- Email: [email protected]
Systemic and Kidney Toxicity of Intraocular Administration of Vascular Endothelial Growth Factor Inhibitors
Case Report Systemic and Kidney Toxicity of Intraocular Administration of Vascular Endothelial Growth Factor Inhibitors Gaëlle Pellé, MD,1 Nasim Shweke, MD,1 Jean-Paul Duong Van Huyen, MD, PhD,2 Leïla Tricot, MD,1 Sadika Hessaïne, MD,3 Véronique Frémeaux-Bacchi, MD, PhD,4 Christian Hiesse, MD,1 and Michel Delahousse, MD1 Intravenous injection of angiogenesis-inhibitor drugs is used widely to treat cancers. Associated renal complications primarily involve proteinuria and hypertension, and thrombotic microangiopathies also have been described. Intravitreal anti–vascular endothelial growth factor (VEGF) therapy currently is used by ophthalmologists to treat neovascularization in age-related macular degeneration. However, there is some evidence that intravitreal anti-VEGF injections may result in systemic absorption, with the potential for injury in organs that are reliant on VEGF, such as the kidney. We report the first case to our knowledge of a patient who developed an acute decrease in kidney function, nonimmune microangiopathic hemolytic anemia with schistocytes, and thrombocytopenia after 4 intravitreal injections of ranibizumab. Light microscopy of a kidney biopsy specimen showed segmental duplications of glomerular basement membranes with endothelial swelling and several recanalized arteriolar thrombi. Because of the increasing use of intravitreal anti-VEGF agents, ophthalmologists and nephrologists should be aware of the associated risk of kidney disease. Early detection is crucial so that intravitreal injections can be stopped before severe kidney disease occurs. Am J Kidney Dis. 57(5):756-759. © 2011 by the National Kidney Foundation, Inc. INDEX WORDS: Thrombotic microangiopathy; age-related macular degeneration; intravitreal anti–vascular endothelial growth factor therapy; complement factor H.
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number of antiangiogenesis agents that target vascular endothelial growth factor (VEGF) pathways are used widely in treatment protocols of many solid cancers. However, several adverse events are associated with the systemic administration of antiVEGF monoclonal antibodies, including kidney disease, of which proteinuria and hypertension are the most frequent.1,2 More severe cases of kidney disease also have been reported, including patients presenting with glomerular disease characteristic of thrombotic microangiopathy (TMA).3-8 The antiangiogenic approach now also is used by ophthalmologists to treat subfoveal choroidal neovascularization in patients with age-related macular degeneration, the leading cause of irreversible blindness in the industrialized world.9 Intravitreal injection of anti-VEGF monoclonal antibodies has revolutionized the care of these patients by preserving and improving their visual acuity. Safety issues associated with these From the 1Service de néphrologie–transplantation rénale, Hôpital Foch, Suresnes, France; and 2Service d’anatomo-pathologie, 3 Centre régional de pharmacovigilance, and 4Service d’immunologie biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Received April 13, 2010. Accepted in revised form November 16, 2010. Originally published online February 7, 2011. Address correspondence to Gaëlle Pellé, MD, Service de néphrologie-transplantation rénale, Hôpital Foch, 40 rue Worth, 92151 Suresnes, France. E-mail: [email protected] © 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2010.11.030 756
intravitreal injections include local ocular adverse events, as well as others that potentially reflect systemic VEGF inhibition, such as arterial thromboembolic events, nonocular hemorrhage, and hypertension.9 Nevertheless, in phase 3 studies of ranibizumab, a recombinant humanized monoclonal antibody against VEGF, the overall incidence of systemic adverse events was similar to treatment with verteporfin or sham-injected controls.10-12 Although published reports of adverse events10-12 do not include kidney toxicity, it has since been shown that intravitreal injection of anti-VEGF antibodies can lead to systemic absorption, with the potential to affect nonocular VEGF-dependent pathways.13 We report the first case to our knowledge of a patient who developed an acute decrease in kidney function, microangiopathic hemolytic anemia, and thrombocytopenia after intravitreal injections of ranibizumab.
