title: Effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.
abstract: OBJECTIVE
  It is known that endothelial cells in the kidney are also strongly VEGF-dependent. Whether intravitreal drugs can be detected within the glomeruli or affect VEGF in glomerular podocytes is not known. Therefore, the aim of this pilot study was to investigate the effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys.
  
  
  METHODS
  The kidneys of eight cynomolgus monkeys, which were intravitreally injected either with 2 mg of aflibercept or with 0.5 mg of ranibizumab, were investigated one and seven days after injection. Two animals served as controls. The distribution of aflibercept, ranibizumab and VEGF was evaluated using anti-Fc- or anti-F(ab)-fragment and anti-VEGF antibodies respectively. The ratio of stained area/nuclei was calculated using a semi-quantitative computer assisted method. Glomerular endothelial cell fenestration was quantified in electron microscopy using a systematic uniform random sampling protocol and estimating the ratio of fenestrae per µm.
  
  
  RESULTS
  Compared to the controls, the anti-VEGF stained area/nuclei ratio of the ranibizumab-treated animals showed no significant changes whereas the stained areas of the aflibercept-treated monkeys showed a significant decrease post-treatment. Immune reactivity (IR) against aflibercept or ranibizumab was detected in aflibercept- or ranibizumab treated animals respectively. The number of fenestrations of the glomerular endothelial cells has shown no significant differences except one day after aflibercept injection in which the number was increased.
  
  
  CONCLUSIONS
  Surprisingly, both drugs could be detected within the capillaries of the glomeruli. After a single intravitreal injection of aflibercept, VEGF IR in the podocytes was significantly reduced compared to controls. Ranibizumab injection had no significant effect on the glomeruli's VEGF level. Whether this is caused by aflibercept's higher affinity to VEGF or because it is used in a higher stoichiometric concentration compared to ranibizumab remains to be investigated.
authors.affiliation: Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tschulakow
authors.affiliation: Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Christner
authors.affiliation: Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany; STZ OcuTox Preclinical Drug Assessment, Hechingen, Germany.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Julien
authors.affiliation: Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Ludinsky
authors.affiliation: Division of Nephrology, Charité University Medicine, Charité Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
authors.affiliation: Section of Experimental Vitreoretinal Surgery, Centre for Ophthalmology, Tuebingen, Germany; STZ OcuTox Preclinical Drug Assessment, Hechingen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schraermeyer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D058449:Intravitreal Injections; D007678:Kidney Glomerulus / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D000069579:Ranibizumab / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab