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.

The clinical case suggests several differential diagnoses: Will this be de novo 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.1–3 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.

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.1 The most frequently reported anti-VEGF-A-related RSE include: incidence of hypertension (HTN; 20–42%) and incidence of proteinuria (20–62%).2 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.1–3 The RSE increased in a dose-dependent manner and when combined with chemotherapy.1–3 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.2

The frequency of RSE after intravitreal administration of anti-VEGF-A was less defined, although they appear to be smaller.4–8 HTN and proteinuria were described in 0.2% and 0.6% of the cases, respectively.4 Some individual clinical cases reported membranous glomerulonephritis (MGN),5 recurrence of MCD6 and severe impairment of renal function in people with preexisting DN.7 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.8

Agents that decrease concentration and inhibit the activity and signaling cascade of VEGF-A at a glomerular level can induce serious renal impairment.1–3,9,10 The first anti-VEGF-A used to treat cancer was bevacizumab. This antibody was also globally prescribed by ophthalmologists.1–4 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.10 Bevacizumab has a propitious size to stay at the injection site, (149kDa), but it can reach the systemic circulation rapidly, thus maintaining a prolonged half-life.9 Although intravitreal doses of bevacizumab (1–2.5mg) are lower than the doses used systemically to treat eye disorders (5mg/kg) and cancer (5–15mg/kg), levels of free-circulating VEGF-A decreased after 24h up to 4 weeks after intravitreal administration.1–4,9,10 In patients with DR, serum levels of VEGF-A decreased one day after receiving intravitreal bevacizumab, but the maximum reduction occurring on day seven.10 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.9 Plasma VEGF-A decreased one week after the first dose, remaining lower than baseline and further decreasing one week after the third dose.9 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.

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.