advances in renal pharmacology Flashcards
new advances in renal pharma - 4
targeting renal inflammasomes to treat hypertension
kidney organoids for developing viral drugs
novel drugs for renal cell carcinoma
regen med approaches
hypertension is associated with inc expression of ____ and ___ and accumulation of ___ and ___ in kidneys
adhesion mols
pro inflammatory cytokines
inflammatory T cells
macrophages
hypertension’s resulting inflammatory events in kidneys are thought to contriubte to ___ ___ and ___
renal fibrosis
kidney damage
can cause reset of blood pressure at chronically elevated levels
hypoxia, inflammation, oxidative stress contribute to chronic kidney disease pathogenisis via
tubular cell injury
hypoxia, inflammation, oxidative stress contribute to chronic kidney disease pathogenisis via tubular cell injury. this can cause
transdifferentiation of kidney fibroblasts to myofibroblasts
hypoxia can result from damage to the
glomerulus
reduces blood flow to nephron
hypoxia triggers
cytokine and chemokine production
thus inflammation
also leads to fibrosis, which further inhibits flow of oxygen
what are inflammasomes
cytosolic signalling complexes
sense danger signals from pathogens or damaged host cells
respond by initiating inflammatory cascade
mediate inflammation in chronic inflammatory disease
examples of chronic inflammatory disease - 4
rheumatoid arthritis
gout
alzheimer’s disease
atherosclerosis
inflammasomes relevance in novel treatment
new evidence - hypertension development and inflammation partially depends on presence of functional NLRP inflammasome complex
which could be targeted for treating renal dysfunction, and high BP in hypertension
inflammasome as novel drug target study
MCC950 (selective small molecule inhibitor of NLRP3 inflammasome) reduces renal inflammation and fibrosis
improves renal function in mice
modest reduction in blood pressure
more research needed
what are organoids
in vitro cellular aggregates that usually contain more than one type of cell from the tissue of origin, and functional structures of organ of origin
how are organoids found
can be grown using pleuripotent stem cells
some already established for various organs e.g. intestine, retina, liver
under research
removes needs for animal testing, more accurate to human cell responses to drugs
closer to personalised medicine - patient derived renal organoids, help predict response
kidney organoid study
mini kidneys that are similarly structured to human kidneys
cultured from patients pleuripotent urine stem cells
allows modelling of various disorders including kidney infection, viruses following kidney transplants
also found in 2019 that kidney organoids express the expected proteins e.g. kidney epithelium cells were podocin positive and proximal tubules were aquaporin positive
causes of renal cell carcinoma/ kidney cancer - 5
smoking
hypertenstion
dialysis
genetic predisposition (PKC)
obesity
kidney cancer is ___ to detect
difficult
as rarely cause pain or bleeding
kidney cancer is ___ to chemotherapy
often resistant
it is easier to treat renal cell carcinoma before ____
metastasis
new drugs for kidney cancer - 3
nivolumab
cabozantinib
levatinib
treatments are pathway specific to patient’s tumour, patients stratified to identify needs and best match - genomic sequencing - personalised meds
most drugs for targeting kidney cancer inhibit the __ pathway
VEGFR
as inhibition dec blood supply to tumour, halting tumour growth
drugs targeting angiogenesis examples - 9
1st - bevacizumab
sorafenib
sunitinib
pazopanib
axitinib
cabozantinib
lenvatinib
temsirolimus
everolimus
drugs targeting angiogenesis - bevacizumab
metastatic colon cancer
2004 approved
now used for multiple cancers
drugs targeting angiogenesis - sorafenib and sunitinib
first antianiogenesis drugs targeting RCC, targets VEGFR
drugs targeting angiogenesis - pazopanib and axitinib
inhibit tyrosine kinase receptors - VEGFRs
drugs targeting angiogenesis - cabozantinib and lenvatinib
more effective VEGFR inhibitors
drugs targeting angiogenesis - temsirolimus and everolimus
inhibit different enzyme linked to angiogenesis called mTOR
targeted therapy in kidney cancer - VHL study
VHL = gene called Von Hippel-Lindau tumour suppressor
inactivated in most with renal carcinoma
accounts for 70% of kidney cancers, links to hypoxia
VHL suppresses tumours by regulating angiogenesis
lead to new therapies such as humanised monoclonal antibodies against VEGF, small mol TK inhibitors, mTOR inhibitors
new drugs have inc survival post diagnosis to
2.5 years
drawbacks of recent drugs
lots of side effects
dont often completely reverse cancer
some do not work on early stage tumours
thus, regen med
current role of regen in kidney
kidney has limited potential to regen
renel regen CD133 glycoprotein study
renal repair after injury depends on clonal expansion of cells
kidney cells that express CD133 are resistant to damage and can proliferate
CD133 expressing cells were treated with chemotherapy cisplatin
this led to cell damage by cisplatin and lost CD133 signature
recovery phase did, however, lead to re acquirement of CD133
lack of CD133 = lack of cell proliferation
so, may be linked to Wnt signalling, whihc is involved in development of various kidney disorders
future - infuse CD133 to help pt repair damaged kidneys
regen med - decellularisation study
rat kidneys have been decellularized via detergent perfusion
which yielded acellular scaffolds
seeded them with epithelial and endothelial cells
perfused cell seeded constructs in whole organ bioreactor
regen med - 3d bioprinting
cells used as ink to print new organs
regen med - regenerating human kidneys in other species study
rat derived nephrons generated in mice by combining transplantation of rat derived nephron progenitors with native nephron progenitor’s conditional elimination
nanoparticles and liposome useand example
Utilizing nanoparticles and liposomes to deliver drugs directly to kidney tissues can improve therapeutic outcomes and reduce systemic side effects
inc penetration of renal tissue, controlled release
e.g. gold nanoparticles for ACE inhibitors directly to kidneys to prevent chronic kidney disease in a study model
wearable artificial kidneys WAK
5 types currently under development
one human trial, no sig side effects
aims to provide continuous dialysis
inc quality of life, mimic natural kidney function better than traditional dialysis machinery
