Kidney toxicity Flashcards
what are the 3 pats of the kidneys anatomys
- Cortex = 90% of blood flow
- Medulla = exposed to high lumenal conc of toxicants for longer periods
- Papilla
why is the kidney susceptible to toxicity
- High renal blood flow = kidney is only 0.5% of total body mass but receives 25% cardiac output
- Glomerular filtration and water reabsorption results in conc of xenobiotic and metabolites in tubular fluid. Non toxic conc in plasma can become toxic in kidney and possibly precipitates in lumen
- Renal transportation of chemicals into tubular cells = active transport can cause tubular accumulation of heavy metal ect
- Biotransformation of parent compounds to toxic metabolites especially in pars recta of proximal tubules
List the location of toxic effects
Glomerulus
Proximal tubules
Renal haemodynamics
Loop of Henle
Distal tubule
Collecting ducts
What toxic effects are found in the glomerulus
Inflammatory response - leads to membrane damage, leakage
Immune complexes (haptens and/or complete antigen), blockage
What toxic effects are found in the proximal tubule
antineoplastics
halogenated hydrocarbons
heavy metals
antibiotics
What toxic effects are found in the renal haemodynamics
Calcineurin inhibitors, NSAIDs, ACE inhibitors and ARBs
- control glomerular filtration rate
What toxic effects are found in the loop of Henle and distal tubule
amphotericin which forms pores in the apical membranes of cells, resulting in loss of solutes
What toxic effects are found in the collecting duct
lithium linked
describe the types of mercury
- Elemental environmental pollutant, high vapour pressure, inhalation; low cytotoxicity, but easily oxidised to…
- Inorganic (Hg2+) occupational, skin/oral
- Organic eg methyl mercury lipophilic skin/oral
GS-Hg-SG formed in the liver from gonjugation with what and where does it go ?
mercury and glutathione
translocation to the kidney in systemic ciruclation then uptaken into proximal tubule cell from tubular fluid
what possibly happens to GS-HG-SG when its uptaken from the tubular fluid to proximal tubule cells
removal of ‘spare’ AA from glutathione to yeild cysteine conjugates
what happens when Hg++ is released
combines with SH groups on proteins,
depletes GSH, leading to mitochondrial stress
inhibits membrane bound enzymes
what shows acute toxicity and therefore cellualr necrosis in pars recta
Enzymes normally found in “brush border” (g-glutamyl transpeptidase, alkaline phosphatase) detected in urine
At higher doses, tubular necrosis occurs
how is cadmium excreted
metallothionenin complex
what is metallothionein
low MW protein with large number of SH groups synthesied in the liver to protect tissues form cadmium
What happens when cadmium is in the kidyes
in renal cells = toxicity
cadmium is pumped out the cell and forms a complex with metallothionenin
- if in the cell complex then this is broken down by lysosomal enzymes to free cadmium again = toxicity
True or False - there is cycling between CdMT and free Cd in cell
True
leads to long half life and results in accumulation in kidneys
When CdMt leaves the hepatocytes it enters the renal proximal tubule cells where it ….
-undergo lysosomal hydrolysis to release cadmium bind reversible binds to SH groups
- when this occurs Mt is degenerated and resynthesied
-cycling oxidative stress
what are halogenated hydrocarbons (Haloalkanes)
carbon tetrachloride (CCL4) Chloroform (CHCl3)
what does proximal tubule damage due to haloalkanes cause
glucosuria, proteinuria, polyuria
anuria and renal failure at high dose
what are the mechanisms of toxicity of haloalkanes
- Activation by mixed function oxidases to toxic metabolites followed by covalent binding
(eg chloroform (CHCl3) metabolised to COCl2 (phosgene) by P450 in liver) - Then parent or metabolite carried in blood from liver to kidney
- Local activation to COCl2 in kidney (prostacyclin synthase) detoxified by reaction with glutathione or cysteine
Most haloalkanes are _ producing _
nephrotoxins
proximal renal tubular damage
haloalkanes are associated with bioactivation via the _
cysteine conjugates B lyase pathways
Hexachlorobutadiene is conjugated with glutathione to produce
PCBG
What happens to PCBG before it enters the bile
- then the GI tract
- under goes y-glutamyl transferase to produce S-(1,1,2,3,4-pentachlorobutadienyl)cysteinylglycine
- Then its converted to PCBC by dipeptidase when reabsorbed in the GI tract
what is PCBC and what happens to it once it leaves the GI tract
- can be reversibly turned into N-Ac-PCBC (via N-acetyl transferase) and back to PCBC (acylase)
- via B lyase its converted to 1,1,2,3,4-pentachlorobutadienythiol and then a thioketene
- PCBC is actively transported into kidney tubule by organic anion transporter, but the cysteinyl glycyl conjugate can also be absorbed via the gamma glutamyl transferase in the tubule cell
what is thioketene
proposed DNA reactive metabolite
What is the cysteine S conjugate B lyases
Located in the Kidney + other tissues. Requires pyridoxal-5-phosphate and a-keto acid
Has aminotransferase + transaminase action
Divert cysteine conjugates from mercapturate formation, localised to proximal tubule
= causes mitochondrial toxicity
describe the beta lyase pathway
