Letter to the Editor
Renal damage associated to intravitreal administration of ranibizumab
Daño renal asociado a la administración intravítrea de ranibizumab
Enrique Morales
, Candela Moliz, Eduardo Gutierrez
Corresponding author
Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain
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=> array:4 [ "nombre" => "Enrique" "apellidos" => "Morales" "email" => array:1 [ 0 => "emoralesr@senefro.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Candela" "apellidos" => "Moliz" ] 2 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Gutierrez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Daño renal asociado a la administración intravítrea de ranibizumab" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Recently, the intravitreal use of this type of antiangiogenic therapies has been a revolution in the field of Ophthalmology.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,4</span></a> 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.</p><p id="par0015" class="elsevierStylePara elsevierViewall">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.</p><p id="par0020" class="elsevierStylePara elsevierViewall">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 2.6<span class="elsevierStyleHsp" style=""></span>mg/dl and proteinuria 2.6<span class="elsevierStyleHsp" style=""></span>g/24<span class="elsevierStyleHsp" style=""></span>h) 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 4.1<span class="elsevierStyleHsp" style=""></span>mg/dl) with a significant increase in the amount of proteinuria (proteinuria 9.4<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h) 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.</p><p id="par0025" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,2</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> 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 <a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6–10</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). 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.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> These renal adverse effects have also reached the world of renal transplantation; recently, it has been reported that 2<span class="elsevierStyleHsp" style=""></span>patients developed impaired renal function and increased proteinuria after intravitreal administration of an anti-VEFG.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">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.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">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.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Crs: serum creatinine; GFR: glomerular filtration rate; MGN: membranous glomerulonephritis; F: female; TMA: thrombotic microangiopathy; M: male.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ref \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Age/gender \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Medical history \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical presentation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Eye disease \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Medication \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Outcome \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0065">3</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diabetes mellitus (3 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction of renal function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proliferative diabetic rethinopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bevacizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0080">6</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypertension (sCr 0.99<span class="elsevierStyleHsp" style=""></span>mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TMA (renal biopsy) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Macular degeneration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ranibizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recovery of Renal Function \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0085">7</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diabetes mellitus (1 patient) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction of renal function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proliferative diabetic rethinopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0090">8</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16/F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Minimal change \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Relapse of nephrotic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Coroidal neovascularization<br>Secondary to myopia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bevacizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Full remission \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0095">9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">68/F<br>59/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diabetic nephropathy (GFR: 21<span class="elsevierStyleHsp" style=""></span>ml/min)<br>Diabetic nephropathy (GFR: 25<span class="elsevierStyleHsp" style=""></span>ml/min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increase in proteinuria<br>Reduction of renal function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proliferative Diabetic retinopathy<br>Proliferative diabetic retinopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ranibizumab<br>Bevacizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hemodialysis<br>Hemodialysis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0100">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">67/M<br>52/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal transplant (sCr 1.7<span class="elsevierStyleHsp" style=""></span>mg/dl)<br>Renal transplant (Crs 2.8<span class="elsevierStyleHsp" style=""></span>mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increase of proteinuria<br>MGN (renal biopsy)<br>Increase of proteinuria<br>Renal function deterioration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Macular degeneration<br>Macular Degeneration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Bevacizumab<br>Ranibizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1609190.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patients reported in the literature with renal involvement after intravitreal administration of anti-VEGF drugs.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "VEGF inhibition and renal thrombotic microangiopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 13 | 8 | 21 |
| 2024 October | 86 | 36 | 122 |
| 2024 September | 103 | 33 | 136 |
| 2024 August | 100 | 60 | 160 |
| 2024 July | 89 | 31 | 120 |
| 2024 June | 124 | 42 | 166 |
| 2024 May | 106 | 49 | 155 |
| 2024 April | 104 | 38 | 142 |
| 2024 March | 68 | 30 | 98 |
| 2024 February | 92 | 50 | 142 |
| 2024 January | 72 | 27 | 99 |
| 2023 December | 74 | 37 | 111 |
| 2023 November | 97 | 34 | 131 |
| 2023 October | 112 | 41 | 153 |
| 2023 September | 129 | 34 | 163 |
| 2023 August | 113 | 33 | 146 |
| 2023 July | 95 | 27 | 122 |
| 2023 June | 90 | 39 | 129 |
| 2023 May | 113 | 37 | 150 |
| 2023 April | 85 | 16 | 101 |
| 2023 March | 89 | 23 | 112 |
| 2023 February | 89 | 21 | 110 |
| 2023 January | 91 | 22 | 113 |
| 2022 December | 84 | 36 | 120 |
| 2022 November | 88 | 30 | 118 |
| 2022 October | 89 | 41 | 130 |
| 2022 September | 90 | 40 | 130 |
| 2022 August | 105 | 65 | 170 |
| 2022 July | 76 | 53 | 129 |
| 2022 June | 86 | 38 | 124 |
| 2022 May | 110 | 43 | 153 |
| 2022 April | 126 | 69 | 195 |
| 2022 March | 173 | 55 | 228 |
| 2022 February | 135 | 40 | 175 |
| 2022 January | 128 | 51 | 179 |
| 2021 December | 75 | 54 | 129 |
| 2021 November | 118 | 40 | 158 |
| 2021 October | 105 | 52 | 157 |
| 2021 September | 123 | 52 | 175 |
| 2021 August | 119 | 59 | 178 |
| 2021 July | 132 | 38 | 170 |
| 2021 June | 107 | 38 | 145 |
| 2021 May | 151 | 74 | 225 |
| 2021 April | 242 | 99 | 341 |
| 2021 March | 133 | 42 | 175 |
| 2021 February | 177 | 50 | 227 |
| 2021 January | 126 | 30 | 156 |
| 2020 December | 109 | 20 | 129 |
| 2020 November | 73 | 25 | 98 |
| 2020 October | 110 | 29 | 139 |
| 2020 September | 114 | 20 | 134 |
| 2020 August | 81 | 22 | 103 |
| 2020 July | 100 | 23 | 123 |
| 2020 June | 117 | 27 | 144 |
| 2020 May | 88 | 31 | 119 |
| 2020 April | 87 | 36 | 123 |
| 2020 March | 117 | 31 | 148 |
| 2020 February | 319 | 34 | 353 |
| 2020 January | 125 | 32 | 157 |
| 2019 December | 137 | 38 | 175 |
| 2019 November | 169 | 38 | 207 |
| 2019 October | 153 | 28 | 181 |
| 2019 September | 179 | 34 | 213 |
| 2019 August | 104 | 26 | 130 |
| 2019 July | 122 | 31 | 153 |
| 2019 June | 110 | 29 | 139 |
| 2019 May | 209 | 71 | 280 |
| 2019 April | 177 | 102 | 279 |
| 2019 March | 120 | 30 | 150 |
| 2019 February | 78 | 20 | 98 |
| 2019 January | 82 | 35 | 117 |
| 2018 December | 148 | 50 | 198 |
| 2018 November | 180 | 30 | 210 |
| 2018 October | 115 | 17 | 132 |
| 2018 September | 111 | 43 | 154 |
| 2018 August | 81 | 25 | 106 |
| 2018 July | 79 | 27 | 106 |
| 2018 June | 60 | 18 | 78 |
| 2018 May | 73 | 22 | 95 |
| 2018 April | 51 | 18 | 69 |
| 2018 March | 46 | 17 | 63 |
| 2018 February | 47 | 7 | 54 |
| 2018 January | 40 | 17 | 57 |
| 2017 December | 42 | 11 | 53 |
| 2017 November | 35 | 6 | 41 |
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