensive agents on proteinuria and renal function. Arch Intern Med 155:1073–1080CrossRefPubMedGoogle Scholar
  25. 25.
    Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG, African American Study of Kidney Disease and Hypertension Study Group (2002) Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK Trial Group. JAMA 288:2421–2431CrossRefPubMedGoogle Scholar
  26. 26.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, Collaborative Study Group (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860. CrossRefPubMedGoogle Scholar
  27. 27.
    Bakris GL, Weir MR, Secic M, Campbell B, Weis-McNulty A (2004) Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int 65:1991–2002. CrossRefPubMedGoogle Scholar
  28. 28.
    Patel TV, Morgan JA, Demetri GD, George S, Maki RG, Quigley M, Humphreys BD (2008) A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst 100:282–284. CrossRefPubMedGoogle Scholar
  29. 29.
    Okuno Y, Kume H, Hosoda C, Homma Y (2011) Development of nephrotic syndrome after administration of sorafenib in a case of metastatic renal cell carcinoma. Case Rep Med 2011:710216. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Takahashi D, Nagahama K, Tsuura Y, Tanaka H, Tamura T (2012) Sunitinib-induced nephrotic syndrome and irreversible renal dysfunction. Clin Exp Nephrol 16:310–315. CrossRefPubMedGoogle Scholar
  31. 31.
    Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH (2010) Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 28:949–954. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bono P, Elfving H, Utriainen T, Osterlund P, Saarto T, Alanko T, Joensuu H (2009) Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann Oncol 20:393–394. CrossRefPubMedGoogle Scholar
  33. 33.
    Feliu J, Salud A, Safont MJ, García-Girón C, Aparicio J, Losa F, Bosch C, Escudero P, Casado E, Jorge M, Bohn U, Pérez-Carrión R, Carmona A, Custodio AB, Maurel J (2015) Correlation of hypertension and proteinuria with outcome in elderly bevacizumab-treated patients with metastatic colorectal cancer. PLoS One 10:e0116527. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Schuster C, Eikesdal HP, Puntervoll H, Geisler J, Geisler S, Heinrich D, Molven A, Lønning PE, Akslen LA, Straume O (2012) Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. PLoS One 7:e38364. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Saif MW (2009) Managing bevacizumab-related toxicities in patients with colorectal cancer. J Support Oncol 7:245–251PubMedGoogle Scholar
  36. 36.
    Cohen EP, Lemann J Jr (1991) The role of the laboratory in evaluation of kidney function. Clin Chem 37:785–796PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Satoru Nihei
    • 1
  • Junya Sato
    • 2
  • Toshiyuki Harada
    • 3
  • Shoichi Kuyama
    • 4
  • Toshiro Suzuki
    • 5
  • Nobutsugu Waga
    • 6
  • Yoshitaka Saito
    • 7
  • Shigeki Kisara
    • 8
  • Atsuko Yokota
    • 9
  • Kouji Okada
    • 10
  • Masami Tsuchiya
    • 11
  • Kazufumi Terui
    • 12
  • Yumiko Tadokoro
    • 13
  • Takeshi Chiba
    • 1
  • Kenzo Kudo
    • 1
  • Satoshi Oizumi
    • 14
  • Akira Inoue
    • 15
  • Naoto Morikawa
    • 16
  1. 1.Division of Clinical Pharmaceutics and Pharmacy Practice, Department of Clinical PharmacyIwate Medical University, School of PharmacyShiwa-gunJapan
  2. 2.Department of PharmacyShizuoka Cancer CenterSunto-gunJapan
  3. 3.Center for Respiratory DiseaseJapan Community Health Care Organization Hokkaido HospitalSapporoJapan
  4. 4.Department of Respiratory MedicineNational Hospital Organization Iwakuni Medical CenterIwakuniJapan
  5. 5.Department of Internal MedicineIwate Prefectural Isawa HospitalOshuJapan
  6. 6.Department of PharmacyIwate Prefectural Isawa Hospital, 61, Ryugababa, Mizusawa-kuOshuJapan
  7. 7.Department of PharmacyHokkaido University HospitalSapporoJapan
  8. 8.Department of PharmacyTohoku University HospitalSendaiJapan
  9. 9.Department of PharmacyFukushima Medical University HospitalFukushimaJapan
  10. 10.Department of Clinical Pharmaceutics and Pharmacy PracticeTohoku Medical and Pharmaceutical UniversitySendaiJapan
  11. 11.Department of PharmacyMiyagi Cancer CenterNatoriJapan
  12. 12.Department of PharmacyHirosaki University HospitalHirosakiJapan
  13. 13.Department of PharmacySaka General HospitalShiogamaJapan
  14. 14.Department of Respiratory MedicineNational Hospital Organization Hokkaido CancerSapporoJapan
  15. 15.Department of Palliative MedicineTohoku University School of MedicineSendaiJapan
  16. 16.Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal MedicineIwate Medical University School of MedicineMoriokaJapan

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