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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 1, pp 195–202 | Cite as

Renin–angiotensin system inhibitors for countering proteinuria induced by angiogenesis inhibitors: a retrospective observational analysis

  • Toshinori HiraiEmail author
  • Yukari Shuji
  • Megumi Takiyama
  • Kazuhiko Hanada
  • Toshimasa Itoh
Original Article

Abstract

Purpose

Occurrence of proteinuria could result in cessation of bevacizumab and ramucirumab treatments. Renin–angiotensin system (RAS) inhibitors exert a renoprotective effect by countering proteinuria. However, the association between renoprotective effect of RAS inhibitors and blood pressure control is unclear. This study assessed the risk factors for proteinuria induced by bevacizumab or ramucirumab and the relationship between renoprotective effect of RAS inhibitors and blood pressure control.

Methods

A retrospective observational analysis was conducted at Tokyo Women’s Medical University, Medical Center East from June 2015 to May 2018. Multivariate logistic regression analysis was used to identify risk factors for proteinuria induced by treatment with bevacizumab and ramucirumab. Renoprotective effect was assessed by analyzing blood pressure data in association with the use of RAS inhibitors.

Results

Out of 208 patients included in this study, proteinuria was observed in 50 (24%) patients. Body mass index ≥ 24 kg/m2 (OR = 2.45, 95% CI 1.21–4.96, p = 0.01), colorectal cancer (OR = 1.95, 95% CI 1.00–3.80, p < 0.05), and use of RAS inhibitors (OR = 0.25 95% CI 0.07–0.92, p = 0.04) were associated with proteinuria induced by treatment with bevacizumab and ramucirumab. A change in systolic blood pressure at second visit was higher in patients with RAS inhibitors compared with those in patients without RAS inhibitors (25 mmHg vs − 5 mmHg, p = 0.04).

Conclusion

Although RAS inhibitors protected patients from proteinuria induced by bevacizumab or ramucirumab, RAS inhibitors could not adequately control their blood pressures in patients with proteinuria.

Keywords

Bevacizumab Ramucirumab Proteinuria Renin–angiotensin system inhibitors Blood pressure 

Notes

Funding

Financial support was not provided for this study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures in this study involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments. For this type of study, formal consent is not required.

