Renal toxicity of intravitreal injection of anti-vascular endothelial growth factor drugs in the treatment of retinopathy_West China Medical Journal

Authors：

ZOU Yutong ,  LIU Fang

Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIU Fang, Email: liufangfh@163.com

Keywords：

Vitreous cavity; anti-vascular endothelial growth factor drugs; renal toxicity; vascular endothelial growth factor; proteinuria; thrombotic microangiopathy

DOI：

10.7507/1002-0179.202012189

Video：

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Anti-vascular endothelial growth factor (VEGF) drugs have been widely used in clinic by inhibiting angiogenesis to treat ocular diseases such as malignant tumors and diabetic retinopathy. However, recent studies have shown that intravitreal injection of anti-VEGF drugs may have significant systemic absorption, leading to a series of renal damages such as worsening hypertension, proteinuria, new glomerular disease, and thrombotic microangiopathy. This article reviews the renal toxicity of intravitreal injection of anti-VEGF drugs in the treatment of diabetic retinopathy and other ocular diseases, aiming to provide recommendations for clinicians.

Citation： ZOU Yutong, LIU Fang. Renal toxicity of intravitreal injection of anti-vascular endothelial growth factor drugs in the treatment of retinopathy. West China Medical Journal, 2022, 37(10): 1588-1593. doi: 10.7507/1002-0179.202012189 Copy

