Letter to the Editor
Reply to letter to editor comment on “Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A”
Respuesta a la carta al editor referida a «Mecanismos celulares y moleculares de la nefropatía diabética, rol del VEGF-A»
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the role of VEGF-A”" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "706" "paginaFinal" => "707" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Delma Veron, Alda Tufro" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Delma" "apellidos" => "Veron" "email" => array:2 [ 0 => "delveron@gmail.com" 1 => "proyectond@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Alda" "apellidos" => "Tufro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Facultad de Ciencias de la Salud, Universidad Estatal de Milagro, Milagro, Ecuador" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pediatrics, Yale University School of Medicine, Connecticut, USA" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Respuesta a la carta al editor referida a «Mecanismos celulares y moleculares de la nefropatía diabética, rol del VEGF-A»" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We appreciate the valuable comments of the authors of the letter to the editor. They allude to the renal side effects (RSE) of anti-VEGF-A antibodies (anti-VEGF-A) administered intravitreally. They also share the story of a patient with diabetic retinopathy (DR) who developed nephrotic syndrome (NS) 10 days after receiving intravitreal anti-VEGF-A. From a multidisciplinary perspective, comments remind nephrologists of the need to treat the different RSE caused by commonly used agents more frequently.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The clinical case suggests several differential diagnoses: Will this be <span class="elsevierStyleItalic">de novo</span> glomerulopathy? Was NS caused by glomerulopathy added to a preexisting diabetic nephropathy (DN)? Did the anti-VEGF-A trigger the DN? A renal biopsy (optical/electronic microscopy) is essential for diagnosing kidney disease and for indicating the specific treatment. In this patient, decreased glomerular/systemic VEGF-A could have mainly affected the podocytes and glomerular basement membrane. If the glomerular endothelium was also affected, the patient could be suffering from thrombotic microangiopathy (TMA), a complication similar to preeclampsia. Notably, important histological alterations of TMA accompanied by relatively minor biological signs useful for clinical diagnosis were described. In addition, Up to 50% of the patients presented exclusively localized MAT to the kidney.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3</span></a> Regarding treatment, is indicated in this patient to suspend the anti-VEGF-A agents due to NS. Treatment of anti-VEGF-A-induced kidney disease will depend on the anatomical pathology of kidneys.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although anti-VEGF-A have been used for more than a decade to treat cancer, their RSE have been underestimated and their exact frequency is unknown.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> The most frequently reported anti-VEGF-A-related RSE include: incidence of hypertension (HTN; 20–42%) and incidence of proteinuria (20–62%).<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Other lesser-described RSE include: TMA; NS; focal segmental glomerulosclerosis (FSGS); collapsing FSGS; immunoglobulin-A glomerulopathy; pauci-immune extracapillary glomerulonephritis; membranoproliferative glomerulonephritis; minimal change disease (MCD); acute and chronic kidney failure; interstitial nephritis; vascular alterations and hydroelectrolytic disorders.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3</span></a> The RSE increased in a dose-dependent manner and when combined with chemotherapy.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3</span></a> The risk of RSE was higher in elderly patients with multiple complications, high cardiovascular risk, diabetes mellitus (DM) and high doses/cycles of anti-VEGF-A.