Journal Information
Vol. 37. Issue. 6.November - December 2017
Pages 563-670
Vol. 37. Issue. 6.November - December 2017
Pages 563-670
Letter to the Editor
DOI: 10.1016/j.nefroe.2017.10.007
Open Access
Renal damage associated to intravitreal administration of ranibizumab
Daño renal asociado a la administración intravítrea de ranibizumab
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Enrique Morales
Corresponding author
emoralesr@senefro.org

Corresponding author.
, Candela Moliz, Eduardo Gutierrez
Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain
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Table 1. Patients reported in the literature with renal involvement after intravitreal administration of anti-VEGF drugs.
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Dear Editor,

Vascular endothelial growth factor (VEGF) promotes angiogenesis and is being produce by several types of tumors. The production of VEGF by tumors is related to aggressiveness, growth and their capabilities to produce metastasis and relapse. Inhibitors of angiogenesis (anti-VEGF) are effective therapeutic options for the treatment of patients with metastatic tumors. They are generally well-tolerated drugs, but the increase in use has shown secondary effects including at the renal level.1,2

Recently, the intravitreal use of this type of antiangiogenic therapies has been a revolution in the field of Ophthalmology.3,4 Age-related macular degeneration, diabetic macular edema, or macular edema secondary to retinal vein occlusion are some of the entities that have been most frequently benefited from the use of anti-VEGF. However, there is little information on the renal adverse effects of these drugs when administered intraocularly.

We describe the case of a patient with chronic kidney disease secondary to diabetic nephropathy who presented impaired renal function and increased proteinuria following the administration of several doses of ranibizumab for the treatment of diabetic retinopathy.

The patient is 56-year-old male, obese, smoker, and diagnosed of type 2 diabetes mellitus with good glycemic control (glycated hemoglobin ≤7% total Hb) on insulin therapy. The patient had severe proliferative diabetic retinopathy with significant decrease in visual acuity and chronic renal failure secondary to biopsy proven diabetic nephropathy (Class IV diabetic glomerulosclerosis). During his follow-up in the Nephrology clinic, in spite of the advanced of his renal insufficiency, he was able to stabilize the progression of his renal disease (serum creatinine 2.6mg/dl and proteinuria 2.6g/24h) with the use of systemic-renin-angiotensin-aldosterone blockers, good blood pressure control and excellent glycemic control (glycated hemoglobin 6.3%). However, in one of the clinic visits, the patient had an acute deterioration of renal function (serum creatinine 4.1mg/dl) with a significant increase in the amount of proteinuria (proteinuria 9.4μg/24h) without changes in their usual medication and with good control of their blood glucose. The only change was the intravitreal administration of ranibizumab as a treatment for diabetic retinopathy. Renal function has continued to deteriorate and renal replacement therapy is pending.

The question to be addressed is whether the intravitreal administration of anti-VEGF drugs may produce renal adverse effects similar to those seen with systemic administration. It is known that the systemic administration of this type of drugs may produce hypertension, proteinuria and thrombotic microangiopathy as secondary renal adverse effects.1,2 Treatment of vitreoretinal neovascular disease has undergone some vertiginous changes over the last 2 decades, from the classic treatments to the use of new drugs that block VEGF such as ranibizumab, bevacizumab and pegaptanib. Among the most common adverse effects associated with this type of therapy are local ocular reactions and, less frequently, systemic processes such as pulmonary thromboembolism or hypertension.5 However, there is little information on renal adverse effects from the intravitreal administration of these anti-VEFG4 monoclonal antibodies. One possible explanation could be the minimal dose used in ophthalmology (400 times less) and the ocular barrier involves a local drug sequestration and a delay in its systemic absorption. However, we must not forget that, although it is a local administration, this retinal blood barrier is altered due to the ongoing ophthalmological processes and that the elimination of these antiangiogenic agents is systemic. Renal involvement by intravitreal administration of antiangiogenic drugs is reflected in several clinical cases reported during the last years 6–10 (Table 1). Pelle et al. reported the case of a hypertensive patient with normal renal function who developed acute renal failure with thrombotic microangiopathy after the administration of ranibizumab for the treatment of macular degeneration.6 The consequences may be more significant, such as the cases of diabetic patients with advanced chronic kidney disease who required dialysis after administration of an anti-VEFG.9 These renal adverse effects have also reached the world of renal transplantation; recently, it has been reported that 2patients developed impaired renal function and increased proteinuria after intravitreal administration of an anti-VEFG.10

Table 1.

