Development of Collapsing Focal and Segmental Glomerulosclerosis After Receiving Intravitreal Vascular Endothelial Growth Factor Blockade

Nobakht, Niloofar; Nguyen, Hoang Anh; Kamgar, Mohammad; Abdelnour, Lama; Rastogi, Anjay; Hanna, Ramy M

doi:10.1016/j.ekir.2019.07.019

Cited by 15 publications

(23 citation statements)

References 9 publications

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“…There are now increasing reports of intravitreal injections resulting in VEGF depletion and glomerular disease including TMA, collapsing focal and segmental sclerosis (FSGS), as well as other causes of nephrotic syndrome. [14][15][16][25][26][27] The renal biopsy findings we presented could be compatible with TMA from VEGF depletion and from SRC. Given the presence of Ssc clinically predating the intravitreal VEGF inhibition injections, it was surmised that the patient's Ssc was likely exacerbated by VEGF blockade and hypertension as well as the oral corticosteroids.…”

Section: Discussionsupporting

confidence: 67%

“…Another agent recently noted to be systemically absorbed and proven to disrupt systemic vascular endothelial growth factor (VEGF) levels are intravitreal injections of VEGF inhibiting monoclonal antibodies. 14 – 16 We present a case of SRC that initially developed after the patient was exposed to corticosteroids. He was subsequently exposed to intravitreal VEGF blockade and had rapidly progressive hypertension with subacute kidney injury refractory to the standard of care therapy.…”

Section: Introductionmentioning

confidence: 99%

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Refractory scleroderma renal crisis precipitated after high-dose oral corticosteroids and concurrent intravitreal injection of bevacizumab

Hanna

Abdelnour

Zuckerman

et al. 2020

SAGE Open Medical Case Reports

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Scleroderma renal crisis is a serious complication that can develop in certain patients with systemic sclerosis. Some risks have been identified as potential triggers of scleroderma renal crisis, including the high-dose oral corticosteroids. Here, we present a patient who developed clinically severe systemic sclerosis and scleroderma renal crisis after exposure to oral corticosteroids and intravitreal vascular endothelial growth factor blockade with bevacizumab for cotton wool spots. The patient’s scleroderma renal crisis was severe, progressive, and refractory to the standard of care therapy: oral captopril. Biopsy showed a diffuse thrombotic microangiopathy and findings consistent with scleroderma renal crisis. We hypothesize that depletion of systemic vascular endothelial growth factor with intravitreal anti–vascular endothelial growth factor injections likely contributed to the particularly severe presentation seen in this case. Though the finding of a monoclonal gammopathy of undetermined significance is another complicating factor, this case suggests that vascular endothelial growth factor inhibition may be a newly recognized trigger of scleroderma renal crisis.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Refractory scleroderma renal crisis precipitated after high-dose oral corticosteroids and concurrent intravitreal injection of bevacizumab

Hanna

Abdelnour

Zuckerman

et al. 2020

SAGE Open Medical Case Reports

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“…With the addition of these three cases, this brings the total potential published cases to 26, including one instance of focal and segmental glomerulosclerosis (FSGS) with collapsing features (cFSGS) in a patient receiving VEGF blockade for AMD, similar to the biopsy in Case 2. The finding of two such cases is notable, especially given link between cFSGS and TMA noted in literature [ 51 ]. This highlights the importance of renal biopsies in identifying unique pathology, which may be induced by intravitreal VEGF blockade.…”

Section: New Developments In the Investigation Of The Systemic Effectmentioning

confidence: 99%

Worsening proteinuria and renal function after intravitreal vascular endothelial growth factor blockade for diabetic proliferative retinopathy

