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Acute renal failure after intravitreal antivascular endothelial growth factor therapy
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MODEL
Journal of the Formosan Medical Association (2016) xx, 1e3
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
CORRESPONDENCE
Acute renal failure after intravitreal antivascular endothelial growth factor therapy Yu-Fang Huang a, Shih-Jen Chen b,c, Min-Yen Hsu a,d, De-Kuang Hwang a,b,c,* a
Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan c Department of Ophthalmology, School of Medicine, National Yang-Ming University, Taipei, Taiwan d Institute of Nano-engineering and Microsystems, National Tsing Hua University, Hsinchu, Taiwan b
Received 20 July 2016; received in revised form 11 September 2016; accepted 14 September 2016
Introduction Macular edema is one of the leading causes of visual impairment in diabetic patients. An intravitreal antivascular endothelial growth factor (anti-VEGF) agent is an effective and crucial treatment. Systemic exposure to these agents after intravitreal administration has been discussed. However, decreasing renal function has scarcely been reported.
Case Report A 67-year-old male with diabetes, hypertension, and chronic kidney disease (CKD) suffered from persistently blurred vision. His creatinine level in serum was 5.52 mg/dL (glomerular filtration rate Z 11.1 mL/min/1.73m2), hemoglobin A1c was 6.0%, and blood pressure (BP) was 150/
Conflicts of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. Department of Ophthalmology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan. E-mail address: [email protected] (D.-K. Hwang).
60 mmHg. Proliferative diabetic retinopathy with diabetic macular edema (DME) was diagnosed and his symptoms improved after an intravitreal injection of 1.25 mg bevacizumab. The patient complained about blurred vision again 1 year later and DME in his right eye was noted again. His creatinine level was 8.81 mg/dL and BP was 182/ 73 mmHg. Intravitreal injection of 0.5 mg ranibizumab was performed after discussing the systemic risk with the patient. The patient had suffered from acute nausea since the first postoperative day and went to the emergency room 4 days later. His BP was 164/72 mmHg but his creatinine level increased to 12.09 mg/dL (Figure 1). Acute on CKD was diagnosed. After emergent hemodialysis and the following regular hemodialysis, his symptoms improved and macular edema subsided for more than 6 months.
Discussion VEGF is a vital factor which regulates glomerular vascular permeability. Renal toxicity varying from proteinuria or thrombotic microangiopathies to renal insufficiency have been reported in patients receiving systemic anti-VEGF therapy. Although the detailed mechanism causing renal damage has not been clarified yet, disruption of the
http://dx.doi.org/10.1016/j.jfma.2016.09.010 0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Huang Y-F, et al., Acute renal failure after intravitreal antivascular endothelial growth factor therapy, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.010
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Figure 1 The patient’s serum creatinine remained steady after intravitreal injection of 1.25 mg bevacizumab; his renal function decreased gradually since March 2015. Four days after intravitreal injection of 0.5 mg ranibizumab, acute chronic kidney disease was diagnosed and his serum creatinine dramatically increased to 12.09 mg/dL.
filtration barrier and decrease in the expression of nephrin have been suggested as two possible explanations for renal toxicity after systemic anti-VEGF therapy.1 In addition, thrombotic microangiography, focal segmental glomerulosclerosis, and tubule-interstitial nephritis have been found in pathology of the affected kidneys.2 Although the dosage of intravitreal anti-VEGF therapy is w400 times lower than that of intravenous anti-VEGF therapy, systemic exposure to these agents could be observed in < 24 hours after intravitreal administration. It has been estimated that the systemic concentration after intravitreal injection of 1.25 mg bevacizumab, 0.5 mg ranibizumab, and 2 mg aflibercept was 59.8e86.5 ng/mL, 0.2e2.36 ng/mL, and 20 ng/mL, with the half-life as 20 days, 2e6 hours, and 1.5 days, respectively. The concentration of free plasma VEGF could be as low as 10 pg/mL 1 day after a single dose of intravitreal injection.3e7 There are only three patients (1 with macular degeneration and 2 with DME) who have been reported to be suffering from acute renal injury after intravitreal antiVEGF therapy. Kidney biopsy in the former case showed segmental duplications of glomerular basement membranes with endothelial swelling, tubular atrophy, and noninflammatory interstitial fibrosis, recanalized arteriolar thrombi, and fibrinogen deposits in the hilus of glomerulus.8 The other two diabetic patients had preexisting Stage 4 CKD and required long-term hemodialysis eventually.9 In the 2-year results of a randomized trial conducted by the Diabetic Retinopathy Clinical Research network, renal and urinary disorders events were also been reported in 7e28% of patients.10 Theoretically, bevacizumab has higher systemic concentration and longer half-life than ranibizumab. However, the patient’s creatinine increased slowly after injection of
bevacizumab but significantly after ranibizumab. There are two possible reasons for that. First, it might be caused by a double-hit injury after two intravitreal injections, while there was a 1-year interval between two treatments. Second, the patient had Stage 5 CKD (glomerular filtration rate < 15 mL/min/1.73m2) at the first presentation but even less residual renal function when he received injection of ranibizumab, which might lead to the acute chronic renal failure episode. There was no other notable cause that might coexist in this patient and would interact with the effect of anti-VEGF in those postoperative days. Although the possible clinical risk factors and dangerous biomarkers for renal damage after anti-VEGF therapy have not been clarified yet, our presenting case implicated that ophthalmologists and internal medicine physicians should pay additional attention and perform a complete framework in performing this therapy for all patients, especially for diabetic patients with preexisting CKD. In addition, this is only a case report, and further collection of cases is needed.
