Adverse renal reactions of tyrosine kinase inhibitor drugs: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Qinxuan ¹ , WEI Jingwen ¹ , LIU Yangyi ¹ , LIU Liu ² , XIONG Ying ³ ,  ZHOU Chunying ⁴ ,  CHEN Xiaolei ⁵

1. West China Clinical Medical College, Sichuan University, Chengdu 610041, P. R. China;
2. School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China;
3. West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
4. Department of General Surgery, Shapingba District People's Hospital, Chongqing 400030, P. R. China;
5. Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

ZHOU Chunying, Email: ZHOUchunying800321@163.com; CHEN Xiaolei, Email: irenecxl@163.com

Keywords：

Tyrosine kinase inhibitors; Tumours; Renal adverse reactions; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202305069

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To systematically review the renal adverse reactions of tyrosine kinase inhibitors (TKI). Methods PubMed, EMbase, Cochrane Library, CNKI, WanFang Data and CBM databases were electronically searched to collect randomized controlled trials (RCTs) on the incidence of renal adverse reactions of TKI from inception to March 30, 2023. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. Meta-analysis was then performed by using RevMan 5.4 software. Results A total of 19 RCTs involving 10 141 patients were included. The results of meta-analysis showed that compared with placebo or blank control, gefitinib, ranvartinib, cabotinib, vandetanib, pazopanib, arotinib, apatinib, and acitinib could lead to an increased risk of proteinuria events, while sildenib did not increase the risk of proteinuria in patients. Anlotinib could increase the risk of hematuria. Vandetanil increased the risk of acute kidney injury. Gefitinib, ranvartinib and apatinib could increase the risk of grade 3-4 renal adverse reactions. Conclusion Current evidence shows that TKI drugs may cause renal damage in patients, and proteinuria is the most common. Vandetanil can cause acute kidney injury, gefitinib, ranvartinib and apatinib are more nephrotoxic. The renal adverse reactions of neratinib, ibutinib and sildenib are relatively few.

Citation： WANG Qinxuan, WEI Jingwen, LIU Yangyi, LIU Liu, XIONG Ying, ZHOU Chunying, CHEN Xiaolei. Adverse renal reactions of tyrosine kinase inhibitor drugs: a systematic review. Chinese Journal of Evidence-Based Medicine, 2023, 23(9): 1046-1052. doi: 10.7507/1672-2531.202305069 Copy