CASE REPORT A 77-year-old man with a history of hypertension controlled by amlodipine and ramipril received 4 intravitreal injections of ranibizumab in the right eye for the treatment of age-related macular degeneration. Before starting anti-VEGF therapy, results of his routine laboratory profile, including measures of kidney function, were within reference ranges. One month after the fourth intravitreal ranibizumab injection, he reported general weakness and edema of the lower limbs and developed hypertension (169/71 mm Hg). Serum creatinine level increased from 0.99 to 1.76 mg/dL (88 to 156 mol/L; corresponding to estimated creatinine clearance using the Cockcroft-Gault formula of 77.4 to 43.6 mL/min/1.73 m2), and he also was noted to have proteinuria (protein excretion, 4.1 g/24 h), hypoalbuminemia (albumin, 3.1 g/dL; reference range, 3.4-5.0 g/dL), and microscopic hematuria. Other abnormal feaAm J Kidney Dis. 2011;57(5):756-759
Toxicity of Intraocular Administration of VEGF Inhibitors tures on the laboratory profile included mild thrombocytopenia (platelets, 129 ⫻ 103/L) and nonimmune microangiopathic hemolytic anemia (hemoglobin, 7.2 g/dL; undetectable haptoglobin; and increased lactate dehydrogenase, 710 IU/L [reference range, 100190 IU/L]). A blood smear showed 0.9% schistocytes. Direct Coombs test was negative. Levels of serum C3, C4, CH50, and factors B, H, and I were within reference ranges; no anticomplement factor H (CFH) immunoglobulin G was detected; and ADAMTS13 activity was normal. Viral (including human immunodeficiency virus), bacteriologic, and immunologic study results were negative. Computed tomographic scan of the chest, abdomen, and pelvis was unremarkable. Percutaneous kidney biopsy was performed. Light microscopy examination showed 10 glomeruli, none of which were sclerosed. Isolated segmental duplications of glomerular basement membranes with endothelial swelling but without mesangiolysis were observed in 3 glomeruli (Fig 1A and B). There were no glomerular hypercellularity, immune deposits, or podocyte injury. Tubular atrophy and noninflammatory interstitial fibrosis were present in one-third of the cortical area. Interlobular arteries showed mild intimal fibrosis. Several recanalized arteriolar thrombi were observed (Fig 1C). Although immunofluorescence did not show glomerular deposition of immunoglobulins, there was evidence of fibrinogen deposits in the hilus of 1 glomerulus (Fig 1D). Electron microscopy study was not available. The patient was treated with corticosteroids and fresh plasma infusion for 2 days, and ranibizumab injections were discontinued. Within 2 months, features of hemolysis had cleared and kidney function had normalized, with a decrease in serum creatinine level to 1.06 mg/dL (94 mol/L; estimated creatine clearance, 72.4 mL/min/1.73 m2) and proteinuria to protein excretion of 0.52 g/24 h. Because no other cause was found to explain these symptoms and they resolved after discontinuation of ranibizumab therapy, the case was reported to the French national adverse-event database as a potential adverse event associated with intravitreal injection of ranibizumab. Because this patient may have had a genetic susceptibility to kidney toxicity from anti-VEGF therapy, we investigated the best characterized polymorphisms in the complement alternative pathway that are associated with age-related macular degeneration or TMA. Strong evidence exists for an association between a tyrosine
to histidine substitution at amino acid 402 of CFH (encoded by a T to C substitution at reference single-nucleotide polymorphism [SNP] identification number rs1061170 [dbSNP; www.ncbi.nlm. nih.gov/projects/SNP/] in exon 9) and the development of agerelated macular degeneration.14 The coding region of exon 9 of CFH was polymerase chain reaction–amplified and sequenced. Our patient was homozygous for the T allele as opposed to the age-related macular degeneration–associated C allele. Two haplotypes, one located in the gene encoding membrane cofactor protein (CD46) and the other in the CFH gene, are associated with an increased risk of TMA.15 The at-risk haplotypes are CD46GGAAC (defined by G alleles at rs2796267 and rs2796268, A alleles at rs1962149 and rs859705, and a C allele at rs7144) and CFH haplotype 3 (we typed the 5 SNPs of the published TGTGT allele: T at rs3753394, G at rs800292, T at rs1061170, G at rs3753396, and T at rs1065489). However, our patient was homozygous for the nonrisk alleles in both cases.
