L19. Renal Toxicity

Question 1

Why is the kidney vulnerable to toxins?

Answer 1

1. Because it has a very high blood flow: it receives 1/5th of the CO (1.2 L/min) despite the fact that the kidney only makes up 0.04% of the body’s weight. It gets very high blood flow relative to its mass.
2. Its excretory function: it concentrates and excretes toxins. Concentration of the toxin in the nephron can directly damage the nephron, it can trigger immune complex deposition, and the pH within the tubules can be altered which can cause precipitates that block the flow through the nephron.

Question 2

What are the functions of the kidney?

Answer 2

1. Maintain fluid/electrolyte and acid balance.
2. Excrete metabolites and xenobiotics (foreign compounds)
3. Regulate blood pressure and secrete various hormones.

Question 3

How can blood flow to the kidney be regulated?

Answer 3

The kidney can regulate it itself.

Question 4

What are the types of capillary beds in the kidney?

Answer 4

1. Glomerular capillaries: where the filtration takes place
2. Peritubular capillaries: allow reabsorption and secretion between blood and inner lumen of nephron. (deeper down in the kidney).

Question 5

How many nephrons are in the kidney? What happens if they are injured?

Answer 5

• The kidney has approx. 1 million nephrons.
• When nephrons get injured, they can repair themselves (if the toxicant is removed), but they cannot regenerate if the injury is extensive and the nephron is completely destroyed.

Question 6

Why are we able to survive a certain amount of injury to the kidneys/nephrons?

Answer 6

Because:

1. we have 2 kidneys (large functional reserve)
2. Both the kidneys AND the nephrons have the ability of hypertrophy if necessary.

Question 7

Describe the structure of a nephron.

Answer 7

1. Starts with the glomerulus inside bowman’s capsule.
2. Proximal convoluted tubule.
3. Loop of henle.
4. Distal convoluted tubule.
5. Collecting duct.

Question 8

Where does urine first start to get made?

Answer 8

Initial urine formation takes place in the glomerulus, where the blood is filtered. Then, there is tubular reabsorption (mostly in proximal convoluted tubule) followed by tubular secretion.

Question 9

How much urine do we excrete per day? Why so little?

Answer 9

We excrete 1 - 1.5L of urine per day. Even though the kidney filters 180L of fluid per day, it reabsorbs almost all of it because it makes sure the body retains the nutrients it needs.

Question 10

Describe where and how glomerular filtration takes place.

Answer 10

Glomerular filtration takes place within Bowman’s capsule. Blood flows in via the afferent arteriole into the fine branches of the glomerulus and then blood flows back out via the efferent arteriole. The filtrate flows into the Bowmans capsule and then into the proximal tubule. The filtrate is composed of fluid, small molecules, and ions because the glomerulus is a macromolecular filter and is under high capillary pressure. Proteins and RBC’s are not filtered through.

Question 11

Describe the pressures that dictate filtration at the glomerulus.

Answer 11

The afferent arteriole has a high pressure that is pushing the fluid out (favours filtration). The osmotic pressure from plasma proteins such as albumin counteracts this pressure and tries to keep fluid in. The net result is an outwards pressure known as the filtration pressure which forces the fluid (containing ions and small molecules out of the glomeruli and into the bowman’s capsule, and then into the proximal tubule.

Question 12

What is the macula densa? Where is it an what is its purpose?

Answer 12

The macula densa is a sensing apparatus found at the junction between the distal convoluted tubule and the afferent arteriole that supplies the glomerulus. (remember the distal convoluted tubule comes back to make contact with it). The macula densa senses the concentration of sodium and chloride in the distal convoluted tubule. If the concentration is too high/too low it vasoconstricts/vasodilates the afferent arteriole to increase/decrease pressure/flow into the glomerulus.

End result: keeping concentration of the distal convoluted tubule within the proper range because it will soon form urine.

Question 13

What are podocytes?