1.	Jiao Q, Bi L, Ren Y, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer, 2018, 17(1): 36.
2.	Drake JM, Lee JK, Witte ON. Clinical targeting of mutated and wild-type protein tyrosine kinases in cancer. Mol Cell Biol, 2014, 34(10): 1722-1732.
3.	Hartmann JT, Haap M, Kopp HG, et al. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr Drug Metab, 2009, 10(5): 470-481.
4.	Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab, 2014, 19(2): 181-192.
5.	Fujita KI, Ishida H, Kubota Y, et al. Toxicities of receptor tyrosine kinase inhibitors in cancer pharmacotherapy: management with clinical pharmacology. Curr Drug Metab, 2017, 18(3): 186-198.
6.	Hamnvik OP, Choueiri TK, Turchin A, et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer, 2015, 121(2): 311-319.
7.	Petrelli F, Borgonovo K, Cabiddu M, et al. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer, 2012, 78(1): 8-15.
8.	Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase Ⅲ trial. J Clin Oncol, 2013, 31(30): 3791-3799.
9.	Park SE, Lee SH, Ahn JS, et al. Increased response rates to salvage chemotherapy administered after PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer. J Thorac Oncol, 2018, 13(1): 106-111.
10.	Symonds RP, Gourley C, Davidson S, et al. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol, 2015, 16(15): 1515-1524.
11.	Thornton K, Kim G, Maher VE, et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U. S. Food and Drug Administration drug approval summary. Clin Cancer Res, 2012, 18(14): 3722-3730.
12.	Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol, 2021, 6(7): 559-568.
13.	Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase Ⅲ, randomized ATLAS trial. Ann Oncol, 2018, 29(12): 2371-2378.
14.	Besse B, Mazières J, Ribassin-Majed L, et al. Pazopanib or placebo in completely resected stage Ⅰ NSCLC patients: results of the phase Ⅱ IFCT-0703 trial. Ann Oncol, 2017, 28(5): 1078-1083.
15.	Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol, 2020, 21(7): 923-934.
16.	Chi Y, Shu Y, Ba Y, et al. Anlotinib monotherapy for refractory metastatic colorectal cancer: a double-blinded, placebo-controlled, randomized phase Ⅲ trial (ALTER0703). Oncologist, 2021, 26(10): e1693-e1703.
17.	Ellis PM, Shepherd FA, Millward M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR. 26): a double-blind, randomised, phase 3 trial. Lancet Oncol, 2014, 15(12): 1379-1388.
18.	du Bois A, Floquet A, Kim JW, et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol, 2014, 32(30): 3374-3382.
19.	Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2017, 18(12): 1688-1700.
20.	Grávalos C, Carrato A, Tobeña M, et al. A randomized phase Ⅱ study of axitinib as maintenance therapy after first-line treatment for metastatic colorectal cancer. Clin Colorectal Cancer, 2018, 17(2): e323-e329.
21.	Machiels JP, Bossi P, Menis J, et al. Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN). Ann Oncol, 2018, 29(4): 985-991.
22.	Kazandjian D, Blumenthal GM, Yuan W, et al. FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res, 2016, 22(6): 1307-1312.
23.	Langerbeins P, Bahlo J, Rhein C, et al. The CLL12 trial protocol: a placebo-controlled double-blind Phase Ⅲ study of ibrutinib in the treatment of early-stage chronic lymphocytic leukemia patients with risk of early disease progression. Future Oncol, 2015, 11(13): 1895-1903.
24.	Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase Ⅲ trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol, 2016, 34(13): 1448-1454.
25.	Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med, 2015, 372(7): 621-630.
26.	Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial. Cancer, 2022, 128(24): 4203-4212.
27.	Iacovelli R, Massari F, Albiges L, et al. Evidence and clinical relevance of tumor flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma. Eur Urol, 2015, 68(1): 154-160.
28.	Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res, 2002, 62(24): 7284-7290.
29.	Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res, 2002, 62(16): 4645-4655.
30.	杨毅, 陈江华. 分子靶向药物与肾脏损伤的研究进展. 现代实用医学, 2020, 32(12): 1443-1445.
31.	Boye M, Wang X, Srimuninnimit V, et al. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in east Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer: quality of life results from a randomized phase Ⅲ trial. Clin Lung Cancer, 2016, 17(2): 150-160.
32.	Zhao Y, Liu J, Cai X, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ, 2019, 367: l5460.
33.	Zhang Z, Zeng K, Zhao S, et al. Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis. Ther Adv Med Oncol, 2019, 11: 1758835919891652.
34.	Kumasaka R, Nakamura N, Shirato K, et al. Side effects of therapy: case 1. Nephrotic syndrome associated with gefitinib therapy. J Clin Oncol, 2004, 22(12): 2504-2505.
35.	Maruyama K, Chinda J, Kuroshima T, et al. Minimal change nephrotic syndrome associated with gefitinib and a successful switch to erlotinib. Intern Med, 2015, 54(7): 823-826.
36.	Tang J, Liu N, Zhuang S. Role of epidermal growth factor receptor in acute and chronic kidney injury. Kidney Int, 2013, 83(5): 804-810.
37.	Gurevich F, Perazella MA. Renal effects of anti-angiogenesis therapy: update for the internist. Am J Med, 2009, 122(4): 322-328.
38.	Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med, 2003, 9(6): 669-676.
39.	Shen G, Zheng F, Ren D, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol, 2018, 11(1): 120.
40.	Sahade M, Caparelli F, Hoff PM. Cediranib: a VEGF receptor tyrosine kinase inhibitor. Future Oncol, 2012, 8(7): 775-781.
41.	Dhillon S. Ripretinib: First approval. Drugs, 2020, 80(11): 1133-1138.
42.	Piscitani L, Sirolli V, Di Liberato L, et al. Nephrotoxicity associated with novel anticancer agents (aflibercept, dasatinib, nivolumab): case series and nephrological considerations. Int J Mol Sci, 2020, 21(14): 4878.