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The frequency of RSE after intravitreal administration of anti-VEGF-A was less defined, although they appear to be smaller.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4–8</span></a> HTN and proteinuria were described in 0.2% and 0.6% of the cases, respectively.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Some individual clinical cases reported membranous glomerulonephritis (MGN),<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> recurrence of MCD<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> and severe impairment of renal function in people with preexisting DN.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> In transplanted kidneys, there was a deterioration of glomerular filtration (GF) and proteinuria related to MGN, changes compatible with acute and chronic rejection, glomerular thrombi and transplant glomerulopathy.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Agents that decrease concentration and inhibit the activity and signaling cascade of VEGF-A at a glomerular level can induce serious renal impairment.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–3,9,10</span></a> The first anti-VEGF-A used to treat cancer was bevacizumab. This antibody was also globally prescribed by ophthalmologists.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–4</span></a> Bevacizumab is a recombinant monoclonal antibody that binds to all VEGF-A isoforms. Its intravitreal administration greatly reduces vitreous VEGF-A, including levels previously increased by DM.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> Bevacizumab has a propitious size to stay at the injection site, (149<span class="elsevierStyleHsp" style=""></span>kDa), but it can reach the systemic circulation rapidly, thus maintaining a prolonged half-life.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Although intravitreal doses of bevacizumab (1–2.5<span class="elsevierStyleHsp" style=""></span>mg) are lower than the doses used systemically to treat eye disorders (5<span class="elsevierStyleHsp" style=""></span>mg/kg) and cancer (5–15<span class="elsevierStyleHsp" style=""></span>mg/kg), levels of free-circulating VEGF-A decreased after 24<span class="elsevierStyleHsp" style=""></span>h up to 4 weeks after intravitreal administration.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–4,9,10</span></a> In patients with DR, serum levels of VEGF-A decreased one day after receiving intravitreal bevacizumab, but the maximum reduction occurring on day seven.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> Moreover, in patients with age-related macular degeneration, intravitreal bevacizumab passed rapidly into the bloodstream and remained in circulation, causing a marked decrease in plasma VEGF-A.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> Plasma VEGF-A decreased one week after the first dose, remaining lower than baseline and further decreasing one week after the third dose.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> In the patient described in the letter to the editor, systemic and glomerular VEGF-A may have decreased markedly at the onset of NS, and so defining the risk ranges would be relevant.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In summary, conducting clinical trials to determine anti-VEGF-A-induced RSE is a pending task. Quantifying GFR and microalbuminuria/proteinuria before and during treatment with anti-VEGF-A could help to detect RSE early. In view of the diagnosis of severe RSE, we consider performing a renal biopsy to be key in early detection. Quantifying GFR, microalbuminuria/proteinuria and plasma VEGF-A before and after each cycle/injection of anti-VEGF-A would provide useful data for the prevention, diagnosis and treatment of RSE. Moreover, free-circulating VEGF-A could be used as an early biomarker of RSE secondary to treatment with anti-VEGF-A.