References 1. 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;134:21e9. 2. den Deurwaarder ES, Desar IM, Steenbergen EJ, Mulders PF, Wetzels JF, van Herpen CM. Kidney injury during VEGF inhibitor therapy. Neth J Med 2012;70:267e71. 3. Semeraro F, Morescalchi F, Duse S, Gambicorti E, Cancarini A. Costagliola. Pharmacokinetic and pharmacodynamic properties of anti-VEGF drugs after intravitreal injection. Curr Drug Metab 2015;16:572e84.
Please cite this article in press as: Huang Y-F, et al., Acute renal failure after intravitreal antivascular endothelial growth factor therapy, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.010
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ARF after anti-VEGF therapy 4. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014;98:1636e41. 5. Davidovic SP, Nikolic SV, Curic NJ, Latinovic SL, Draskovic DO, Cabarkapa VS, et al. Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy. Eur J Ophthalmol 2012;22:792e8. 6. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179e82. 7. Matsuyama K, Ogata N, Matsuoka M, Wada M, Takahashi K, Nishimura T. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010; 94:1215e8.
3 8. Pelle G, Shweke N, Duong Van Huyen JP, Tricot L, Hessaı¨ne S, Fre ´meaux-Bacchi V, et al. Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. Am J Kidney Dis 2011;57:756e9. 9. Georgalas I, Papaconstantinou D, Papadopoulos K, Pagoulatos D, Karagiannis D, Koutsandrea C. Renal injury following intravitreal anti-VEGF administration in diabetic patients with proliferative diabetic retinopathy and chronic kidney diseaseea possible side effect? Curr Drug Saf 2014;9: 156e8. 10. Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016;123:1351e9.
Please cite this article in press as: Huang Y-F, et al., Acute renal failure after intravitreal antivascular endothelial growth factor therapy, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.010
MODEL
Journal of the Formosan Medical Association (2016) xx, 1e3
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
CORRESPONDENCE
Acute renal failure after intravitreal antivascular endothelial growth factor therapy Yu-Fang Huang a, Shih-Jen Chen b,c, Min-Yen Hsu a,d, De-Kuang Hwang a,b,c,* a
Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan c Department of Ophthalmology, School of Medicine, National Yang-Ming University, Taipei, Taiwan d Institute of Nano-engineering and Microsystems, National Tsing Hua University, Hsinchu, Taiwan b
Received 20 July 2016; received in revised form 11 September 2016; accepted 14 September 2016
Introduction Macular edema is one of the leading causes of visual impairment in diabetic patients. An intravitreal antivascular endothelial growth factor (anti-VEGF) agent is an effective and crucial treatment. Systemic exposure to these agents after intravitreal administration has been discussed. However, decreasing renal function has scarcely been reported.
Case Report A 67-year-old male with diabetes, hypertension, and chronic kidney disease (CKD) suffered from persistently blurred vision. His creatinine level in serum was 5.52 mg/dL (glomerular filtration rate Z 11.1 mL/min/1.73m2), hemoglobin A1c was 6.0%, and blood pressure (BP) was 150/
Conflicts of interest: The authors have no conflicts of interest relevant to this article. * Corresponding author. Department of Ophthalmology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan. E-mail address: [email protected] (D.-K. Hwang).
60 mmHg. Proliferative diabetic retinopathy with diabetic macular edema (DME) was diagnosed and his symptoms improved after an intravitreal injection of 1.25 mg bevacizumab. The patient complained about blurred vision again 1 year later and DME in his right eye was noted again. His creatinine level was 8.81 mg/dL and BP was 182/ 73 mmHg. Intravitreal injection of 0.5 mg ranibizumab was performed after discussing the systemic risk with the patient. The patient had suffered from acute nausea since the first postoperative day and went to the emergency room 4 days later. His BP was 164/72 mmHg but his creatinine level increased to 12.09 mg/dL (Figure 1). Acute on CKD was diagnosed. After emergent hemodialysis and the following regular hemodialysis, his symptoms improved and macular edema subsided for more than 6 months.
Discussion VEGF is a vital factor which regulates glomerular vascular permeability. Renal toxicity varying from proteinuria or thrombotic microangiopathies to renal insufficiency have been reported in patients receiving systemic anti-VEGF therapy. Although the detailed mechanism causing renal damage has not been clarified yet, disruption of the
http://dx.doi.org/10.1016/j.jfma.2016.09.010 0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Huang Y-F, et al., Acute renal failure after intravitreal antivascular endothelial growth factor therapy, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.010
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MODEL
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Y.-F. Huang et al.
