16 - Renal tox Flashcards
(35 cards)
Role of kidneys
- Renin and erythropoietin
- Acid-base balance
- Metabolises vit D3
- Excreting N from purine metabolism (Uric acid)
- Regulate fluid vol. + electrolyte
Arterioles respond to:
- Sympathetic N. stim
- Angiotensin II
- Arginine vasopressin (AVP)
- ADH
- Endothelin
- Adenosine
- Noradrenalin
Renin-Angiotensin-Aldosterone System (RAAS)
Maintains homeostasis
* Target of BP meds
* Maintain perfusion pressure in vasculature
* Renin ➔ Angiotensinogen ➔ Angiotensin I ➔ Angiotensin II (converted in lungs)
What does angiotensin II cause?
- VasoCONSTRICTION of small arterioles
- Na+ reabs in PROXIMAL tubule
- ALDOSTERONE release from zona glomerulosa cells (adrenal cortex)
Why is the renal system sensitive to xenobiotics?
- Recieve 20-25% cardiac output (but < 1% BW)
- Metabolically active
- Concentrate drug by removing water
- Glomeruli and interstitium are susceptible to immune attack
Biomarkers of damage in renal system
Location of damage specific to a nephrotoxicants
* Cystatin C ➔ glomerulus + proximal T
* KIM-1 ➔ proximal T
Cocaine and renal biomarkers
Cocaine cause thrombotic microangiopathy ➔ ↑ in serum Cystatin C levels
KIM-1
Urine KIM-1 levels can indicate damage to PROXIMAL tubules
* Could be caused by cadmium
* Appear much earlier than proteinuria ➔ useful
Normal GFR depends on:
- Adequate blood flow to the glomerulus
- Adequate glomerular filtration pressure
- Glomerular permeability
- Low intratubular pressure
Afferent arteriolar constriction
↓ GFR
* ↓ blood flow
* ↓ capilllary pressure
Obstruction of the tubular lumen
↓ or NO GFR
* Caused by cast formation
* ↑ tubular pressure, when this exceeds glomerular capillary pressure ➔ filtration ↓ or STOP
Back-leak in glomerular filtration
Occurs when the paracellular space between cells ↑ ➔ glomerular filtrate leaks into the extracellular space and bloodstream
Cellular changes in injured Renal cells
Irregular distribution of membrane proteins (e.g. Na+,K+-ATPase, and β1 integrins) result in LOSS of:
* Cell polarity
* Tight-junction integrity
* Cell-substrate adhesion
Acute Tubular Necrosis (ATN)
Occurs when lethally injured cells undergo oncosis or apoptosis ➔ released into tubular lumen
* Cast formation
* OBSTRUCTION
What are causes of ATN?
- Severe Hypoxic Insult
- Rhabdomyolysis
- Haemolysis
- Nephrotoxins
- Heavy metals
Histological features of ATN
- Loss of brush border
- Tubular dilation
- Cast formation
- Granular casts
Oncosis
Lysis of multiple contiguous cells which mainly accompanies high doses of nephrotoxicants
When is oncosis more likely to occur?
When ATP depleted
* ↓ ATP ➔ ion homeostasis dysregulated since Na+K+ATPase activity ↓
* K+ EFFLUX, Na+ & Cl INFLUX ➔ swelling and rupture
Prerenal renal failure (prerenal AKI)
Due to poor perfusion of nephrons leading to ↓ in GFR
* Angiotensin converting enzyme inhibitors
* Non-steroidal anti-inflammatory drugs
Intrarenal factors inducing AKI
Tubular tox, endo injury, glomerulopathy, interstitial nephritis ➔ ↓ GFR
* Aminoglycosides
* Heavy metals
* Cocaine
Aminoglycosides Tubular Toxicity Mechanism
- Freely filtered
- Proximal T reabs. after binding of anionic phospholipids at brush border
- Endocytosis
- Trapping in lysosomes ➔ inhibition of lysosomal hydrolases causing phospholipidosis
- Most likely leads to bursting ➔ release of tox lysosomal contents
Heavy Metals: Mercury
(Inorganic) Accumulates in renal tissue and bound to endogenous ligands
* Interferes with Ca2+ homeostasis and mitochondrial health
* Oxidative stress
Mercury and immunological involvement
Antibodies against glomerular basement membrane indicate immunological involvement in destruction of glomerulus
* Via immune complex deposition
Heavy Metals: Cadmium
Accumulates in kidney
* Cadmium metallothionine complexes (CM) is formed in intestine/liver following oral exposure to inorganic cadmium
* CM freely filtered + reabs at Prox. T
* Lysosomes degrade the complex to free Cd2+ which causes Prox. T dysfunction