Answer 13

Podocytes are cells found in the glomerulus that have extensions, called foot processes, which wrap around the blood vessels/capillary of the glomerulus. They give structure to the basement membrane which is a very porous filter.

Question 14

What type of collagen network is the basement membrane?

Answer 14

Type 4 collagen network.

Question 15

What is a sign of injury to the glomerulus?

Answer 15

If there are significant amounts of protein in the urine. This is because the filtration system lets small ions and molecules go through in basically the same concentration present in the plasma, however larger proteins are retained if the kidney is properly functioning.

Question 16

What happens to the filtrate when it enters the proximal convoluted tubule?

Answer 16

• 2/3 of the filtrate is reabsorbed immediately as it enters the proximal convoluted tubule. The rest is reabsorbed as it passes through the nephron.
• Active transport systems allow for things like sodium/glucose to be reabsorbed and water follows passively.
• The proximal tubule has a high ATP requirement because ATP is the energy source for the active transport pumps.
• The proximal convoluted tubule contains specialized subregions that are better at absorbing one thing over another.

Question 17

What is the main nephrotoxic site? What else is it a site for?

Answer 17

• The proximal tubule is the main nephrotoxic site. Toxins may block ATP production, block enzymes or transporters, or impair blood flow (leading to ischemia).
• The proximal tubule is also the site for renal P450 metabolizing enzymes.

Question 18

Describe what happens to the filtrant in the loop of henle and the distal convoluted tubule and collecting duct.

Answer 18

• Moving down the loop of Henle, additional reabsorption occurs, especially water and sodium. By the time the fluid gets to the convoluted tubule, the urine is fairly concentrated.
• The distal tubule and the collecting duct system is where control the volume and concentration of urine to a certain extent but it is not a major site of toxicant activity.

Question 19

Where do most toxins affect the kidney?

Answer 19

The cortex of the kidney, which is where the main part of the nephron is, and most of them will damage the initial part of the nephron.

Question 20

Can toxicants also affect deeper parts of the kidney?

Answer 20

Some toxicants can affect the medulla and the papillae of the kidney. These areas have higher lumina concentration of toxicants and they have slower blood flow which may increase exposure.

Question 21

What is acute tubular necrosis?

Answer 21

Tubular necrosis is cell death occurring in the tubules of the nephron. “Acute” refers to the fact that the necrosis is happening quickly and that it can happen with acute exposure (one exposure to a toxicant at a high enough dose is enough to trigger nerosis).

Question 22

What are the 2 types of acute tubular necrosis? Describe them.

Answer 22

1. Toxic acute tubular necrosis: Tubular cells are directly exposed to a toxic substance.
2. Ischemic acute tubular necrosis: Tubular cells do not get enough oxygen because the toxins are interfering with blood flow (which they are highly sensitive to because of their high metabolism). You can have patchy damage due to ischemic tubular necrosis.

Question 23

What can cause glomerular damage?

Answer 23

Certain diseases (such as IgA disease) or toxicants which can both cause formation of immune complexes. This can cause immune complex deposition in the glomerulus and is characterized by inflammation of the glomerulus (glomerulonephritis).

Question 24

What is immune complex deposition?

Answer 24

If you have immune complexes (antigens + antibodies bound to each other) in the blood, they can be filtered out and they can clog up the glomerulus. You can also form immune complexes directly on the basement membrane of the glomerulus. The antigens & antibodies get stuck in the basement membrane which activates the complement system and causes an influx of immune cells like neutrophils which causes injury to the tubules. This is commonly known as membranous nephropathy (a pathological problem with the nephron). Podocyte injury also occurs due to immune complex formation.

Question 25

What is a toxicant that can cause glomerulonephritis? How?

Answer 25

Mercury is capable of causing immune complex deposition in the glomerulus which causes glomerulonephritis. Damage to the kidney with mercury can occur via acute OR chronic exposure. This is because IgG can react with mercury present in the basement membrane.