1.	Hanna RM, Barsoum M, Arman F, et al. Nephrotoxicity induced by intravitreal vascular endothelial growth factor inhibitors: emerging evidence. Kidney Int, 2019, 96(3): 572-580.
2.	Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 1989, 246(4935): 1306-1309.
3.	Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev, 1997, 18(1): 4-25.
4.	Guo D, Jia Q, Song HY, et al. Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J Biol Chem, 1995, 270(12): 6729-6733.
5.	Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J, 2001, 20(11): 2768-2778.
6.	Takahashi T, Ueno H, Shibuya M. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene, 1999, 18(13): 2221-2230.
7.	Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem, 1998, 273(46): 30336-30343.
8.	Soker S, Takashima S, Miao HQ, et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell, 1998, 92(6): 735-745.
9.	Lopes-Coelho F, Martins F, Pereira SA, et al. Anti-angiogenic therapy: current challenges and future perspectives. Int J Mol Sci, 2021, 22(7): 3765.
10.	DrugBank. Bevacizumab. (2022-09-12)[2022-09-17]. https://go.drugbank.com/drugs/DB00112.
11.	Stewart MW. Treatment of diabetic retinopathy: recent advances and unresolved challenges. World J Diabetes, 2016, 7(16): 333-341.
12.	DrugBank. Ranibizumab. (2022-09-02)[2022-09-17]. https://go.drugbank.com/indications/DBCOND0082791.
13.	DrugBank. Pegaptanib. (2021-12-04)[2022-09-17]. https://go.drugbank.com/drugs/DB04895.
14.	涂远茂. 抗血管内皮生长因子及其受体靶向药物的肾脏毒性. 肾脏病与透析肾移植杂志, 2018, 27(6): 570-575.
15.	Food and Drug Administration. Center for drug evaluation and research. (2015-12-06)[2022-09-17]. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125156Orig1s106.pdf.
16.	Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina, 2017, 37(10): 1847-1858.
17.	Avery RL, Gordon GM. Systemic safety of prolonged monthly anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis. JAMA Ophthalmol, 2016, 134(1): 21-29.
18.	徐兰, 杨海春, 马骥, 等. 新生小鼠足细胞损伤对肾小球发育的影响. 中华肾脏病杂志, 2006, 22(10): 617-622.
19.	Majumder S, Advani A. VEGF and the diabetic kidney: more than too much of a good thing. J Diabetes Complications, 2017, 31(1): 273-279.
20.	宋凯云, 刘必成, 汤日宁. 内皮-足细胞对话在糖尿病肾病中的研究进展. 中华肾脏病杂志, 2019, 35(3): 231-235.
21.	Estrada CC, Maldonado A, Mallipattu SK. Therapeutic inhibition of VEGF signaling and associated nephrotoxicities. J Am Soc Nephrol, 2019, 30(2): 187-200.
22.	Cheungpasitporn W, Chebib FT, Cornell LD, et al. Intravitreal antivascular endothelial growth factor therapy may induce proteinuria and antibody mediated injury in renal allografts. Transplantation, 2015, 99(11): 2382-2386.
23.	Kenworthy JA, Davis J, Chandra V, et al. Worsening proteinuria following intravitreal anti-VEGF therapy for diabetic macular edema. J Vitreoretin Dis, 2019, 3(2): 54-56.
24.	Hanna RM, Abdelnour L, Hasnain H, et al. Intravitreal bevacizumab-induced exacerbation of proteinuria in diabetic nephropathy, and amelioration by switching to ranibizumab. SAGE Open Med Case Rep, 2020, 8: 2050313X20907033.
25.	Izzedine H, Rixe O, Billemont B, et al. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis, 2007, 50(2): 203-218.
26.	Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med, 2008, 358(11): 1129-1136.
27.	方芳, 陶琳, 牛建英, 等. Nephrin、血管内皮生长因子及其受体表达与先兆子痫大鼠蛋白尿的关系. 中华肾脏病杂志, 2010, 26(6): 460-465.
28.	Veron D, Reidy KJ, Bertuccio C, et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int, 2010, 77(11): 989-999.
29.	Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int, 2004, 65(6): 2003-2017.
30.	Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6): 1248-1264.
31.	Balci S, Sahin O, Ozcaliskan S, et al. Immediate changes in blood pressure during intravitreal anti-VEGF agents’ applications in exudative age-related macular degeneration patients. Int Ophthalmol, 2020, 40(10): 2515-2522.
32.	Rasier R, Artunay O, Yuzbasioglu E, et al. The effect of intravitreal bevacizumab (avastin) administration on systemic hypertension. Eye (Lond), 2009, 23(8): 1714-1718.
33.	Risimic D, Milenkovic S, Nikolic D, et al. Influence of intravitreal injection of bevacizumab on systemic blood pressure changes in patients with exudative form of age-related macular degeneration. Hellenic J Cardiol, 2013, 54(6): 435-440.
34.	Glassman AR, Liu D, Jampol LM, et al. Changes in blood pressure and urine albumin-creatinine ratio in a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema. Invest Ophthalmol Vis Sci, 2018, 59(3): 1199-1205.
35.	Georgalas I, Papaconstantinou D, Papadopoulos K, et al. Renal injury following intravitreal anti-VEGF administration in diabetic patients with proliferative diabetic retinopathy and chronic kidney disease-a possible side effect?. Curr Drug Saf, 2014, 9(2): 156-158.
36.	Shye M, Hanna RM, Patel SS, et al. Worsening proteinuria and renal function after intravitreal vascular endothelial growth factor blockade for diabetic proliferative retinopathy. Clin Kidney J, 2020, 13(6): 969-980.
37.	Khneizer G, Al-Taee A, Bastani B. Self-limited membranous nephropathy after intravitreal bevacizumab therapy for age-related macular degeneration. J Nephropathol, 2017, 6(3): 134-137.
38.	Morales E, Moliz C, Gutierrez E. Renal damage associated to intravitreal administration of ranibizumab. Nefrologia, 2017, 37(6): 653-655.
39.	Kameda Y, Babazono T, Uchigata Y, et al. Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease. J Diabetes Investig, 2018, 9(4): 937-939.
40.	Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res, 2011, 17(18): 5858-5866.
41.	Hanna RM, Tran NT, Patel SS, et al. Thrombotic microangiopathy and acute kidney injury induced after intravitreal injection of vascular endothelial growth factor inhibitors VEGF blockade-related TMA after intravitreal use. Front Med (Lausanne), 2020, 7: 579603.
42.	Pérez-Valdivia MA, López-Mendoza M, Toro-Prieto FJ, et al. Relapse of minimal change disease nephrotic syndrome after administering intravitreal bevacizumab. Nefrologia, 2014, 34(3): 421-422.
43.	Sato T, Kawasaki Y, Waragai T, et al. Relapse of minimal change nephrotic syndrome after intravitreal bevacizumab. Pediatr Int, 2013, 55(3): e46-e48.
44.	Hanhart J, Comaneshter DS, Freier Dror Y, et al. Mortality in patients treated with intravitreal bevacizumab for age-related macular degeneration. BMC Ophthalmol, 2017, 17(1): 189.
45.	Hanhart J, Comaneshter DS, Vinker S. Mortality after a cerebrovascular event in age-related macular degeneration patients treated with bevacizumab ocular injections. Acta Ophthalmol, 2018, 96(6): e732-e739.
46.	Dalvin LA, Starr MR, AbouChehade JE, et al. Association of intravitreal anti-vascular endothelial growth factor therapy with risk of stroke, myocardial infarction, and death in patients with exudative age-related macular degeneration. JAMA Ophthalmol, 2019, 137(5): 483-490.
47.	Maloney MH, Schilz SR, Herrin J, et al. Risk of systemic adverse events associated with intravitreal anti-VEGF therapy for diabetic macular edema in routine clinical practice. Ophthalmology, 2019, 126(7): 1007-1015.
48.	Modi YS, Tanchon C, Ehlers JP. Comparative safety and tolerability of anti-VEGF therapy in age-related macular degeneration. Drug Saf, 2015, 38(3): 279-293.
49.	Zhang J, Wang Y, Li L, et al. Diabetic retinopathy may predict the renal outcomes of patients with diabetic nephropathy. Ren Fail, 2018, 40(1): 243-251.