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">Ecuadorian Secretariat of Higher Education, Science, Technology and Innovation (<span class="elsevierStyleGrantSponsor" id="gs1">Senescyt</span>), Prometheus Project. <span class="elsevierStyleGrantSponsor" id="gs2">Universidad Estatal de Milagro</span> (<span class="elsevierStyleGrantNumber" refid="gs2">UNEMI-OCAS-SO-03072014-N 8-DV</span>, <span class="elsevierStyleGrantNumber" refid="gs2">UNEMI-OCAS-SO-30052016-N°5-DV</span>).</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Veron D, Tufro A. Respuesta a la carta al editor referida a «Mecanismos celulares y moleculares de la nefropatía diabética, rol del VEGF-A». Nefrologia. 2016;36:706–707.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "All anti-vascular endothelial growth factor drugs can induce “pre-eclampsia-like syndrome”: a RARe study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Vigneau" 1 => "N. Lorcy" 2 => "T. Dolley-Hitze" 3 => "F. Jouan" 4 => "Y. Arlot-Bonnemains" 5 => "B. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 3 | 4 |
| 2024 October | 35 | 42 | 77 |
| 2024 September | 41 | 22 | 63 |
| 2024 August | 44 | 54 | 98 |
| 2024 July | 29 | 32 | 61 |
| 2024 June | 50 | 25 | 75 |
| 2024 May | 51 | 34 | 85 |
| 2024 April | 38 | 38 | 76 |
| 2024 March | 33 | 22 | 55 |
| 2024 February | 30 | 32 | 62 |
| 2024 January | 32 | 29 | 61 |
| 2023 December | 20 | 20 | 40 |
| 2023 November | 33 | 20 | 53 |
| 2023 October | 44 | 40 | 84 |
| 2023 September | 63 | 23 | 86 |
| 2023 August | 48 | 23 | 71 |
| 2023 July | 31 | 29 | 60 |
| 2023 June | 28 | 17 | 45 |
| 2023 May | 27 | 28 | 55 |
| 2023 April | 21 | 14 | 35 |
| 2023 March | 31 | 22 | 53 |
| 2023 February | 22 | 21 | 43 |
| 2023 January | 31 | 19 | 50 |
| 2022 December | 48 | 26 | 74 |
| 2022 November | 34 | 24 | 58 |
| 2022 October | 46 | 29 | 75 |
| 2022 September | 48 | 33 | 81 |
| 2022 August | 37 | 44 | 81 |
| 2022 July | 38 | 61 | 99 |
| 2022 June | 32 | 20 | 52 |
| 2022 May | 34 | 35 | 69 |
| 2022 April | 30 | 35 | 65 |
| 2022 March | 49 | 35 | 84 |
| 2022 February | 35 | 38 | 73 |
| 2022 January | 34 | 36 | 70 |
| 2021 December | 30 | 52 | 82 |
| 2021 November | 33 | 51 | 84 |
| 2021 October | 43 | 47 | 90 |
| 2021 September | 32 | 38 | 70 |
| 2021 August | 31 | 45 | 76 |
| 2021 July | 33 | 38 | 71 |
| 2021 June | 28 | 30 | 58 |
| 2021 May | 45 | 50 | 95 |
| 2021 April | 67 | 53 | 120 |
| 2021 March | 45 | 54 | 99 |
| 2021 February | 42 | 33 | 75 |
| 2021 January | 36 | 24 | 60 |
| 2020 December | 28 | 25 | 53 |
| 2020 November | 30 | 15 | 45 |
| 2020 October | 28 | 31 | 59 |
| 2020 September | 28 | 11 | 39 |
| 2020 August | 43 | 9 | 52 |
| 2020 July | 38 | 12 | 50 |
| 2020 June | 33 | 15 | 48 |
| 2020 May | 50 | 11 | 61 |
| 2020 April | 29 | 24 | 53 |
| 2020 March | 31 | 22 | 53 |
| 2020 February | 44 | 30 | 74 |
| 2020 January | 37 | 21 | 58 |
| 2019 December | 23 | 23 | 46 |
| 2019 November | 30 | 29 | 59 |
| 2019 October | 21 | 222 | 243 |
| 2019 September | 28 | 17 | 45 |
| 2019 August | 17 | 19 | 36 |
| 2019 July | 38 | 24 | 62 |
| 2019 June | 37 | 28 | 65 |
| 2019 May | 40 | 18 | 58 |
| 2019 April | 44 | 25 | 69 |
| 2019 March | 40 | 25 | 65 |
| 2019 February | 24 | 17 | 41 |
| 2019 January | 28 | 19 | 47 |
| 2018 December | 137 | 46 | 183 |
| 2018 November | 245 | 15 | 260 |
| 2018 October | 251 | 21 | 272 |
| 2018 September | 134 | 12 | 146 |
| 2018 August | 73 | 20 | 93 |
| 2018 July | 62 | 15 | 77 |
| 2018 June | 75 | 16 | 91 |
| 2018 May | 101 | 14 | 115 |
| 2018 April | 132 | 15 | 147 |
| 2018 March | 163 | 20 | 183 |
| 2018 February | 127 | 11 | 138 |
| 2018 January | 118 | 10 | 128 |
| 2017 December | 91 | 4 | 95 |
| 2017 November | 64 | 8 | 72 |
| 2017 October | 49 | 10 | 59 |
| 2017 September | 59 | 7 | 66 |
| 2017 August | 66 | 7 | 73 |
| 2017 July | 67 | 6 | 73 |
| 2017 June | 64 | 8 | 72 |
| 2017 May | 64 | 7 | 71 |
| 2017 April | 54 | 4 | 58 |
| 2017 March | 56 | 5 | 61 |
| 2017 February | 44 | 6 | 50 |
| 2017 January | 19 | 4 | 23 |
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