Question 26

Describe a study that was done on chronic mercury exposure.

Answer 26

In china, people were using a popular cream that was meant to lighten the colour of the skin. The cream had mercury in it. Gradually using the cream over time, the mercury was absorbed (because it was injuring the surface of the skin) and the people developed a mercury toxicity.

Question 27

What types of compounds can injure the proximal convoluted tubule?

Answer 27

Anti-cancer drugs, some antibiotics, poisons from funghi (mycotoxins), and heavy metals.

Question 28

How can antibiotics cause injury to the proximal convoluted tubule?

Answer 28

Antibiotics, such as aminoglycosides, in a very high dose for any period of time (sustained period or initially), are filtered by the glomerulus and are reabsorbed in the proximal convoluted tubule. When they’re reabsorbed they can go into lysosomes and rupture them, causing extensive cell injury.

Question 29

What damage can ethylene glycol cause? What is it found in? Who is vulnerable?

Answer 29

Ethylene glycol is what makes up antifreeze. It poses a big risk for domestic animals, children, alcoholics and wildlife. Alcoholics consume it out of desperation because it is related to ethanol and can give a drunk feeling and help with withdrawal. Animals like cats and dogs are attracted to its smell so they will consume it if it is spilled.

Why is it toxic:
When it’s consumed, it’s filtered at the glomerulus and is directly toxic to the cells of the proximal tubule. It is also metabolized to oxalic acid which causes injury to the tubules. Furthermore, the oxalic acid can go on to precipitate in the tubules and obstruct them as calcium oxalate, leading to renal tubular necrosis. The oxalate crystals can precipitate all throughout the tubular system (distally, proximally, in the collecting ducts). The casts that form from the obstruction have a variety of different things in them (RBCs, WBCs, epithelial cells, etc.)

Question 30

What plant contains oxalic acid?

Answer 30

Rhubarb leaves contain oxalic acid, but the stem does not. therefore, the leaves are toxic but the stem is edible.

Question 31

What is Orellanine?

Answer 31

Orellanine is a mycotoxin from a mushroom. It is a nephrotoxin and it can cause tubular necrosis. It does this by causing free radical production in the tubules. Symptoms are delayed (it takes a few days or weeks before you actually know what happened). A person who has eaten a significant amount of the mushroom can end up with severe kidney failure. It can be acute or chronic. If it is too extensive to recover from, you may need a kidney transplant (go on dialysis until a transplant is available).

Question 32

What can cause injury to the distal convoluted tubule?

Answer 32

Not many things can cause damage to the distal convoluted tubule, but melamine and cisplatin (anti-cancer drug) can.

Question 33

What is melamine & where was it found?

Answer 33

Melamine is a plastic derivative with a high nitrogen content. When it is ground up it looks like powdered milk. In china, some companies adulterated powdered milk by adding in ground up melamine. This was because the tests for protein in powdered milk relied on nitrogen-level detection. It was a lot cheaper than actual powdered milk so it went into baby formula and pet food. The baby formula was only sold in china and 300 thousand children got kidney failure because of it. The pet food was sold in North America and a lot of pets died or had serious disease.

Question 34

How is melamine nephrotoxic?

Answer 34

Melamine crystallizes and deposits build up in the distal tubule. This leads to occlusion of the tubule and distal tubule necrosis. This can ultimately cause hemorrhage and inflammation which results in acute kidney injury and you can end up with kidney stones. Melamine can cause either very serious acute or chronic kidney disease.

Question 35

What is cisplatin? How is it toxic?

Answer 35

An anti-cancer drug that can cause both proximal and distal tubular necrosis. If people are on this drug for cancer, their kidney function is closely monitored and the dose is modified to be able to treat cancer while retaining kidney function.
Cisplatin is taken into the renal tubular cells, then it causes death of these cells in combination with ROS, vascular injury, and ischemia.
You can get acute kidney failure if the drug is not monitored. It also triggers apoptosis in the tubular cells by affecting the mitochondria and triggering capsase (a family of protease enzymes playing essential roles in programmed cell death) release which is what triggers the apoptosis.

