PMID- 30642877
OWN - NLM
STAT- MEDLINE
DCOM- 20191104
LR  - 20200309
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 30
IP  - 2
DP  - 2019 Feb
TI  - Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities.
PG  - 187-200
LID - 10.1681/ASN.2018080853 [doi]
AB  - Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial 
      growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in 
      oncology, with new drugs continuously in development. In this review, we consider 
      the experimental and clinical evidence behind the diverse nephrotoxicities 
      associated with the inhibition of this pathway. We also review the renal effects 
      of VEGF inhibition's mediation of key downstream signaling pathways, specifically 
      MAPK/ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin 
      (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble 
      decoy receptor) is associated with renal-specific thrombotic microangiopathy 
      (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF 
      receptors is preferentially associated with glomerulopathies such as minimal 
      change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has 
      largely been associated with tubulointerstitial injury. Inhibition of mTOR is 
      most commonly associated with albuminuria and podocyte injury, but has also been 
      linked to renal-specific TMA. In all, we review the experimentally validated 
      mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well 
      as the wide range of clinical manifestations that have been reported with their 
      use. We also highlight potential avenues for future research to elucidate 
      mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.
CI  - Copyright (c) 2019 by the American Society of Nephrology.
FAU - Estrada, Chelsea C
AU  - Estrada CC
AD  - Division of Nephrology, Department of Medicine, Stony Brook University, Stony 
      Brook, New York; and.
FAU - Maldonado, Alejandro
AU  - Maldonado A
AD  - Division of Nephrology, Department of Medicine, Stony Brook University, Stony 
      Brook, New York; and.
FAU - Mallipattu, Sandeep K
AU  - Mallipattu SK
AD  - Division of Nephrology, Department of Medicine, Stony Brook University, Stony 
      Brook, New York; and sandeep.mallipattu@stonybrookmedicine.edu.
AD  - Renal Section, Northport Veterans Affairs Medical Center, Northport, New York.
LA  - eng
GR  - F32 DK112618/DK/NIDDK NIH HHS/United States
GR  - I01 BX003698/BX/BLRD VA/United States
GR  - K08 DK102519/DK/NIDDK NIH HHS/United States
GR  - R01 DK112984/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Review
DEP - 20190114
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 15C2VL427D (aflibercept)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
SB  - IM
MH  - Animals
MH  - Bevacizumab/*therapeutic use
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice
MH  - Molecular Targeted Therapy/*methods
MH  - Nephrotic Syndrome/diagnosis/*drug therapy
MH  - Prognosis
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Randomized Controlled Trials as Topic
MH  - Receptors, Vascular Endothelial Growth Factor/drug effects/genetics/*therapeutic 
      use
MH  - Recombinant Fusion Proteins/*therapeutic use
MH  - Signal Transduction
MH  - Treatment Outcome
MH  - Vascular Endothelial Growth Factor A/drug effects/*genetics
PMC - PMC6362621
OTO - NOTNLM
OT  - VEGF
OT  - hypertension
OT  - nitric oxide
OT  - proteinuria
OT  - signaling
EDAT- 2019/01/16 06:00
MHDA- 2019/11/05 06:00
PMCR- 2020/02/01
CRDT- 2019/01/16 06:00
PHST- 2019/01/16 06:00 [pubmed]
PHST- 2019/11/05 06:00 [medline]
PHST- 2019/01/16 06:00 [entrez]
PHST- 2020/02/01 00:00 [pmc-release]
AID - ASN.2018080853 [pii]
AID - 2018080853 [pii]
AID - 10.1681/ASN.2018080853 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2019 Feb;30(2):187-200. doi: 10.1681/ASN.2018080853. Epub 2019 
      Jan 14.