Patients reported in the literature with renal involvement after intravitreal administration of anti-VEGF drugs.

Ref  Age/gender  Medical history  Clinical presentation  Eye disease  Medication  Outcome 
3    Diabetes mellitus (3 patients)  Reduction of renal function  Proliferative diabetic rethinopathy  Bevacizumab   
6  77/F  Hypertension (sCr 0.99mg/dl)  TMA (renal biopsy)  Macular degeneration  Ranibizumab  Recovery of Renal Function 
7    Diabetes mellitus (1 patient)  Reduction of renal function  Proliferative diabetic rethinopathy     
8  16/F  Minimal change  Relapse of nephrotic syndrome  Coroidal neovascularization
Secondary to myopia 
Bevacizumab  Full remission 
9  68/F
59/M 
Diabetic nephropathy (GFR: 21ml/min)
Diabetic nephropathy (GFR: 25ml/min) 
Increase in proteinuria
Reduction of renal function 
Proliferative Diabetic retinopathy
Proliferative diabetic retinopathy 
Ranibizumab
Bevacizumab 
Hemodialysis
Hemodialysis 
10  67/M
52/M 
Renal transplant (sCr 1.7mg/dl)
Renal transplant (Crs 2.8mg/dl) 
Increase of proteinuria
MGN (renal biopsy)
Increase of proteinuria
Renal function deterioration 
Macular degeneration
Macular Degeneration 
Bevacizumab
Ranibizumab 
 

Crs: serum creatinine; GFR: glomerular filtration rate; MGN: membranous glomerulonephritis; F: female; TMA: thrombotic microangiopathy; M: male.

In conclusion, due to the widespread use of this type of drugs in a patient population such as diabetes may demand, strict follow-up protocols by ophthalmologists and nephrologists (blood pressure measurement, determination of proteinuria and serum creatinine) before and after of the administration of the antiangiogenicos. These measures will help to establish an early diagnosis of the possible renal complications.

References
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VEGF inhibition and renal thrombotic microangiopathy.
N Engl J Med, 358 (2008), pp. 1129-1136
[2]
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Renal effects of anti-angiogenesis therapy: update for the internist.
Am J Med, 122 (2009), pp. 322-328
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A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema.
Ophthalmology, 114 (2007), pp. 1860-1867
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Safety implications of vascular endothelial growth factor blockade for subjects receiving intravitreal anti-vascular endothelial growth factor therapies.
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Systemic adverse drug reactions secondary to anti-VEGF intravitreal injection in patients with neovascular age-related macular degeneration.
Curr Vasc Pharmacol, 9 (2011), pp. 629-646
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Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors.
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Complications of intravitreal injections – own experience.
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[9]
I. Georgalas, D. Papaconstantinou, K. Papadopoulos, D. Pagoulatos, D. Karagiannis, C. Koutsandrea.
Renal injury following intravitreal anti-VEGF administration in diabetic patients with proliferative diabetic retinopathy and chronic kidney disease: a possible side effect?.
Curr Drug Saf, 9 (2014), pp. 156-158
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W. Cheungpasitporn, F.T. Chebib, L.D. Cornell, M.L. Brodin, S.H. Nasr, C.A. Schinstock, et al.
Intravitreal antivascular endothelial growth factor therapy may induce proteinuria and antibody mediated injury in renal allografts.
Transplantation, 99 (2015), pp. 2382-2386

Please cite this article as: Morales E, Moliz C, Gutierrez E. Daño renal asociado a la administración intravítrea de ranibizumab. Nefrologia. 2017;37:653–655.

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