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

Michael Shye, Ramy M Hanna, Sapna S Patel, Ngoc Tram-Tran, Jean Hou, Collin Mccannel, Maham Khalid, Mina Hanna, Lama Abdelnour, Ira Kurtz, Michael Shye, Ramy M Hanna, Sapna S Patel, Ngoc Tram-Tran, Jean Hou, Collin Mccannel, Maham Khalid, Mina Hanna, Lama Abdelnour, Ira Kurtz

Abstract

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.

Keywords: VEGF depletion; acute kidney injury; aflibercept; bevacizumab; diabetic retinopathy; focal and segmental sclerosis; nephrotic syndrome; proteinuria; ranibizumab; vascular endothelial growth factor.

© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

FIGURE 1
FIGURE 1
EGFR, VEGF, TKI and mTOR signaling pathways: Akt, protein kinase B (PKB); C-Kit, mast/stem cell growth factor receptor; DAG, diacyl glycerol; ERB, EGFR related-receptor protein (Her2Neu is on type of this); MAPK, mitogen-activated protein kinase; Mek, dual threonine and tyrosine recognition kinase; NOS, nitric oxide synthase; PKC, protein kinase C; PDGFR, platelet-derived growth factor receptor; PI3, phosphatidylinositol-4,5-bisphosphate 3-kinase; PLCϒ, phospholipase C-gamma; RAF, serine/threonine kinase/cellular homolog of viral RAF gene; RAS, rat sarcoma protein; VEGF A–D, vascular endothelial growth factor A–D; VEGFR 1–3, vascular endothelial growth factor receptor 1–3. Adapted from Selamet et al. [10].
FIGURE 2
FIGURE 2
Summary of pharmacokinetic studies showing serum drug levels, serum half-lives from systemically and intravitreally injected VEGF inhibitors. [Drug], concentration of drug every 2 weeks; mg, milligrams; mg/kg, milligram/kilogram; OD, right eye; OU, left eye; q(x) weeks, every (x) weeks; s[Drug], serum concentration of drug; T1/2, half-life (in days).
FIGURE 3
FIGURE 3
Trend of serum Cr, urinalysis proteinuria, urine protein/Cr ratio and urine albumin/Cr ratio for Patient 1 versus date. Red box, bevacizumab administration; blue box, ranibizumab administration. UPC, urine protein/Cr ratio.
FIGURE 4
FIGURE 4
Trend of serum Cr, urinalysis proteinuria, urine protein/Cr ratio and urine albumin/Cr ratio for Patient 2 versus date. UPC, urine protein/Cr ratio.
FIGURE 5
FIGURE 5
Renal biopsy micrographs for Patient 2 showing diabetic nephropathy and focal and segmental sclerosis with collapsing features. Renal biopsy reveals underlying diffuse and nodular diabetic glomerulosclerosis (A, Jones methenamine silver 600×). There were lesions of segmental sclerosis with focal collapsing features (B, Trichrome stain 600×) characterized by capillary luminal obliteration by insudates and segmental tuft deflation, with overlying podocyte hyperplasia and prominent cytoplasmic vacuolization (black arrow). There was also concomitant acute tubular necrosis (C, asterisk, hematoxylin and eosin, 200×), with interstitial edema and a mixed interstitial inflammatory infiltrate (interstitial nephritis).
FIGURE 6
FIGURE 6
Trend of serum Cr, urinalysis proteinuria, urine protein/Cr ratio and urine albumin/Cr ratio for Patient 3 versus date. Black arrow, ranibizumab initiation; UACR, albumin/Cr ratio.
FIGURE 7
FIGURE 7
Renal biopsy micrographs for Patient 3 showing diabetic nephropathy and drug-induced acute interstitial nephritis. Renal biopsy revealed diffuse and nodular diabetic glomerulosclerosis (A, Jones methenamine silver 600×). There were diffuse interstitial edema and extensive interstitial inflammation (B) with associated tubular inflammation and acute necrosis, consistent with interstitial nephritis.

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