Question 36

What can cause damage to the loop of henle or the collecting ducts?

Answer 36

• Xenobiotics of low solubility may precipitate in the distal nephron, causing inflammation, etc. Some drugs such as sulfonamide (antibiotic) and acyclovir (antiviral) can do this as well.
• An overdose of fluoride can lead to a decrease of sodium chloride absorption because they are competitively reabsorbed.

Question 37

What can cause damage to the renal medulla?

Answer 37

Most often, damage is caused by NSAIDs (aspirin, ibuprofen). They can cause renal toxicity if taken at high doses or moderate doses for long periods of time. Not everyone has problems, but it is possible for some people to have renal toxicity with these drugs.

Question 38

How are NSAIDs renotoxic?

Answer 38

• Arachidonic acid is the substrate for the synthesis of prostaglandins via COX-1 and COX-2. In the kidneys, prostaglandins ensure vasodilation of the afferent arterioles. COX-2 inhibitors (NSAIDs and especially selective COX-2 inhibitors), especially, can result in a large decrease in the blood flow to the glomerulus, causing ischemic damage.
• With the vasoconstriction of the glomerulus and changes deeper in the nephron, you can get papillary necrosis.

Question 39

What is papillary necrosis?

Answer 39

Papillary necrosis is necrosis that can extend from the papilla to the inner medulla. It is damage of medullary interstitial cells, nephrons, and vessels. It may be from chronic ischemia due to vasoconstriction caused by decrease in prostaglandin levels from taking NSAIDs. You wouldn’t expect it with intermittent use of normal analgesic doses of NSAIDs, usually just with high dose use for long periods of time or mixing of drugs.

Question 40

How are toxicity tests done for the kidney?

Answer 40

• Animal models differ from people and the effects on their kidneys are not necessarily transferrable to people.
• In humans, the main information we have been able to get is from histopathology: people who had serious kidney injury and had their kidneys removed can then allow pathologists to see where the injury was and what went wrong.
• Urinalysis can also be used: looking at what is present in the urine can often tell you if something is wrong with the kidney
• Measuring blood electrolytes and protein metabolism (BUN/creatinine) can provide information of what is being filtered and reabsorbed.

Question 41

What can cause chronic renal failure?

Answer 41

Chronic use of analgesics, lithium (psychiatric drug), and cyclosporine (immunosuppressant).

Question 42

Where can mercury be found?

Answer 42

It is a common toxicant that can be found in food/water.

Question 43

Why was the mad hatter crazy?

Answer 43

He would make hats out of animal fur. And mercury was used to preserve the hide, so he was chronically exposed to mercury.

Question 44

How can acute toxicity due to mercury occur?

Answer 44

Acute toxicity can affect the proximal tubule. Mercury vapour or mercuric chloride is rapidly transported to the proximal tubule and injures the mitochondria of the tubule cells which causes necrosis. As a result, high exposures of these things can lead to acute renal failure.

Question 45

How can acute mercury toxicity be detected? Can it be repaired?

Answer 45

• The enzymes that are normally found in the tubular cells will be detected in the urine when the tubular cells die and release their contents.
• All the solutes which should be reabsorbed are not reabsorbed and are ending up in the urine instead.
• If it is borderline, then you get kidney injury but the necrosis is not too extensive, the symptoms described above can occur and renal toxicity will be detected int he urine.
• If it is only one dose that is causing the toxicity, and injury is only moderate, than the kidney can repair itself and you can get back ti a reasonably normal level of function (recall nephron has a large functional reserve).

Question 46

What happens with chronic exposure to mercury?

Answer 46

• Immune complexes deposit in the basement membrane of the glomerulus.
• You get glomerular dysfunction and all the inflammatory processes being activated in the glomerulus coupled with free radical damage and cytokine release.