DISCUSSION The patient had no familial history of atypical hemolytic uremic syndrome or TMA and did not present with any of its associated clinical features: diarrhea-type symptoms, malignant hypertension, cancer, infection, defective regulation of the complement alternative pathway, or suggestion of connective tissue disease, and ADAMTS13 activity was normal. Because the phenotypic spectrum of CFH gene variants includes both renal (membranoproliferative glomerulonephritis) and ocular (basal laminar drusen and age-related macular degeneration) effects, we studied CFH polymorphisms.14 Our patient carried neither the CFH variant known to increase the risk of agerelated macular degeneration nor either of the 2 haplotypes located in the gene encoding membrane cofactor protein or the CFH gene associated with an increased risk of endothelial injury. However, we cannot exclude the possibility that this patient has a
Figure 1. Histologic findings in kidney biopsy specimen. (A, B, C) Light microscopy shows (A, B, arrows) segmental duplication of the glomerular basement membrane together with (B, arrowhead) endothelial swelling and (C) a recanalized arteriolar thrombosis. (D) Immunofluorescence with an antifibrinogen antibody shows fibrinogen deposit at the vascular pole of the glomerulus. Am J Kidney Dis. 2011;57(5):756-759
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specific genetic background that increases the risk of endothelial injury when exposed to an environmental factor, such as an anti-VEGF agent. We thus suspected potential drug toxicity. More than 50 drugs and other substances have been associated with the development of microvascular endothelial injury.16,17 At the time of diagnosis, the patient was not receiving any of these medications. Systemic administration of antiangiogenic monoclonal antibodies has been reported to cause microvascular endothelial injury in 11 patients.3-8 Eremina et al3 reported 6 cases of patients treated with an intravenous humanized anti-VEGF antibody in whom glomerular disease characterized by microvascular endothelial injury developed. In an adult mouse model, they showed that deleting VEGF production by conditional gene targeting in only renal podocytes resulted in thrombotic glomerular injury.3 They postulated that disruption of VEGF function could lead to loss of the healthy fenestrated glomerular endothelium and promote the development of microvascular injury.3 Anti-VEGF agents are detectable in the systemic circulation after intravitreal anti-VEGF injections despite the blood-ocular barrier.13 This might promote the occurrence of systemic adverse events. In our case, both the timing of onset after 4 intravitreal injections and the occurrence of remission after treatment withdrawal support our hypothesis that the kidney toxicity observed was related to ranibizumab. The kidney biopsy specimen with features of segmental duplication of glomerular basement membrane, endothelial swelling, several recanalized arteriolar thrombi, and fibrinogen deposit in the hilus of 1 glomerulus is consistent with microvascular endothelial injury. However, it is difficult to definitively establish a diagnosis of TMA in the absence of an ultrastructural study with electron microscopy. This case nevertheless provides further evidence that intravitreal anti-VEGF injections can cause systemic manifestation of endothelial damage. Early recognition of drug-associated injury is crucial to avoid