17. renal tox

where does cisplatin cause damage

proximal and distal tubule

3 main functions of kidney

1. maintain fluid/electrolyte and acid/base balance
2.Excrete metabolites, xenobiotics
3. Regulate BP, secrete hormones

BUN

Blood urea nitrogen
evaluates kidney function

Creatinine

Filtered by kidneys but not reabsorbed - rapid evaluation of kidney function

2 reasons kidneys are vulnerable

1. High blood flow - anything in circulation will get to it
2.Excretory function - it concentrate toxins while eliminating them

Kidney recieves what % of cardiac output

21% - over 1L/min

% body weight of kidneys

0.04%

Autoregulation of kidneys

Kidneys autoregulate their blood flow
even if BP is abnormal, kidneys will still function
as long as its between 80-170

The total circulating volume of blood passes every \___ minutes

6

2 capillary beds of kidney

1. glomerular
2. Peritubular

What in the kidney can lead to precipitation of various substances

intratubular pH

How many nephrons does each kidney have

1 million

T or F Nephrons can regenerate

F - only repair themselves

What happens when nephrons are starved of blood for too long

die

Collecting ducts

As urine is formed, goes into ducts that will get larger and larger until it leads to bladder

Main reason kidneys are resistant to damage

Have large functional reserve - can survive with 1 kidney

What does kidney do to take over function of lost nephrons

Hypertrophy- grow in size
Occurs when you lose a kidney

3 parts of nephron

glomerulus
tubules
collecting duct

What is glomerular filtration

Blood will flow through bowmans capsule into proximal tubule

What happens after glomerular filtration

tubular reabsorption and secretion

How much is filtered and reabsorbed per day

180L filtered
178.5 reabsorbed

Capillary pressure in glomerulus

high

What kind of filter is glomerulus

macromolecular

3 forces acting on glomerulus

Hydrostatic pressure
Osmotic pressure
Pressure inside bowmans capsule

Hydrostatic pressure of glomerulus

forces fluid out

Osmotic pressure

opposing pressure
Due to plasma proteins - will retain fluid inside

Pressure inside bowmans capsule

opposing pressure

Net pressure in glomerulus

Net outward pressure of 10mmhg - fluid leaves vessels

Pressure of blood flowing through glomerulus is altered due to what

amount of salt detected in the distal convoluted tubule

What controls blood flow through glomerulus

smooth muscle of arterioles contracting or relaxing
sympathetic nerve endings
macula densa cells in contact with distal tubule and the arteriole

What are glomerular capillaries surrounded by

Podocytes

Role of basement membrane in glomerular capillaries

Acts as filter since capillaries are full of holes

Role of podocytes

hold filter (basement membrane) in place
make molecules that coat basement membrane

Action of podocytes

Make and determine the filtration properties of the basement membrane

3 layers of glomerular capillary

Endothelium (fenestrated)
Basement membrane ( - charge, filter)
Epithelium - podocytes

% of fluid that gets filtered into capsule

20%

Where is does most reabsorption occur

Proximal tubule

Most vulnerable area of nephrone

proximal tubule

Kind of transport in proximal tubule

active transport for glucose, Na, amino acids
water will follow

Where does active transport occur in proximal tubule

At basolateral membrane

Where are co transport mechanisms for sodium in proximal tubule

at luminal membrane

Proximal tubule absorbs what % of filtered solutes and water

60-80%

Proximal tubule requirement

high ATP
this makes it more vulnerable

Where are renal p450s

proximal tubule
this makes it more vulnerable

Action of toxins at proximal tubule

Block ATP production
Block enzymes/transporters
Impair blood flow

Main actions at loop of henle

reabsorption of electrolytes
where urine is concentrated

How is urine concentrated at loop of henle

Active transport of sodium
Passive absorption of water (osmotic forces)

Cause of Acute renal failure - Intrarenal failure

direct damage to kidneys by inflammation, toxins, drugs, infection, or reduced blood supply

Cause of Acute renal failure - Prerenal failure

Sudden and severe drop BP

Cause of Acute renal failure - Postrenal failure

Sudden obstruction of urine flow

90% of blood flow goes to

renal cortex (where nephrons are)

What parts of renal system will have higher luminal concentration of toxicants

Medulla and papillae

What happens to toxin that is secreted unchanged

Will become more concentrated as it gets through the nephron

What are the problems caused by incr concentration of toxins if they are secreted unchanged