Question 47

What is nephrotic syndrome? What causes it?

Answer 47

• It can result from chronic and acute mercury-induced renal toxicity.
• Proteins in the blood are getting through the basement membrane of the glomerulus and they end up getting filtered out into the tubules when they shouldn’t be. Proteins cannot get reabsorbed from the tubules so they end up in the urine and take other things along with them (i.e. fluids).

Question 48

What happens id nephrotic syndrome lasts for a long time?

Answer 48

If increase glomerular permeability goes on for a long time, the person will become malnourished and they will have changes in the forces of their blood because albumin will be lost and albumin is the main contributor for the osmotic pressure of the blood.

This can lead to:

• altered coagulation, fluid retention/edema, decrease in plasma volume and cardiac output, affected signalling to the kidney.
• The end result is proteinuria (protein in the urine), hypoalbuminemia (low protein in blood), retention of fluid, and edema (tissue swelling).

Question 49

What is the cycle of mercury in the environment?

Answer 49

1. Mercury is emitted into the atmosphere, mainly by coal-fired power plants.
2. Mercury smoke mixes with the clouds.
3. When it rains the mercury lands in the soil and water and is absorbed by plants and small marine life.
4. It then bioaccumulates because fish eat contaminated plants and humans and other creatures like birds eat fish.

Question 50

What can mercury affect in humans?

Answer 50

Brain, heart, kidneys, lungs, immune system. It is also teratogenic. It can affect the development of the fetal brain and peripheral nervous system if the pregnant woman is exposed to high levels of mercury.

Question 51

What is the grasshopper effect and how is it related to mercury?

Answer 51

• With every season, the air is warming and cooling and the air currents tend to go north, when the temperature goes back down the mercury goes back down. The end result is that mercury gets concentrated up in the north. Even though the mercury is mostly released from burning coal in industries in the south, it goes to the north and affects everything (including humans). It goes up the food chain, bioaccumulating over time and biomagnifying up the food chain. This is why dangers to fetus’ are exacerbated in the north, due to the bioaccumulation of mercury in animals (like seals) that are human diet.

Question 52

Why are the kidneys vulnerable to air pollution?

Answer 52

• Small particles are problematic because they go straight from the alveoli into the blood stream and the kidneys get a high blood flow.
• PM2.5 often results in membranous nephropathy: the particles are stuck in the basement membrane and trigger the complex immune reaction.
• Aside from PM2.5, antibodies generated in the lungs due to pollutants may deposit in the kidneys (immune complex deposition).

Question 53

Describe a study relating PM2.5 and kidney function.

Answer 53

An 8 year cohort study was done on over 2 million veterans. the level of PM2.5 exposure was related to their kidney function. They showed that being exposed to small particles impairs glomerular filtration rate (drops by 1/3), increases chronic kidney disease, and increases end-stage kidney disease (the point at which you need dialysis/transplant). There is no safe level of PM2.5 but increased concentration is directly correlated with increased risk of impairments as discussed above.

Question 54

What is on of the worst things you can be exposed to with regards to small particles? Why?

Answer 54

Diesel exhaust.

• In vivo and in vitro studies were performed in Taiwan. In Taiwan, there is very high levels of air pollution and they have air quality monitoring stations which allowed for the study to take place.
• They took rats and housed them near the monitoring stations and kept them there for 6 months (control rats were kept inside with air filtration). They found really big kidney problems in the rats that were exposed to the fine particles (mostly diesel). They found that it damaged the mitochondria through ROS damage, apoptosis, ER stress, misfolded proteins, and autophagy (atrophy in attempt to survive).

Question 55

What are the mechanisms of kidney injury found in the rats due to exposure to diesel?

Answer 55

• Mechanisms of kidney injury: apoptosis and autophagy, inflammation, immune response, damage to endothelial lining of the kidneys (including vasculature), oxidative stress.