re-exposure and recurrent illness. Patients who receive intravenous anti-VEGF agents for cancer currently undergo frequent monitoring of the laboratory profile, which facilitates early diagnosis. However, patients who receive intravitreal anti-VEGF injections are not required to undergo specific biological monitoring, which potentially may lead to delayed recognition of systemic toxicity. In view of our report, it might be useful to compile registries and databases to accurately estimate the proportion of patients developing kidney disease after intravitreal antiangiogenic therapy. Because of the increasing use of intravitreal antiVEGF agents in the treatment of age-related macular 758
degeneration, as well for other indications, such as diabetic retinopathy,18 ophthalmologists and nephrologists should be aware of the potential for kidney disease related to the use of these agents. Early recognition of anti-VEGF–induced kidney disease is crucial, and if detected, intravitreal injections should be discontinued. We recommend surveillance protocols to include regular monitoring of blood pressure and routine tests of kidney measures (proteinuria and serum creatinine) and microangiopathic hemolytic anemia (complete blood cell count, serum haptoglobin, schistocytes, and lactate dehydrogenase) for patients undergoing treatment with intravitreal antiVEGF agents.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49(2):186-193. 2. Gurevich F, Perazella MA. Renal effects of anti-angiogenesis therapy: update for the internist. Am J Med. 2009;122(4): 322-328. 3. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358(11):1129-1136. 4. Izzedine H, Brocheriou I, Deray G, Rixe O. Thrombotic microangiopathy and anti-VEGF agents. Nephrol Dial Transplant. 2007;22:1481-1482. 5. Frangie C, Lefaucheur C, Medioni J, Jacquot C, Hill GS, Nochy D. Renal thrombotic microangiopathy caused by anti VEGF antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol. 2007;8:177-178. 6. Roncone D, Satoskar A, Nadasdy T, Monk JP, Rovin BH. Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol. 2007;3:287-293. 7. Stokes MB, Erazo MC, D’Agati VD. Glomerular disease related to anti-VEGF therapy. Kidney Int. 2008;74:1487-1491. 8. Bollée G, Patey N, Cazajous G, et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant. 2009;24(2):682-685. 9. Bressler NM. Antiangiogenic approaches to age-related macular degeneration today. Ophthalmology. 2009 Oct; 116(10 suppl):S15-23. 10. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. 11. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. 12. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145(2):239-248. Am J Kidney Dis. 2011;57(5):756-759
Toxicity of Intraocular Administration of VEGF Inhibitors 13. Csaky K, Do DV. Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol. 2009;148(5):647-656. 14. Boon CJ, van de Kar NC, Klevering BJ, et al. The spectrum of phenotypes caused by variants in the CFH gene. Mol Immunol. 2009;46(8-9):1573-1594. 15. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676-1687.
Am J Kidney Dis. 2011;57(5):756-759
16. Benz K, Amann K. Thrombotic microangiopathy: new insights. Curr Opin Nephrol Hypertens. 2010;19(3):242-247. 17. Zakarija A, Kwaan HC, Moake JL, et al. Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008). Kidney Int Suppl. 2009;112:S20-24. 18. Jardeleza MS, Miller JW. Review of anti-VEGF therapy in proliferative diabetic retinopathy. Semin Ophthalmol. 2009;24(2): 87-92.