Damage in distal region
These regions have slower blood flow - prolong exposure

Acute tubular necrosis

Death of cells at different regions along the nephron

Evidence of acute tubular necrosis

Casts - dead epithelial cells that clump up and clog tubules

Main problems in bowmans capsule and glomerulus

Immune complex deposition

Immune complex deposition

deposition of a complex of antibodies that bind antigens located along the basement membrane

Where does immune complex deposition often occur

bowmans capsule and glomerulus

What does complex of antibodies do (immune complex deposition)

attract immune mediators - inflammatory response

What do circulating immune complexes do

stick to basement membrane when they are filtered
cause immune response

What toxicant causes immune complex deposition

Chronic mercury exposure

What anti body is present during chronic mercury exposure

IgG throughout the basement membrane of glomerulus

Why do immune complexes get deposited in renal system if they can occur in any capillary

high blood flow and high capillary pressure in glomerulus

3 parts of immune response intiated by immune complex deposition

1. inflammation
2. Complement activation
3. Recruitment of neutrophils

What can antigen-antibody complexes damage

Podocytes - effacement

Most common place for toxins to damage kidney

proximal tubule

Main toxins that can effect proximal tubule

Antibiotics
Anticancer drugs
Mycotoxins
Heavy metals

Mycotoxin orellanine

fungus
mushroom nephrotoxin

What does mycotoxin orellanine produce

free radical production

What does mycotoxin orellanine do to body

cause renal tubular necrosis
Delayed onset of symptoms
results in kidney failure

Kidney failure due to mycotoxin orellanine can go 2 ways

1. acute and recover
2. Progress to chronic failure

Kidneys infected with mycotoxin orellanine will show

tubular degeneration
Distortion
and necrosis

Proximal tubule will concentrate which substances

Mercury
cadmium
antibiotics : neomycin
gentamycin
streptomycin

Type of antibiotics that effect proximal tubule

Aminoglycosides

Example of aminoglycoside

Gentamycin

Where do antibiotics go once reach proximal tubule

reabsorbed
binds to anionic lipids

What happens to antibiotics after binding to anionic lipids

taken up into lysosomes via endocytosis

What happens once antibiotics are inside lysosome

willl cause rupture of lysosome to release enzymes and free radicals (which normally help them kill bacteria)

How do antibiotics cause tubular necrosis

Ruptured lysosomes release free radicals that cause damage to cell

Common name for ethylene glycol

Antifreeze

Where is ethylene glycol toxic

proximal tubules

What happens to proximal tubule when ethylene glycol is ingested

immediate toxicity to tubular epithelial cells (renal tubular necrosis)

Metabolism of ethylene glycol

Metabolized into oxalic acid
React to form calcium oxalate and cause kidney stones

Why would ethylene glycol be ingested

Sweet smelling and tasting
Possible alcoholics drink it
children stumble upon it

Ethylene glycol metabolized by what (how is this toxic)

alcohol dehydrogenase - becomes Glycoaldehyde
ALDH becomes glyoxylic acid
damaging to kidneys

Where is oxalic acid found naturally

Variety of plants - leaves of rhubarb

Where is nephrotoxicty caused by melamine and cisplatin

distal tubule

crystal deposition due to melamine causes

tubular necrosis
hemorrhage
inflamamtion

Toxicity of cisplatin necrosis

Taken up by tubular cells
Cause vascular injury - alter GFR
trigger inflammation
distal and proximal tubular necrosis

Cisplatin mechanism of apoptosis

alters function of mitochondria
Will now release enzymes for apoptosis

What causes damage in loop of henle

high levels of fluoride
compounds with low solubility can precipitate (acyclovir, sulfonamides)

How does fluoride cause damage to loop of henle

Decr NaCl reabsorption in distal portion of nephron

How do compounds with low solubility damage loop of henle

Precipitate causing crystals in collecting ducts
precipitation will trigger inflammation, dilation and tubular epithelial hyperplasia

What toxicant effects medulla

NSAIDS (acute) and mixtures of analgesics (chronic)

Action of NSAIDS

block COX 1 and COX2

How to NSAIDS effect medulla

blocks cox2
cox2 has housekeeping roles in kidney
block prostaglandins --\> too much vasoconstrition--\> reduced GFR

Cox2 housekeeping roles

Make vasodilator prostaglandins

Action of vasodilator prostaglandins

maintain flow through afferent arteriole to maintain normal GFR

What happens when vasodilator prostanglandins blocked

Too much vasoconstriction --\> reduced GFR --\> incr concentration of compounds in distal nephron
NSAIDS do this