1. Hanna RM, Barsoum M, Arman F, et al. Nephrotoxicity induced by intravitreal vascular endothelial growth factor inhibitors: emerging evidence. Kidney Int, 2019, 96(3): 572-580.
2. Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 1989, 246(4935): 1306-1309.
3. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev, 1997, 18(1): 4-25.
4. Guo D, Jia Q, Song HY, et al. Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J Biol Chem, 1995, 270(12): 6729-6733.
5. Takahashi T, Yamaguchi S, Chida K, et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J, 2001, 20(11): 2768-2778.
6. Takahashi T, Ueno H, Shibuya M. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene, 1999, 18(13): 2221-2230.
7. Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem, 1998, 273(46): 30336-30343.
8. Soker S, Takashima S, Miao HQ, et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell, 1998, 92(6): 735-745.
9. Lopes-Coelho F, Martins F, Pereira SA, et al. Anti-angiogenic therapy: current challenges and future perspectives. Int J Mol Sci, 2021, 22(7): 3765.
10. DrugBank. Bevacizumab. (2022-09-12)[2022-09-17]. https://go.drugbank.com/drugs/DB00112.
11. Stewart MW. Treatment of diabetic retinopathy: recent advances and unresolved challenges. World J Diabetes, 2016, 7(16): 333-341.
12. DrugBank. Ranibizumab. (2022-09-02)[2022-09-17]. https://go.drugbank.com/indications/DBCOND0082791.
13. DrugBank. Pegaptanib. (2021-12-04)[2022-09-17]. https://go.drugbank.com/drugs/DB04895.
14. 涂远茂. 抗血管内皮生长因子及其受体靶向药物的肾脏毒性. 肾脏病与透析肾移植杂志, 2018, 27(6): 570-575.
15. Food and Drug Administration. Center for drug evaluation and research. (2015-12-06)[2022-09-17]. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125156Orig1s106.pdf.
16. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. Retina, 2017, 37(10): 1847-1858.
17. Avery RL, Gordon GM. Systemic safety of prolonged monthly anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis. JAMA Ophthalmol, 2016, 134(1): 21-29.
18. 徐兰, 杨海春, 马骥, 等. 新生小鼠足细胞损伤对肾小球发育的影响. 中华肾脏病杂志, 2006, 22(10): 617-622.
19. Majumder S, Advani A. VEGF and the diabetic kidney: more than too much of a good thing. J Diabetes Complications, 2017, 31(1): 273-279.
20. 宋凯云, 刘必成, 汤日宁. 内皮-足细胞对话在糖尿病肾病中的研究进展. 中华肾脏病杂志, 2019, 35(3): 231-235.
21. Estrada CC, Maldonado A, Mallipattu SK. Therapeutic inhibition of VEGF signaling and associated nephrotoxicities. J Am Soc Nephrol, 2019, 30(2): 187-200.
22. Cheungpasitporn W, Chebib FT, Cornell LD, et al. Intravitreal antivascular endothelial growth factor therapy may induce proteinuria and antibody mediated injury in renal allografts. Transplantation, 2015, 99(11): 2382-2386.
23. Kenworthy JA, Davis J, Chandra V, et al. Worsening proteinuria following intravitreal anti-VEGF therapy for diabetic macular edema. J Vitreoretin Dis, 2019, 3(2): 54-56.
24. Hanna RM, Abdelnour L, Hasnain H, et al. Intravitreal bevacizumab-induced exacerbation of proteinuria in diabetic nephropathy, and amelioration by switching to ranibizumab. SAGE Open Med Case Rep, 2020, 8: 2050313X20907033.
25. Izzedine H, Rixe O, Billemont B, et al. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis, 2007, 50(2): 203-218.
26. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med, 2008, 358(11): 1129-1136.
27. 方芳, 陶琳, 牛建英, 等. Nephrin、血管内皮生长因子及其受体表达与先兆子痫大鼠蛋白尿的关系. 中华肾脏病杂志, 2010, 26(6): 460-465.
28. Veron D, Reidy KJ, Bertuccio C, et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int, 2010, 77(11): 989-999.
29. Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int, 2004, 65(6): 2003-2017.
30. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6): 1248-1264.
31. Balci S, Sahin O, Ozcaliskan S, et al. Immediate changes in blood pressure during intravitreal anti-VEGF agents’ applications in exudative age-related macular degeneration patients. Int Ophthalmol, 2020, 40(10): 2515-2522.