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number of antiangiogenesis agents that target vascular endothelial growth factor (VEGF) pathways are used widely in treatment protocols of many solid cancers. However, several adverse events are associated with the systemic administration of antiVEGF monoclonal antibodies, including kidney disease, of which proteinuria and hypertension are the most frequent.1,2 More severe cases of kidney disease also have been reported, including patients presenting with glomerular disease characteristic of thrombotic microangiopathy (TMA).3-8 The antiangiogenic approach now also is used by ophthalmologists to treat subfoveal choroidal neovascularization in patients with age-related macular degeneration, the leading cause of irreversible blindness in the industrialized world.9 Intravitreal injection of anti-VEGF monoclonal antibodies has revolutionized the care of these patients by preserving and improving their visual acuity. Safety issues associated with these From the 1Service de néphrologie–transplantation rénale, Hôpital Foch, Suresnes, France; and 2Service d’anatomo-pathologie, 3 Centre régional de pharmacovigilance, and 4Service d’immunologie biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. Received April 13, 2010. Accepted in revised form November 16, 2010. Originally published online February 7, 2011. Address correspondence to Gaëlle Pellé, MD, Service de néphrologie-transplantation rénale, Hôpital Foch, 40 rue Worth, 92151 Suresnes, France. E-mail: [email protected] © 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2010.11.030 756
intravitreal injections include local ocular adverse events, as well as others that potentially reflect systemic VEGF inhibition, such as arterial thromboembolic events, nonocular hemorrhage, and hypertension.9 Nevertheless, in phase 3 studies of ranibizumab, a recombinant humanized monoclonal antibody against VEGF, the overall incidence of systemic adverse events was similar to treatment with verteporfin or sham-injected controls.10-12 Although published reports of adverse events10-12 do not include kidney toxicity, it has since been shown that intravitreal injection of anti-VEGF antibodies can lead to systemic absorption, with the potential to affect nonocular VEGF-dependent pathways.13 We report the first case to our knowledge of a patient who developed an acute decrease in kidney function, microangiopathic hemolytic anemia, and thrombocytopenia after intravitreal injections of ranibizumab.
CASE REPORT A 77-year-old man with a history of hypertension controlled by amlodipine and ramipril received 4 intravitreal injections of ranibizumab in the right eye for the treatment of age-related macular degeneration. Before starting anti-VEGF therapy, results of his routine laboratory profile, including measures of kidney function, were within reference ranges. One month after the fourth intravitreal ranibizumab injection, he reported general weakness and edema of the lower limbs and developed hypertension (169/71 mm Hg). Serum creatinine level increased from 0.99 to 1.76 mg/dL (88 to 156 mol/L; corresponding to estimated creatinine clearance using the Cockcroft-Gault formula of 77.4 to 43.6 mL/min/1.73 m2), and he also was noted to have proteinuria (protein excretion, 4.1 g/24 h), hypoalbuminemia (albumin, 3.1 g/dL; reference range, 3.4-5.0 g/dL), and microscopic hematuria. Other abnormal feaAm J Kidney Dis. 2011;57(5):756-759
Toxicity of Intraocular Administration of VEGF Inhibitors tures on the laboratory profile included mild thrombocytopenia (platelets, 129 ⫻ 103/L) and nonimmune microangiopathic hemolytic anemia (hemoglobin, 7.2 g/dL; undetectable haptoglobin; and increased lactate dehydrogenase, 710 IU/L [reference range, 100190 IU/L]). A blood smear showed 0.9% schistocytes. Direct Coombs test was negative. Levels of serum C3, C4, CH50, and factors B, H, and I were within reference ranges; no anticomplement factor H (CFH) immunoglobulin G was detected; and ADAMTS13 activity was normal. Viral (including human immunodeficiency virus), bacteriologic, and immunologic study results were negative. Computed tomographic scan of the chest, abdomen, and pelvis was unremarkable. Percutaneous kidney biopsy was performed. Light microscopy examination showed 10 glomeruli, none of which were sclerosed. Isolated segmental duplications of glomerular basement membranes with endothelial swelling but without mesangiolysis were observed in 3 glomeruli (Fig 1A and B). There were no glomerular hypercellularity, immune deposits, or podocyte injury. Tubular atrophy and noninflammatory interstitial fibrosis were present in one-third of the cortical