Figure 1 The patient’s serum creatinine remained steady after intravitreal injection of 1.25 mg bevacizumab; his renal function decreased gradually since March 2015. Four days after intravitreal injection of 0.5 mg ranibizumab, acute chronic kidney disease was diagnosed and his serum creatinine dramatically increased to 12.09 mg/dL.
filtration barrier and decrease in the expression of nephrin have been suggested as two possible explanations for renal toxicity after systemic anti-VEGF therapy.1 In addition, thrombotic microangiography, focal segmental glomerulosclerosis, and tubule-interstitial nephritis have been found in pathology of the affected kidneys.2 Although the dosage of intravitreal anti-VEGF therapy is w400 times lower than that of intravenous anti-VEGF therapy, systemic exposure to these agents could be observed in < 24 hours after intravitreal administration. It has been estimated that the systemic concentration after intravitreal injection of 1.25 mg bevacizumab, 0.5 mg ranibizumab, and 2 mg aflibercept was 59.8e86.5 ng/mL, 0.2e2.36 ng/mL, and 20 ng/mL, with the half-life as 20 days, 2e6 hours, and 1.5 days, respectively. The concentration of free plasma VEGF could be as low as 10 pg/mL 1 day after a single dose of intravitreal injection.3e7 There are only three patients (1 with macular degeneration and 2 with DME) who have been reported to be suffering from acute renal injury after intravitreal antiVEGF therapy. Kidney biopsy in the former case showed segmental duplications of glomerular basement membranes with endothelial swelling, tubular atrophy, and noninflammatory interstitial fibrosis, recanalized arteriolar thrombi, and fibrinogen deposits in the hilus of glomerulus.8 The other two diabetic patients had preexisting Stage 4 CKD and required long-term hemodialysis eventually.9 In the 2-year results of a randomized trial conducted by the Diabetic Retinopathy Clinical Research network, renal and urinary disorders events were also been reported in 7e28% of patients.10 Theoretically, bevacizumab has higher systemic concentration and longer half-life than ranibizumab. However, the patient’s creatinine increased slowly after injection of
bevacizumab but significantly after ranibizumab. There are two possible reasons for that. First, it might be caused by a double-hit injury after two intravitreal injections, while there was a 1-year interval between two treatments. Second, the patient had Stage 5 CKD (glomerular filtration rate < 15 mL/min/1.73m2) at the first presentation but even less residual renal function when he received injection of ranibizumab, which might lead to the acute chronic renal failure episode. There was no other notable cause that might coexist in this patient and would interact with the effect of anti-VEGF in those postoperative days. Although the possible clinical risk factors and dangerous biomarkers for renal damage after anti-VEGF therapy have not been clarified yet, our presenting case implicated that ophthalmologists and internal medicine physicians should pay additional attention and perform a complete framework in performing this therapy for all patients, especially for diabetic patients with preexisting CKD. In addition, this is only a case report, and further collection of cases is needed.
References 1. 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;134:21e9. 2. den Deurwaarder ES, Desar IM, Steenbergen EJ, Mulders PF, Wetzels JF, van Herpen CM. Kidney injury during VEGF inhibitor therapy. Neth J Med 2012;70:267e71. 3. Semeraro F, Morescalchi F, Duse S, Gambicorti E, Cancarini A. Costagliola. Pharmacokinetic and pharmacodynamic properties of anti-VEGF drugs after intravitreal injection. Curr Drug Metab 2015;16:572e84.
Please cite this article in press as: Huang Y-F, et al., Acute renal failure after intravitreal antivascular endothelial growth factor therapy, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.010
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ARF after anti-VEGF therapy 4. Avery RL, Castellarin AA, Steinle NC, Dhoot DS, Pieramici DJ, See R, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J Ophthalmol 2014;98:1636e41. 5. Davidovic SP, Nikolic SV, Curic NJ, Latinovic SL, Draskovic DO, Cabarkapa VS, et al. Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy. Eur J Ophthalmol 2012;22:792e8. 6. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114:2179e82. 7. Matsuyama K, Ogata N, Matsuoka M, Wada M, Takahashi K, Nishimura T. Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before and after intravitreal injection of bevacizumab. Br J Ophthalmol 2010; 94:1215e8.
3 8. Pelle G, Shweke N, Duong Van Huyen JP, Tricot L, Hessaı¨ne S, Fre ´meaux-Bacchi V, et al. Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. Am J Kidney Dis 2011;57:756e9. 9. Georgalas I, Papaconstantinou D, Papadopoulos K, Pagoulatos D, Karagiannis D, Koutsandrea C. Renal injury following intravitreal anti-VEGF administration in diabetic patients with proliferative diabetic retinopathy and chronic kidney diseaseea possible side effect? Curr Drug Saf 2014;9: 156e8. 10. Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016;123:1351e9.
Please cite this article in press as: Huang Y-F, et al., Acute renal failure after intravitreal antivascular endothelial growth factor therapy, Journal of the Formosan Medical Association (2016), http://dx.doi.org/10.1016/j.jfma.2016.09.010