Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center

Abstract

Expanded clinical experience with patients taking antiangiogenic compounds has come with increasing recognition of the renal adverse effects. Because renal histology is rarely sought in those patients, the renal consequences are underestimated. Antiangiogenic-treated-cancer patients, who had a renal biopsy for renal adverse effects from 2006 to 2013, were included in the current study. Clinical features and renal histologic findings were reviewed. Our cohort was 100 patients (58 women) with biopsy-proven kidney disease using anti-vascular endothelial growth factor (VEGF) therapy with a mean age of 59.8 years (range, 20-85 yr). Patients were referred for proteinuria, hypertension, and/or renal insufficiency. Kidney biopsy was performed 6.87 ± 7.18 months after the beginning of treatment. Seventy-three patients experienced renal thrombotic microangiopathy (TMA) and 27 patients had variable glomerulopathies, mainly minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS). MCN/cFSGS-like lesions developed mainly with tyrosine-kinase inhibitors, whereas TMA complicated anti-VEGF ligand. Thirty-one percent of TMA patients had proteinuria up to 1 g/24 h. Half of TMA cases are exclusively renal localized. Pathologic TMA features are intraglomerular exclusively. MCN/cFSGS glomeruli displayed a high abundance of KI-67, but synaptopodin was not detected. Conversely, TMA glomeruli exhibited a normal abundance of synaptopodin-like control, whereas KI-67 was absent. Median follow-up was 12 months (range, 1-80 mo). Fifty-four patients died due to cancer progression. Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents. No patient developed severe renal failure requiring dialysis. Drug continuation or reintroduction resulted in a more severe recurrence of TMA in 3 out of 4 patients requiring maintenance of anti-VEGF agents despite renal TMA. In conclusion, TMA and MCN/cFSGS are the most frequent forms of renal involvement under anti-VEGF therapy. Careful risk-benefit assessment for individual patients should take into account risk factors related to the host and the tumor.

FIGURE 1

Collapsing glomerulopathy (CG) and thrombotic microangiopathy (TMA) lesions in renal biopsies from patients with anti-VEGF agents. CG: there is a collapse of the capillary tuft (A) with overlying swollen and hyperplastic epithelial cells (B) (HES, original magnification × 200) often having a pseudocrescent-like appearance (C) (Masson trichrome, × 200). TMA: luminal thrombosis within the glomerular capillary (D) (Masson trichrome, × 200). The capillary basement membranes were thickened with double-contoured appearance of the capillary wall, best appreciated with methenamine silver stain (E) (× 200) associated with mesangiolysis (F) (Masson trichrome, × 200).

FIGURE 2

Graphic overview of the staining patterns in both kidney biopsies. The relative abundance of Wnt-1 was reduced in podocytes from patients with MCN/cFSGS when compared to control kidney tissues and TMA (A). MCN/cFSGS glomeruli displayed a high abundance of KI-67, whereas KI-67 was absent in TMA glomeruli (B). Staining for synaptopodin showed a positive podocyte-like staining pattern in TMA-proven glomeruli and was absent or significantly weaker in MCN/cFSGS (C). Abbreviation: Synapto = synaptopodin.