area. Interlobular arteries showed mild intimal fibrosis. Several recanalized arteriolar thrombi were observed (Fig 1C). Although immunofluorescence did not show glomerular deposition of immunoglobulins, there was evidence of fibrinogen deposits in the hilus of 1 glomerulus (Fig 1D). Electron microscopy study was not available. The patient was treated with corticosteroids and fresh plasma infusion for 2 days, and ranibizumab injections were discontinued. Within 2 months, features of hemolysis had cleared and kidney function had normalized, with a decrease in serum creatinine level to 1.06 mg/dL (94 mol/L; estimated creatine clearance, 72.4 mL/min/1.73 m2) and proteinuria to protein excretion of 0.52 g/24 h. Because no other cause was found to explain these symptoms and they resolved after discontinuation of ranibizumab therapy, the case was reported to the French national adverse-event database as a potential adverse event associated with intravitreal injection of ranibizumab. Because this patient may have had a genetic susceptibility to kidney toxicity from anti-VEGF therapy, we investigated the best characterized polymorphisms in the complement alternative pathway that are associated with age-related macular degeneration or TMA. Strong evidence exists for an association between a tyrosine
to histidine substitution at amino acid 402 of CFH (encoded by a T to C substitution at reference single-nucleotide polymorphism [SNP] identification number rs1061170 [dbSNP; www.ncbi.nlm. nih.gov/projects/SNP/] in exon 9) and the development of agerelated macular degeneration.14 The coding region of exon 9 of CFH was polymerase chain reaction–amplified and sequenced. Our patient was homozygous for the T allele as opposed to the age-related macular degeneration–associated C allele. Two haplotypes, one located in the gene encoding membrane cofactor protein (CD46) and the other in the CFH gene, are associated with an increased risk of TMA.15 The at-risk haplotypes are CD46GGAAC (defined by G alleles at rs2796267 and rs2796268, A alleles at rs1962149 and rs859705, and a C allele at rs7144) and CFH haplotype 3 (we typed the 5 SNPs of the published TGTGT allele: T at rs3753394, G at rs800292, T at rs1061170, G at rs3753396, and T at rs1065489). However, our patient was homozygous for the nonrisk alleles in both cases.
DISCUSSION The patient had no familial history of atypical hemolytic uremic syndrome or TMA and did not present with any of its associated clinical features: diarrhea-type symptoms, malignant hypertension, cancer, infection, defective regulation of the complement alternative pathway, or suggestion of connective tissue disease, and ADAMTS13 activity was normal. Because the phenotypic spectrum of CFH gene variants includes both renal (membranoproliferative glomerulonephritis) and ocular (basal laminar drusen and age-related macular degeneration) effects, we studied CFH polymorphisms.14 Our patient carried neither the CFH variant known to increase the risk of agerelated macular degeneration nor either of the 2 haplotypes located in the gene encoding membrane cofactor protein or the CFH gene associated with an increased risk of endothelial injury. However, we cannot exclude the possibility that this patient has a
Figure 1. Histologic findings in kidney biopsy specimen. (A, B, C) Light microscopy shows (A, B, arrows) segmental duplication of the glomerular basement membrane together with (B, arrowhead) endothelial swelling and (C) a recanalized arteriolar thrombosis. (D) Immunofluorescence with an antifibrinogen antibody shows fibrinogen deposit at the vascular pole of the glomerulus. Am J Kidney Dis. 2011;57(5):756-759
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Pellé et al
specific genetic background that increases the risk of endothelial injury when exposed to an environmental factor, such as an anti-VEGF agent. We thus suspected potential drug toxicity. More than 50 drugs and other substances have been associated with the development of microvascular endothelial injury.16,17 At the time of diagnosis, the patient was not receiving any of these medications. Systemic administration of antiangiogenic monoclonal antibodies has been reported to cause microvascular endothelial injury in 11 patients.3-8 Eremina et al3 reported 6 cases of patients treated with an intravenous humanized anti-VEGF antibody in whom glomerular disease characterized by microvascular endothelial injury developed. In an adult mouse model, they showed that deleting VEGF production by conditional gene targeting in only renal podocytes resulted in thrombotic glomerular injury.3 They postulated that disruption of VEGF function could lead to loss of the