Table 2.

Summary of literature on clinical systemic effects of intravitreal anti-VEGF injection

Systemic effect/pathology	n	Study type	Reference
A. Evidence of drug absorption and systemic VEGF inhibition
Absorption in AMD, dec. systemic VEGF (Bev, Aflb) >Ran	56	Prospective observational study	Avery et al. [16]
Absorption in AMD/DME/CRVO, dec. systemic VEGF (Bev, Aflib) >Ran	151	Prospective observational study	Avery et al. [17]
Absorption of drug in AMD, dec systemic VEGF	610	Retrospective study of RCT data	Rogers et al. [20]
Dec. systemic VEGF (Bev, Aflib)	38	Prospective randomized observational study	Zehetner et al. [21]
Dec. systemic VEGF (Bev, Aflib)	72	Prospective non randomized clinical study	Hirano et al. [28]
Dec. systemic VEGF (Bev, Aflib) >Ran	436	Prospective randomized clinical study	Jampol et al. [29]
B. Animal studies showing anti-VEGF binding to glomeruli
Absorption of drug, binding at glomerulus	N/A	Animal (Simian) study	Tschulakow et al. [30]
C. Effects on hypertension after intravitreal injection
Limited short-term rise in blood pressure at 1 h	135	Prospective observational study	Lee et al. [32]
Long- and short-term rise in systolic blood pressure	82	Observational study	Rasier et al. [33]
No significant change in blood pressure	57	Observational study	Risimic et al. [34]
Higher blood pressure linked to need for more VEGFi	2916	Retrospective study	Shah et al. [35]
D. Trial data
Increased proteinuria 45% of patients (not statistically significant)	40	Prospective observational Study	Bagheri et al. [31]
Significant rise in diastolic blood pressure
Significant rise in hemoglobin and platelets
No change in eGFR 7–30 days after injection (Bev, Aflib, Ran)	69	Retrospective observational study	Kameda et al. [36]
No long-term change in HTN or category of albuminuria	660	Planned retrospective analysis of trial	Glassman et al. [37]
No association with # VEGFi injections and proteinuria	43	Retrospective observational study	O’Neill et al. [38]
Significant rise in UPCR in patients with preexisting proteinuria	53	Prospective observational study	Chung et.al. [64]
E. Population studies showing increased morbidity and mortality
Increased risk of CVA in DME patients	N/A	Meta-analysis	Avery et al. [18]
Increased AC mortality in AMD patients	1063	Retrospective observational studya	Hanhart et al. [39]
Increased risk of mortality after MI in AMD patients	211 (with MI)	Retrospective observational studyb	Hanhart et al. [40]
Increased risk of mortality after CVA in AMD patients	948 (with CVA)	Retrospective observational studyb	Hanhart et al. [41]
No finding of CVA, MI, AC mortality in AMD patients	504	Retrospective observational studyb	Dalvin et al. [42]
No finding of increased CVA in DME patients	2541, 690 (with VEGFi)	Retrospective observational studyb	Starr et al. [43]

^#, number of (injections); AC, all-cause mortality; Aflib, aflibercept; Bev, bevacizumab; dec., decreased; HTN, hypertension; MI, myocardial infarction; n, number of study subjects; Ran, ranibizumab; RCT, randomized controlled trial; VEGFi, vascular endothelial growth factor inhibitors. Green lettering = positive result linking VEGFi and renal outcome; orange lettering = equivocal result; red lettering = negative result.

^aAge- and gender-matched control served as comparator group.

^bAge- and gender-matched control with a CV or CVA event served as comparator group.