References

  1. 1.
    Soria JC, Mauguen A, Reck M, Sandler AB, Saijo N, Johnson DH, Burcoveanu D, Fukuoka M, Besse B, Pignon JP (2013) Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 24(1):20–30.  https://doi.org/10.1093/annonc/mds590 CrossRefGoogle Scholar
  2. 2.
    Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15(11):1224–1235.  https://doi.org/10.1016/s1470-2045(14)70420-6 CrossRefGoogle Scholar
  3. 3.
    Jang HJ, Kim BJ, Kim JH, Kim HS (2017) The addition of bevacizumab in the first-line treatment for metastatic colorectal cancer: an updated meta-analysis of randomized trials. Oncotarget 8(42):73009–73016.  https://doi.org/10.18632/oncotarget.20314 CrossRefGoogle Scholar
  4. 4.
    Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stahle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–2496.  https://doi.org/10.1056/NEJMoa1103799 CrossRefGoogle Scholar
  5. 5.
    Clarke JM, Hurwitz HI, Rangwala F (2014) Understanding the mechanisms of action of antiangiogenic agents in metastatic colorectal cancer: a clinician’s perspective. Cancer Treat Rev 40(9):1065–1072.  https://doi.org/10.1016/j.ctrv.2014.07.001 CrossRefGoogle Scholar
  6. 6.
    Zhao T, Wang X, Xu T, Xu X, Liu Z (2017) Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: a systematic review and comprehensive meta-analysis. Oncotarget 8(31):51492–51506.  https://doi.org/10.18632/oncotarget.18190 Google Scholar
  7. 7.
    Abdel-Rahman O, ElHalawani H (2014) Proteinuria in patients with solid tumors treated with ramucirumab: a systematic review and meta-analysis. Chemotherapy 60(5–6):325–333.  https://doi.org/10.1159/000437253 CrossRefGoogle Scholar
  8. 8.
    Iwasa S, Nakajima TE, Nagashima K, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y (2013) Lack of association of proteinuria and clinical outcome in patients treated with bevacizumab for metastatic colorectal cancer. Anticancer Res 33(1):309–316Google Scholar
  9. 9.
    Vogt L, Waanders F, Boomsma F, de Zeeuw D, Navis G (2008) Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J Am Soc Nephrol 19(5):999–1007.  https://doi.org/10.1681/asn.2007060693 CrossRefGoogle Scholar
  10. 10.
    McKay RR, Rodriguez GE, Lin X, Kaymakcalan MD, Hamnvik OP, Sabbisetti VS, Bhatt RS, Simantov R, Choueiri TK (2015) Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 21(11):2471–2479.  https://doi.org/10.1158/1078-0432.ccr-14-2332 CrossRefGoogle Scholar
  11. 11.
    Pinter M, Weinmann A, Worns MA, Hucke F, Bota S, Marquardt JU, Duda DG, Jain RK, Galle PR, Trauner M, Peck-Radosavljevic M, Sieghart W (2017) Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United European Gastroenterol J 5(7):987–996.  https://doi.org/10.1177/2050640617695698 CrossRefGoogle Scholar
  12. 12.
    Nihei S, Sato J, Harada T, Kuyama S, Suzuki T, Waga N, Saito Y, Kisara S, Yokota A, Okada K, Tsuchiya M, Terui K, Tadokoro Y, Chiba T, Kudo K, Oizumi S, Inoue A, Morikawa N (2018) Antiproteinuric effects of renin-angiotensin inhibitors in lung cancer patients receiving bevacizumab. Cancer Chemother Pharmacol 81(6):1051–1059.  https://doi.org/10.1007/s00280-018-3580-1 CrossRefGoogle Scholar
  13. 13.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53(6):982–992.  https://doi.org/10.1053/j.ajkd.2008.12.034 CrossRefGoogle Scholar
  14. 14.
    Agarwal R, Light RP (2009) GFR, proteinuria and circadian blood pressure. Nephrol Dial Transpl 24(8):2400–2406.  https://doi.org/10.1093/ndt/gfp074 CrossRefGoogle Scholar
  15. 15.
    Yano Y, Sato Y, Fujimoto S, Konta T, Iseki K, Moriyama T, Yamagata K, Tsuruya K, Yoshida H, Asahi K, Kurahashi I, Ohashi Y, Watanabe T (2012) Association of high pulse pressure with proteinuria in subjects with diabetes, prediabetes, or normal glucose tolerance in a large Japanese general population sample. Diabetes Care 35(6):1310–1315.  https://doi.org/10.2337/dc11-2245 CrossRefGoogle Scholar
  16. 16.
  17. 17.
    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(2):439–448.  https://doi.org/10.1016/j.ejca.2009.11.001 CrossRefGoogle Scholar
  18. 18.
    Nakaya A, Kurata T, Yokoi T, Iwamoto S, Torii Y, Katashiba Y, Ogata M, Hamada M, Kon M, Nomura S (2016) Retrospective analysis of bevacizumab-induced hypertension and clinical outcome in patients with colorectal cancer and lung cancer. Cancer Med 5(7):1381–1387.  https://doi.org/10.1002/cam4.701 CrossRefGoogle Scholar
  19. 19.
