Self-limited membranous nephropathy after intravitreal bevacizumab therapy for age-related macular degeneration

Abstract

Background: Monoclonal antibodies targeting vascular endothelial growth factor (VEGF), such as bevacizumab, are administered intravitreally for the treatment of wet or exudative age-related macular degeneration (ARMD). Systemic use of bevacizumab has been linked to a wide range of renal adverse effects including proteinuria and hypertension. Case Presentation: We present the case of a 77-year-old Caucasian male with a past medical history of hypertension, vitamin D deficiency and paroxysmal atrial fibrillation who presented to primary care clinic with a 2-week history of bilateral lower extremity edema, 2 months after completing four monthly intravitreal injections of bevacizumab for ARMD. Examination was remarkable for blood pressure of 187/91 mm Hg and severe bilateral lower extremity edema. Work up revealed unremarkable complete blood count (CBC), comprehensive metabolic panel (CMP), lipid panel, and echocardiography, except for 491 mg/dL albuminuria. Metoprolol and furosemide were added to hydrochlorothiazide and lisinopril. Work up by nephrology consult team five months later was notable for a urinalysis revealing 3 red blood cells/high power field (RBC/HPF), 24-hour urine protein of 8.6 g, and serum creatinine of 1.2 mg/dL. Viral hepatitis panel, total complement activity (CH50), C3, C4, anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), serum and urine protein electrophoresis were all unremarkable. Renal biopsy was consistent with membranous nephropathy. Age-appropriate cancer screening was negative. Random urine protein-to-creatinine ratio declined to 2 g/g and then to 0.56 g/g at 7 and 10 months follow up, respectively. Serum blood urea nitrogen (BUN) and creatinine remained normal throughout the course of illness and patient did not require any immunosuppressive treatment. Conclusions: The wide range of nephrotoxicity after systemic bevacizumab has been well documented. Our case describes a self-limited biopsy-proven membranous nephropathy after intravitreal bevacizumab injections.

Nephrotoxicity induced by intravitreal vascular endothelial growth factor inhibitors: emerging evidence

“…20,28,29,31,33,34 The literature has documented several case reports of the nephrotoxicity of agents that target VEGF and related signaling pathways. 20,[22][23][24]30,31,33,34,[36][37][38][39][40][41][42][43][44][45][46][47][48] Figure 1 summarizes the cellular pathways affected by VEGF and related signaling system blockade. 49…”

“…Despite increasing numbers of case reports, it is not well recognized that the use of intravitreal anti-VEGF agents can result in endothelial toxicity and renal injury. 21,31,36,40,41,43,[46][47][48]59,60 A spectrum of side effects has been documented, which include worsening of baseline hypertension 21 or the development of de novo hypertension. 61,62 The development of proteinuria, malignant hypertension, TMA, and nephrotic syndrome have also been reported.…”

“…59 Khneizer et al reported decreased eGFR after intravitreal bevacizumab injections in a patient with AMD. 36 Morales et al reported a case of decreased eGFR in a patient with biopsy-proven diabetic nephropathy after the injection of ranibizumab intravitreally. 46 Pelle et al reported a patient with TMA after intravitreal injection of ranibizumab.…”

Worsening Proteinuria Following Intravitreal Anti-VEGF Therapy for Diabetic Macular Edema

“…Those reports that proceeded to renal biopsy have described a number of various pathological findings. Perhaps the most consistently reported is the ability of intravitreal bevacizumab to induce an idiopathic membranous nephropathy in both native kidneys, 7,8 as well as a deceased donor renal allograft. 9 Other researchers have reported a thrombotic microangiopathy on renal biopsy, 10 and relapse of minimal change disease, 11,12 whereas some have simply reported a worsening acute kidney injury requiring the emergent institution of renal replacement therapy 1,6 without a biopsy being performed.…”

“…9 Other researchers have reported a thrombotic microangiopathy on renal biopsy, 10 and relapse of minimal change disease, 11,12 whereas some have simply reported a worsening acute kidney injury requiring the emergent institution of renal replacement therapy 1,6 without a biopsy being performed. Long-term renal outcomes have been inconsistent, with cases reporting a wide range of outcomes from resolution with simple withdrawal of anti-VEGF therapy, 8,13 a requirement for immunosuppressive therapy directed at the underlying glomerular pathology, 7 to dialysis-dependent renal failure. 1,6 It is interesting to note that a slightly different spectrum of pathology has been observed with systemic anti-VEGF therapy, with thrombotic microangiopathy, collapsing focal segmental glomerulosclerosis (theorized to perhaps be due to concomitant pamidronate use), cryoglobulinemic glomerulonephritis, and immune complex-associated focal proliferative glomerulonephritis being described.…”