1. Jiao Q, Bi L, Ren Y, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer, 2018, 17(1): 36.
2. Drake JM, Lee JK, Witte ON. Clinical targeting of mutated and wild-type protein tyrosine kinases in cancer. Mol Cell Biol, 2014, 34(10): 1722-1732.
3. Hartmann JT, Haap M, Kopp HG, et al. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr Drug Metab, 2009, 10(5): 470-481.
4. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab, 2014, 19(2): 181-192.
5. Fujita KI, Ishida H, Kubota Y, et al. Toxicities of receptor tyrosine kinase inhibitors in cancer pharmacotherapy: management with clinical pharmacology. Curr Drug Metab, 2017, 18(3): 186-198.
6. Hamnvik OP, Choueiri TK, Turchin A, et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer, 2015, 121(2): 311-319.
7. Petrelli F, Borgonovo K, Cabiddu M, et al. Relationship between skin rash and outcome in non-small-cell lung cancer patients treated with anti-EGFR tyrosine kinase inhibitors: a literature-based meta-analysis of 24 trials. Lung Cancer, 2012, 78(1): 8-15.
8. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase Ⅲ trial. J Clin Oncol, 2013, 31(30): 3791-3799.
9. Park SE, Lee SH, Ahn JS, et al. Increased response rates to salvage chemotherapy administered after PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer. J Thorac Oncol, 2018, 13(1): 106-111.
10. Symonds RP, Gourley C, Davidson S, et al. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol, 2015, 16(15): 1515-1524.
11. Thornton K, Kim G, Maher VE, et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U. S. Food and Drug Administration drug approval summary. Clin Cancer Res, 2012, 18(14): 3722-3730.
12. Qin S, Li Q, Gu S, et al. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol, 2021, 6(7): 559-568.
13. Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase Ⅲ, randomized ATLAS trial. Ann Oncol, 2018, 29(12): 2371-2378.
14. Besse B, Mazières J, Ribassin-Majed L, et al. Pazopanib or placebo in completely resected stage Ⅰ NSCLC patients: results of the phase Ⅱ IFCT-0703 trial. Ann Oncol, 2017, 28(5): 1078-1083.
15. Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol, 2020, 21(7): 923-934.
16. Chi Y, Shu Y, Ba Y, et al. Anlotinib monotherapy for refractory metastatic colorectal cancer: a double-blinded, placebo-controlled, randomized phase Ⅲ trial (ALTER0703). Oncologist, 2021, 26(10): e1693-e1703.
17. Ellis PM, Shepherd FA, Millward M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR. 26): a double-blind, randomised, phase 3 trial. Lancet Oncol, 2014, 15(12): 1379-1388.
18. du Bois A, Floquet A, Kim JW, et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol, 2014, 32(30): 3374-3382.
19. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2017, 18(12): 1688-1700.
20. Grávalos C, Carrato A, Tobeña M, et al. A randomized phase Ⅱ study of axitinib as maintenance therapy after first-line treatment for metastatic colorectal cancer. Clin Colorectal Cancer, 2018, 17(2): e323-e329.
21. Machiels JP, Bossi P, Menis J, et al. Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN). Ann Oncol, 2018, 29(4): 985-991.
22. Kazandjian D, Blumenthal GM, Yuan W, et al. FDA approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res, 2016, 22(6): 1307-1312.
23. Langerbeins P, Bahlo J, Rhein C, et al. The CLL12 trial protocol: a placebo-controlled double-blind Phase Ⅲ study of ibrutinib in the treatment of early-stage chronic lymphocytic leukemia patients with risk of early disease progression. Future Oncol, 2015, 11(13): 1895-1903.
24. Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase Ⅲ trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol, 2016, 34(13): 1448-1454.
25. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med, 2015, 372(7): 621-630.
26. Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial. Cancer, 2022, 128(24): 4203-4212.
27. Iacovelli R, Massari F, Albiges L, et al. Evidence and clinical relevance of tumor flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma. Eur Urol, 2015, 68(1): 154-160.
28. Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res, 2002, 62(24): 7284-7290.
29. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res, 2002, 62(16): 4645-4655.
30. 杨毅, 陈江华. 分子靶向药物与肾脏损伤的研究进展. 现代实用医学, 2020, 32(12): 1443-1445.
31. Boye M, Wang X, Srimuninnimit V, et al. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in east Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer: quality of life results from a randomized phase Ⅲ trial. Clin Lung Cancer, 2016, 17(2): 150-160.
32. Zhao Y, Liu J, Cai X, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ, 2019, 367: l5460.
33. Zhang Z, Zeng K, Zhao S, et al. Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis. Ther Adv Med Oncol, 2019, 11: 1758835919891652.
34. Kumasaka R, Nakamura N, Shirato K, et al. Side effects of therapy: case 1. Nephrotic syndrome associated with gefitinib therapy. J Clin Oncol, 2004, 22(12): 2504-2505.
35. Maruyama K, Chinda J, Kuroshima T, et al. Minimal change nephrotic syndrome associated with gefitinib and a successful switch to erlotinib. Intern Med, 2015, 54(7): 823-826.
36. Tang J, Liu N, Zhuang S. Role of epidermal growth factor receptor in acute and chronic kidney injury. Kidney Int, 2013, 83(5): 804-810.
37. Gurevich F, Perazella MA. Renal effects of anti-angiogenesis therapy: update for the internist. Am J Med, 2009, 122(4): 322-328.
38. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med, 2003, 9(6): 669-676.
39. Shen G, Zheng F, Ren D, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol, 2018, 11(1): 120.
40. Sahade M, Caparelli F, Hoff PM. Cediranib: a VEGF receptor tyrosine kinase inhibitor. Future Oncol, 2012, 8(7): 775-781.
41. Dhillon S. Ripretinib: First approval. Drugs, 2020, 80(11): 1133-1138.
42. Piscitani L, Sirolli V, Di Liberato L, et al. Nephrotoxicity associated with novel anticancer agents (aflibercept, dasatinib, nivolumab): case series and nephrological considerations. Int J Mol Sci, 2020, 21(14): 4878.

Chinese Journal of Evidence-Based Medicine

Adverse renal reactions of tyrosine kinase inhibitor drugs: a systematic review

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content