In the Liver/Bile = GSH conjuagtes xenobiotics which then is converted to the cysteine conjugate (via gamma glutamyl transferase)
- travels via systemic circulation -
Proximal tubule = turns to thiokentene via Cys conjugate B-lyase
How is the glomerular filtration rate controled
Filtration pressure maintained by control of blood flow
- vasoconstriction
- vasodilation
how is vasoconstriction mediated
Renin-Angiotensin system
- renin secretion increased, converts angiotensinogen ultimately to angiotensin II (AII) – this constricts both afferent and efferent arterioles leading to net increase in intraglomerular pressure
how is vasodilation mediated
prostaglandin release
- PGE2 secretion leads to net dilation of afferent arteriole (increasing overall blood flow)
what are the therapeutic agents that target renal haemodynamics
Calcineurin inhibitors (Cyclosporine & tacrolimus)
NSAIDs
Amphotericin B
Angiotensin converting enzyme (ACE) inhibitors & angiotensin receptor blocking (ARB) agents
what does calceurin inhibitors do
Increase renin synthesis leading to increase in AII release
Decrease PGE2 and COX2 – net result is reduced renal blood flow and GFR
what does NSAIDs do
Decrease PGE2 release – a problem if blood flow to glomerulus is reduced:
PGE2 is important to avoid Angiotensin II resulting in unchecked vasoconstriction
what does amphotericin B do
Forms pores in membrane - influx of Ca2+ vasoconstriction
Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blocking (ARB) agents
Angiotensin II synthesis decreases – efferent arteriole is preferentially dilated, leading to decrease in intraglomerular pressure.
Important in renovascular disease such as renal artery stenosis
how does antibiotics effect the kidneys
- Reabsorbed into proximal tubular cells by endocytotic processes via the megalin-cubulin complex
- Accumulates in lysosomes, golgi bodies and ER
- In lysosomes, inhibits lysosomal phospholipases and other membrane phospholipid-processing enzymes
- Lysosomal membrane disruption and mitochondrial dysfunction
How does aminogycoside toxicity effect the proximal tubule
binds to membrane -> taken up by endocytosis -> accumulates in lysosomes -> toxicity
- luminal aminoglycoside conc increases as fluid is absorbed along length of PCT
what occur in the early stages of aminoglycoside treatment
competes with proteins for endocytosis = protein appears in urine
what is the effects of cephalosporins in the kidneys
selective toxicity to proximal tubule cells
- Absorbed from systemic circulation by cation/anion transporter (on basolateral membrane)
- Not a substrate for efflux transporters, so highly retained within proximal tubule cells
- Only antibiotics which are transported cause toxicity
- Mechanisms include mitochondrial injury and lipid peroxidation
how is cephaloridine taken up
OAT1 transporters at basolateral membrane as its not a substrate for efflux pumps
what is fanconi syndrome
organic solutes lost to urine increased NA loss increased H20 loss
how do we administer cisplatin without killing patients
co-administer with an uptake blocker
How does the renal system handle cisplatin
cisplatin = nephrotoxic
- Because it is efficiently taken up into proximal tubule but rate of secretion is lower
- Higher exposure results in destruction of mitochondria → proximal tubular cell death
Organic solutes lost to urine increased Na loss increased H2O loss – Fanconi syndrome
what is the function of ADH (vasopressin)
Inserts Water Pores into Collecting Duct Cells Membrane to enable re-absorption of solute-free water from the collecting duct
how is lithium nephrotoxic
competes for ADH receptor - reuslting in polyuria
what are the methods for detecting and evaluating chemical induced renal injury
- Polyuria
- Decreased reabsorption =(Glucosuria/ aminoaciduria, pH/electrolytes)
- Proteinuria
- Anuria (Tubular obstruction)
How does proteinuria show renal injury
- Low MW proteins, esp. b2 microglobulin, in urine (normally taken into tubular cells by endocytosis)
- Albumin: damage to glomerulus (reabsorbed by endocytosis in mild injury, becomes saturated in severe injury)
- proximal tubule enzymes
how does creatinine clearance give a measure of renal function
- In early stages plasma creatinine may remain within normal limits for population
- Production dependent upon muscle bulk - loss or gain of muscle affects value
- Plasma concentration affected by hydration state
why is there a need for novel biomarkers
Only a MARKED loss of renal mass results in a lack of function
- traditional clinical parameters only detect loss of function
- Novel biomarkers detect damage to tissue
list some novel biomarkers
Collagen IV - glomerular basement membrane
a-GST - proximal tubules
RPA-2 - loop of henle
y-GST = distal tubule/collecting tubules
RPA-1 = collecting duct (RPA-1 renal papillary antigen – a marker of renal papillary necrosis)
what is kidney injury molecule -1 (KIM-1)
a transmembrane glycoprotein with very low expression levels in normal kidney
- expression increases markedly after ischemic re-perfusion injurgy
- A marker of proliferating, de-differentiated proximal tubule cells; shed from membrane after cleavage by MMP.
- Measured in both serum and urine and expressed in both humans and rodents.