healthy fenestrated glomerular endothelium and promote the development of microvascular injury.3 Anti-VEGF agents are detectable in the systemic circulation after intravitreal anti-VEGF injections despite the blood-ocular barrier.13 This might promote the occurrence of systemic adverse events. In our case, both the timing of onset after 4 intravitreal injections and the occurrence of remission after treatment withdrawal support our hypothesis that the kidney toxicity observed was related to ranibizumab. The kidney biopsy specimen with features of segmental duplication of glomerular basement membrane, endothelial swelling, several recanalized arteriolar thrombi, and fibrinogen deposit in the hilus of 1 glomerulus is consistent with microvascular endothelial injury. However, it is difficult to definitively establish a diagnosis of TMA in the absence of an ultrastructural study with electron microscopy. This case nevertheless provides further evidence that intravitreal anti-VEGF injections can cause systemic manifestation of endothelial damage. Early recognition of drug-associated injury is crucial to avoid re-exposure and recurrent illness. Patients who receive intravenous anti-VEGF agents for cancer currently undergo frequent monitoring of the laboratory profile, which facilitates early diagnosis. However, patients who receive intravitreal anti-VEGF injections are not required to undergo specific biological monitoring, which potentially may lead to delayed recognition of systemic toxicity. In view of our report, it might be useful to compile registries and databases to accurately estimate the proportion of patients developing kidney disease after intravitreal antiangiogenic therapy. Because of the increasing use of intravitreal antiVEGF agents in the treatment of age-related macular 758
degeneration, as well for other indications, such as diabetic retinopathy,18 ophthalmologists and nephrologists should be aware of the potential for kidney disease related to the use of these agents. Early recognition of anti-VEGF–induced kidney disease is crucial, and if detected, intravitreal injections should be discontinued. We recommend surveillance protocols to include regular monitoring of blood pressure and routine tests of kidney measures (proteinuria and serum creatinine) and microangiopathic hemolytic anemia (complete blood cell count, serum haptoglobin, schistocytes, and lactate dehydrogenase) for patients undergoing treatment with intravitreal antiVEGF agents.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49(2):186-193. 2. Gurevich F, Perazella MA. Renal effects of anti-angiogenesis therapy: update for the internist. Am J Med. 2009;122(4): 322-328. 3. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358(11):1129-1136. 4. Izzedine H, Brocheriou I, Deray G, Rixe O. Thrombotic microangiopathy and anti-VEGF agents. Nephrol Dial Transplant. 2007;22:1481-1482. 5. Frangie C, Lefaucheur C, Medioni J, Jacquot C, Hill GS, Nochy D. Renal thrombotic microangiopathy caused by anti VEGF antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol. 2007;8:177-178. 6. Roncone D, Satoskar A, Nadasdy T, Monk JP, Rovin BH. Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol. 2007;3:287-293. 7. Stokes MB, Erazo MC, D’Agati VD. Glomerular disease related to anti-VEGF therapy. Kidney Int. 2008;74:1487-1491. 8. Bollée G, Patey N, Cazajous G, et al. Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial Transplant. 2009;24(2):682-685. 9. Bressler NM. Antiangiogenic approaches to age-related macular degeneration today. Ophthalmology. 2009 Oct; 116(10 suppl):S15-23. 10. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431. 11. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444. 12. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145(2):239-248. Am J Kidney Dis. 2011;57(5):756-759
Toxicity of Intraocular Administration of VEGF Inhibitors 13. Csaky K, Do DV. Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies. Am J Ophthalmol. 2009;148(5):647-656. 14. Boon CJ, van de Kar NC, Klevering BJ, et al. The spectrum of phenotypes caused by variants in the CFH gene. Mol Immunol. 2009;46(8-9):1573-1594. 15. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676-1687.
Am J Kidney Dis. 2011;57(5):756-759
16. Benz K, Amann K. Thrombotic microangiopathy: new insights. Curr Opin Nephrol Hypertens. 2010;19(3):242-247. 17. Zakarija A, Kwaan HC, Moake JL, et al. Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008). Kidney Int Suppl. 2009;112:S20-24. 18. Jardeleza MS, Miller JW. Review of anti-VEGF therapy in proliferative diabetic retinopathy. Semin Ophthalmol. 2009;24(2): 87-92.
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