    Lafayette RA, McCall B, Li N, Chu L, Werner P, Das A, Glassock R (2014) Incidence and relevance of proteinuria in bevacizumab-treated patients: pooled analysis from randomized controlled trials. Am J Nephrol 40(1):75–83.  https://doi.org/10.1159/000365156 CrossRefGoogle Scholar
  20. 20.
    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(3):217–220Google Scholar
  21. 21.
    Yen CJ, Muro K, Kim TW, Kudo M, Shih JY, Lee KW, Chao Y, Kim SW, Yamazaki K, Sohn J, Cheng R, Zhang Y, Binder P, Mi G, Orlando M, Chung HC (2018) Ramucirumab safety in east asian patients: a meta-analysis of six global, randomized, double-blind, placebo-controlled, phase III clinical trials. J Glob Oncol 4:1–12.  https://doi.org/10.1200/jgo.17.00227 CrossRefGoogle Scholar
  22. 22.
    Praga M, Hernandez E, Herrero JC, Morales E, Revilla Y, Diaz-Gonzalez R, Rodicio JL (2000) Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy. Kidney Int 58(5):2111–2118.  https://doi.org/10.1111/j.1523-1755.2000.00384.x CrossRefGoogle Scholar
  23. 23.
    Rosenstock JL, Pommier M, Stoffels G, Patel S, Michelis MF (2018) Prevalence of proteinuria and albuminuria in an obese population and associated risk factors. Front Med (Lausanne) 5:122.  https://doi.org/10.3389/fmed.2018.00122 CrossRefGoogle Scholar
  24. 24.
    Kim JK, Ju YS, Moon SJ, Song YR, Kim HJ, Kim SG (2013) High pulse pressure and metabolic syndrome are associated with proteinuria in young adult women. BMC Nephrol 14:45.  https://doi.org/10.1186/1471-2369-14-45 CrossRefGoogle Scholar
  25. 25.
    Whaley-Connell A, Sowers JR (2017) Obesity and kidney disease: from population to basic science and the search for new therapeutic targets. Kidney Int 92(2):313–323.  https://doi.org/10.1016/j.kint.2016.12.034 CrossRefGoogle Scholar
  26. 26.
    Kawarazaki W, Fujita T (2016) The role of aldosterone in obesity-related hypertension. Am J Hypertens 29(4):415–423.  https://doi.org/10.1093/ajh/hpw003 CrossRefGoogle Scholar
  27. 27.
    Yang Y, Li HY, Zhou Q, Peng ZW, An X, Li W, Xiong LP, Yu XQ, Jiang WQ, Mao HP (2016) Renal function and all-cause mortality risk among cancer patients. Medicine (Baltimore) 95(20):e3728.  https://doi.org/10.1097/md.0000000000003728 CrossRefGoogle Scholar
  28. 28.
    Kim MJ, Kang YU, Kim CS, Choi JS, Bae EH, Ma SK, Kweon SS, Kim SW (2013) Proteinuria as a risk factor for mortality in patients with colorectal cancer. Yonsei Med J 54(5):1194–1201.  https://doi.org/10.3349/ymj.2013.54.5.1194 CrossRefGoogle Scholar
  29. 29.
    Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, Woodward M, Chalmers J, Zanchetti A, MacMahon S (2007) Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens 25(5):951–958.  https://doi.org/10.1097/HJH.0b013e3280bad9b4 CrossRefGoogle Scholar
  30. 30.
    Xu R, Sun S, Huo Y, Yun L, Huang S, Li G, Yan S (2015) Effects of ACEIs versus ARBs on proteinuria or albuminuria in primary hypertension: a meta-analysis of randomized trials. Medicine (Baltimore) 94(39):e1560.  https://doi.org/10.1097/md.0000000000001560 CrossRefGoogle Scholar
  31. 31.
    Shibata M, Sato KK, Uehara S, Koh H, Kinuhata S, Oue K, Kambe H, Morimoto M, Hayashi T (2017) Blood pressure components and the risk for proteinuria in Japanese men: the Kansai Healthcare Study. J Epidemiol 27(11):505–510.  https://doi.org/10.1016/j.je.2016.10.010 CrossRefGoogle Scholar
  32. 32.
    Chen HB, Lu JX, Li Q, Bao YQ, Tang JL, Lu HJ, Xiang KS, Jia WP (2009) The protective effect of the RAS inhibitor on diabetic patients with nephropathy in the context of VEGF suppression. Acta Pharmacol Sin 30(2):242–250.  https://doi.org/10.1038/aps.2008.28 CrossRefGoogle Scholar
  33. 33.
    Frey MK, Dao F, Olvera N, Konner JA, Dickler MN, Levine DA (2017) Genetic predisposition to bevacizumab-induced hypertension. Gynecol Oncol 147(3):621–625.  https://doi.org/10.1016/j.ygyno.2017.09.017 CrossRefGoogle Scholar
  34. 34.
    Lane C, Brown M, Dunsmuir W, Kelly J, Mangos G (2006) Can spot urine protein/creatinine ratio replace 24 h urine protein in usual clinical nephrology? Nephrology (Carlton) 11(3):245–249.  https://doi.org/10.1111/j.1440-1797.2006.00564.x CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PharmacyTokyo Women’s Medical University, Medical Center EastTokyoJapan
  2. 2.Department of Pharmacometrics and PharmacokineticsMeiji Pharmaceutical UniversityTokyoJapan

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