title: Anti-VEGF antibody treatment accelerates polycystic kidney disease.
abstract: Polycystic kidney growth implies expansion of the vasculature, suggesting that vascular endothelial growth factor (VEGF)-dependent processes play a critical role and that VEGF is a putative therapeutic target. Whether an anti-VEGF antibody improves renal cystic disease has not been determined. We administrated 5 mg/kg B20.4.1, an anti-VEGF-A antibody, or vehicle intraperitoneally twice weekly to 4-wk-old male normal (+/+) and cystic (Cy/+) Han:SPRD rats for 6 wk. Renal function, urinary protein excretion, organ/body weight ratios, cyst volume, tubular epithelial cell (TEC) proliferation, renal VEGF, hypoxia-inducible factor (HIF)-1α and -2α expression, renal histology, and kidney hypoxia visualized by [(18)F]fluoromisonidazole positron emission tomography were assessed. The treated compared with untreated +/+ rats had lower TEC proliferation rates, whereas Cy/+ rats receiving B20.4.1 displayed an increased proximal TEC proliferation rate, causing enhanced cyst and kidney growth. The +/+ and Cy/+ rats receiving B20.4.1 had severe renal failure and extensive glomerular damage. Proteinuria, which was highest in anti-VEGF-treated Cy/+ and lowest in untreated normal littermates, was positively correlated with renal HIF-1α and negatively correlated with VEGF expression. The untreated Cy/+ vs. +/+ rats had higher overall [(18)F]fluoromisonidazole uptake. The +/+ rats receiving B20.4.1 vs. untreated had increased [(18)F]fluoromisonidazole uptake, whereas the uptake was unchanged among treated vs. untreated Cy/+ animals. In conclusion, B20.4.1 caused an exaggerated cystic response of the proximal tubules in cystic rats and severe kidney injury that was associated with low renal VEGF and high HIF-1α levels. Anti-VEGF drug therapy may therefore not be a treatment option for polycystic kidney disease.
authors.affiliation: Zürich Center for Integrated Human Physiology, ETH Zürich, Zürich, Switzerland.
authors.forename: Shagun
authors.initials: S
authors.lastname: Raina
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Xueqi
authors.initials: X
authors.lastname: Wang
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Rudolf P
authors.initials: RP
authors.lastname: Wüthrich
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000009:adverse effects* / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D049109:Cell Proliferation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008297:Male; D008920:Misonidazole / Q000031:analogs & derivatives; D009929:Organ Size; D007690:Polycystic Kidney Diseases / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D012720:Severity of Illness Index; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D057134:Antibodies, Neutralizing; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008920:Misonidazole; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C031843:fluoromisonidazole