Shye

Hanna

Patel

et al. 2020

Clinical Kidney Journal

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Systemic vascular endothelial growth factor (VEGF) inhibitions can induce worsening hypertension, proteinuria and glomerular diseases of various types. These agents can also be used to treat ophthalmic diseases like proliferative diabetic retinopathy, diabetic macular edema, central retinal vein occlusion and age-related macular degeneration. Recently, pharmacokinetic studies confirmed that these agents are absorbed at levels that result in biologically significant suppression of intravascular VEGF levels. There have now been 23 other cases published that describe renal sequela of intravitreal VEGF blockade, and they unsurprisingly mirror known systemic toxicities of VEGF inhibitors. We present three cases where stable levels of proteinuria and chronic kidney disease worsened after initiation of these agents. Two of our three patients were biopsied. The first patient’s biopsy showed diabetic nephropathy and focal and segmental glomerulosclerosis (FSGS) with collapsing features and acute interstitial nephritis (AIN). The second patient’s biopsy showed AIN in a background of diabetic glomerulosclerosis. This is the second patient seen by our group, whose biopsy revealed segmental glomerulosclerosis with collapsing features in the setting of intravitreal VEGF blockade. Though FSGS with collapsing features and AIN are not the typical lesions seen with systemic VEGF blockade, they have been reported as rare case reports previously. In addition to reviewing known elements of intravitreal VEGF toxicity, the cases presented encompass renal pathology data supporting that intravitreal VEGF blockade can result in deleterious systemic and renal pathological disorders.

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“…There are 26 published cases showing worsening hypertension, proteinuria, and glomerular disease after intravitreal VEGF inhibition ( 2 , 4 , 32 – 46 ). Our group has published nine cases ( 2 , 4 , 45 , 46 ). There are three more in this case series and one more under review.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelial cells rely on VEGF signaling as trophic signals and for control of diacylglycerol kinase epsilon (DAG-ε). DAG-ε can induce thrombosis if not tightly regulated ( 1 – 4 ). Podocytes rely on VEGF for cytoskeletal organization via nephrin, and trophic signaling is also mediated in podocyte cells via VEGF signaling (autocrine or otherwise) ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Thrombotic Microangiopathy and Acute Kidney Injury Induced After Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors VEGF Blockade-Related TMA After Intravitreal Use

et al. 2020

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Vascular endothelial growth factor (VEGF) inhibition can cause worsening hypertension, proteinuria, chronic kidney injury, and glomerular disease. Thrombotic microangiopathy (TMA) and other nephrotic disorders have been reported with systemic VEGF blockade. These same agents are given intravitreally for age-related macular degeneration (AMD) and diabetic retinopathy (DR), albeit at lower doses than those given for systemic indications. Systemic absorption of anti-VEGF agents when given intravitreally has been shown consistently along with evidence of significant intravascular VEGF suppression. While worsening hypertension has only been seen in some large-scale studies, case reports show worsening proteinuria and diverse glomerular diseases. These include TMA-associated lesions like focal and segmental glomerulosclerosis with collapsing features (cFSGS). In this paper, we report three cases of TMA likely associated with the use of intravitreal anti-VEGF therapy. These patients developed the signature lesion of VEGF blockade in a 6 to 11 month time frame after starting intravitreal VEGF inhibitors. The literature is reviewed showing similar cases. Intravitreal VEGF blockade may cause these adverse events in a hitherto unidentified subgroup of patients. Well-controlled prospective observational trials are needed to determine the event rate and identify which subgroups of patients are at increased risk. A registry for patients who develop worsening hypertension, proteinuria exacerbation, and glomerular diseases from intravitreal VEGF blockade is proposed.

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Development of Collapsing Focal and Segmental Glomerulosclerosis After Receiving Intravitreal Vascular Endothelial Growth Factor Blockade

Cited by 15 publications

References 9 publications

Refractory scleroderma renal crisis precipitated after high-dose oral corticosteroids and concurrent intravitreal injection of bevacizumab

Refractory scleroderma renal crisis precipitated after high-dose oral corticosteroids and concurrent intravitreal injection of bevacizumab

Worsening proteinuria and renal function after intravitreal vascular endothelial growth factor blockade for diabetic proliferative retinopathy

Thrombotic Microangiopathy and Acute Kidney Injury Induced After Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors VEGF Blockade-Related TMA After Intravitreal Use

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