32. Rasier R, Artunay O, Yuzbasioglu E, et al. The effect of intravitreal bevacizumab (avastin) administration on systemic hypertension. Eye (Lond), 2009, 23(8): 1714-1718.
33. Risimic D, Milenkovic S, Nikolic D, et al. Influence of intravitreal injection of bevacizumab on systemic blood pressure changes in patients with exudative form of age-related macular degeneration. Hellenic J Cardiol, 2013, 54(6): 435-440.
34. Glassman AR, Liu D, Jampol LM, et al. Changes in blood pressure and urine albumin-creatinine ratio in a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema. Invest Ophthalmol Vis Sci, 2018, 59(3): 1199-1205.
35. Georgalas I, Papaconstantinou D, Papadopoulos K, et al. Renal injury following intravitreal anti-VEGF administration in diabetic patients with proliferative diabetic retinopathy and chronic kidney disease-a possible side effect?. Curr Drug Saf, 2014, 9(2): 156-158.
36. Shye M, Hanna RM, Patel SS, et al. Worsening proteinuria and renal function after intravitreal vascular endothelial growth factor blockade for diabetic proliferative retinopathy. Clin Kidney J, 2020, 13(6): 969-980.
37. Khneizer G, Al-Taee A, Bastani B. Self-limited membranous nephropathy after intravitreal bevacizumab therapy for age-related macular degeneration. J Nephropathol, 2017, 6(3): 134-137.
38. Morales E, Moliz C, Gutierrez E. Renal damage associated to intravitreal administration of ranibizumab. Nefrologia, 2017, 37(6): 653-655.
39. Kameda Y, Babazono T, Uchigata Y, et al. Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease. J Diabetes Investig, 2018, 9(4): 937-939.
40. Blake-Haskins JA, Lechleider RJ, Kreitman RJ. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res, 2011, 17(18): 5858-5866.
41. Hanna RM, Tran NT, Patel SS, et al. Thrombotic microangiopathy and acute kidney injury induced after intravitreal injection of vascular endothelial growth factor inhibitors VEGF blockade-related TMA after intravitreal use. Front Med (Lausanne), 2020, 7: 579603.
42. Pérez-Valdivia MA, López-Mendoza M, Toro-Prieto FJ, et al. Relapse of minimal change disease nephrotic syndrome after administering intravitreal bevacizumab. Nefrologia, 2014, 34(3): 421-422.
43. Sato T, Kawasaki Y, Waragai T, et al. Relapse of minimal change nephrotic syndrome after intravitreal bevacizumab. Pediatr Int, 2013, 55(3): e46-e48.
44. Hanhart J, Comaneshter DS, Freier Dror Y, et al. Mortality in patients treated with intravitreal bevacizumab for age-related macular degeneration. BMC Ophthalmol, 2017, 17(1): 189.
45. Hanhart J, Comaneshter DS, Vinker S. Mortality after a cerebrovascular event in age-related macular degeneration patients treated with bevacizumab ocular injections. Acta Ophthalmol, 2018, 96(6): e732-e739.
46. Dalvin LA, Starr MR, AbouChehade JE, et al. Association of intravitreal anti-vascular endothelial growth factor therapy with risk of stroke, myocardial infarction, and death in patients with exudative age-related macular degeneration. JAMA Ophthalmol, 2019, 137(5): 483-490.
47. Maloney MH, Schilz SR, Herrin J, et al. Risk of systemic adverse events associated with intravitreal anti-VEGF therapy for diabetic macular edema in routine clinical practice. Ophthalmology, 2019, 126(7): 1007-1015.
48. Modi YS, Tanchon C, Ehlers JP. Comparative safety and tolerability of anti-VEGF therapy in age-related macular degeneration. Drug Saf, 2015, 38(3): 279-293.
49. Zhang J, Wang Y, Li L, et al. Diabetic retinopathy may predict the renal outcomes of patients with diabetic nephropathy. Ren Fail, 2018, 40(1): 243-251.

West China Medical Journal

Renal toxicity of intravitreal injection of anti-vascular endothelial growth factor drugs in the treatment of retinopathy

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