Unlikely association of nephrectomy post-mRCC with anti-VEGF-induced renal TMA

To the Editor: Rini et al. reported that thrombotic microangiopathy (TMA), a potentially life-threatening toxicity resulting from vascular endothelial growth factor (VEGF) inhibition, may be more likely in uninephrectomized renal cell carcinoma (RCC) patients, while no patient with a non-RCC malignancy in their cohort experienced TMA [1]. Literature review as well as our personal data casts doubt on the importance of a solitary kidney in TMA resulting from VEGF inhibition [2–10] (Table 1). In 18 TMA reported cases in literature, only 6 cases of RCC patients who had experienced nephrectomy, chronic kidney disease, diabetes and hypertension have been mentioned [3,8–10]. In our personal experience (unpublished data), only 5 out of 20 TMA cases had metastatic RCC (mRCC), underwent nephrectomy and had hypertension. The other 12 literature cases [2,4–7] (66.6%) as well as our own 15 remaining TMA cases (75%) had both kidneys, and < 26% of them were diabetic and/or hypertensive and/or renal insufficient (Table 1). TMA related to anti-VEGF–VEGFR agents (anti-VEGF agent such as bevacizumab or VEGF Trap, or VEGFR inhibitors such as sunitinib, sorafenib or pazopanib) is clearly a class effect, and the underlying renal and oncological conditions can, at best, be considered an undiscriminating predisposing factor. Moreover, the pathophysiology of TMA induced by the combination bevacizumab and sunitinib is clearly in relation to VEGF pathway inhibition. Characteristics of patients who developed TMA related to anti-VEGF agents: RCC vs non-RCC malignancies TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor; RCC, renal cell carcinoma; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDH, lacticodeshydrogenase. Characteristics of patients who developed TMA related to anti-VEGF agents: RCC vs non-RCC malignancies TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor; RCC, renal cell carcinoma; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDH, lacticodeshydrogenase. Fifty percent of our patients did not show haematologic signs of TMA. Despite the fact that TMA related to anti-VEGF therapy might be selectively of renal expression, only half of the biopsied patients had grade 3 or 4 proteinuria. Therefore, TMA is under-diagnosed, and clinicians should be more attentive to mild renal anomalies in those patients. Patients showing proteinuria need special referral to nephrologists. Close follow-up of hypertension and/or proteinuria in all patients by the oncologists cannot be overemphasized. Conflict of interest statement. None declared.