Effects of a Single Intravitreal Injection of Aflibercept and Ranibizumab on Glomeruli of Monkeys

Tschulakow, Alexander; Christner, Sarah; Julien, Sylvie; Ludinsky, Maximilian; Giet, Markus van der; Schraermeyer, Ulrich

doi:10.1371/journal.pone.0113701

Cited by 27 publications

(30 citation statements)

References 49 publications

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“…We found reduced VEGF and CFH levels in murine kidneys 48 hours after intravitreal injection. This confirmed primate studies that detected anti-VEGF agents in glomeruli one day after intravitreal injection (74). Furthermore, glomerular dysfunction has been reported for all intravitreal VEGF antagonists currently used in patients (75, 76).…”

Section: Discussionsupporting

confidence: 86%

VEGF regulates local inhibitory complement proteins in the eye and kidney

Keir¹,

Firth²,

Aponik³

et al. 2016

Journal of Clinical Investigation

125

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Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-α/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists.

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Section: Discussionsupporting

confidence: 86%

VEGF regulates local inhibitory complement proteins in the eye and kidney

Keir¹,

Firth²,

Aponik³

et al. 2016

Journal of Clinical Investigation

125

View full text Add to dashboard Cite

show abstract

“…In vitro studies have reported that VEGF in the kidney, which was highly expressed by the podocytes and activates VEGF receptor 2 on glomerular capillary endothelial cells, plays an important role in maintaining normal glomerular structure and function, and its inhibition might be associated with endothelial dysfunction and podocyte dysregulation [2][3][4][5]12 . The doses of the intravitreously administered VEGF inhibitors in the present study were much lower than those administered intravenously 13 ; however, aflibercept and ranibizumab could be detected in the glomerular capillaries in monkeys after one intravitreal injection 14 . In addition, a few cases of AKI events after intravitreal anti-VEGF therapy have been reported, although we were unable to explain the differences observed between the current study and the AKI cases 7,8 .…”

Section: Discussioncontrasting

confidence: 54%

Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease

Kameda

Babazono

Uchigata

et al. 2018

J of Diabetes Invest

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The present study aimed to determine whether intravitreal administration of vascular endothelial growth factor inhibitors is associated with deterioration of renal function, as seen with systemic administration, in patients with diabetes and chronic kidney disease. Estimated glomerular filtration rates before and after 160 intravitreal injections of vascular endothelial growth factor inhibitors (aflibercept, bevacizumab or ranibizumab) were compared in 69 patients with diabetes and with a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2. We also determined the incidence of acute kidney injury. The data showed no significant difference in the estimated glomerular filtration rate before and after vascular endothelial growth factor inhibitor administration in all patients and in patient subgroups based on each inhibitor. Furthermore, no episodes of acute kidney injury occurred. In conclusion, intravitreal administration of vascular endothelial growth factor inhibitors is unlikely to be associated with a deterioration of renal function in patients with diabetes and chronic kidney disease.

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“…1,2,8 That is not all, as VEGF blockade can also induce changes in pro-thrombotic pathways (Diacyl-glycerol (DAG)-Kinase epsilon), in addition it affects nitric oxide signaling. 2,8 These are very well documented for systemic anti-VEGF toxicity and increasingly being shown in patients receiving intravitreal VEGF injections which are now known to be systemically absorbed according to Avery et al 3,9 An additional study by Tschulakow et al 10 also shows that not all VEGF blocking agents present the same risk. He shows that ranibizumab is present for shorter periods of time at simian glomeruli than aflibercept, effects systemic VEGF less, and that ranibizumab does not induce changes in endothelial fenestrations of glomerular capillaries seen with longer acting anti-VEGF agents like aflibercept.…”

Section: Discussionmentioning

confidence: 99%

Intravitreal bevacizumab-induced exacerbation of proteinuria in diabetic nephropathy, and amelioration by switching to ranibizumab

Hanna

Abdelnour

Hasnain

et al. 2020

SAGE Open Medical Case Reports

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Certain diabetic and hypertensive patients started on intravitreal vascular endothelial growth factor inhibition for diabetic retinopathy may experience worsening of hypertension and proteinuria. The etiology of this is the newly recognized absorption of intravitreally injected vascular endothelial growth factor inhibitors, and the susceptibility of patients with pre-existing renal disease to exacerbations depends on the degree of systemic absorption. There are eighteen reported cases of worsening hypertension, woresening proteinuria, worsening renal function, thrombotic microangiopathy, and glomerular disease noted after initiation of intravitreal vascular endothelial growth factor blockade. This nineteenth case demonstrates worsening hypertension and proteinuria with the start of bevacizumab. Both blood pressure and proteinuria parameters showed overall improvement with switching to the less absorbed and lower potency agent ranibizumab. There was a slight rise in serum creatinine after bevacizumab therapy, which stabilized at a new baseline, and the serum creatinine remained stable on ranibizumab. There were no other nephrotoxic exposures that explained the mild rise in serum creatinine. Because of improvement in renal function and proteinuria, a renal biopsy was deferred for the time. This case re-demonstrates the risk of worsening proteinuria with vascular endothelial growth factor inhibitors when given intravitreally in some patients. The demonstration of improvement in blood pressure and proteinuria with the use of lower potency agents like ranibizumab is novel and an important concept confirming observations from pharmacokinetic studies. The switch to ranibizumab offers a therapeutic option when proteinuria worsens with intravitreal vascular endothelial growth factor blockade, and the patient requires ongoing intravitreal therapy for treatment of diabetic retinopathy.

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Effects of a Single Intravitreal Injection of Aflibercept and Ranibizumab on Glomeruli of Monkeys

Cited by 27 publications

References 49 publications

VEGF regulates local inhibitory complement proteins in the eye and kidney

VEGF regulates local inhibitory complement proteins in the eye and kidney

Renal function after intravitreal administration of vascular endothelial growth factor inhibitors in patients with diabetes and chronic kidney disease

Intravitreal bevacizumab-induced exacerbation of proteinuria in diabetic nephropathy, and amelioration by switching to ranibizumab

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