17. renal tox

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where does cisplatin cause damage

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1

where does cisplatin cause damage

proximal and distal tubule

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2

3 main functions of kidney

  1. maintain fluid/electrolyte and acid/base balance 2.Excrete metabolites, xenobiotics

  2. Regulate BP, secrete hormones

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3

BUN

Blood urea nitrogen evaluates kidney function

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4

Creatinine

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

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5

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

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6

Kidney recieves what % of cardiac output

21% - over 1L/min

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7

% body weight of kidneys

0.04%

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8

Autoregulation of kidneys

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

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9

The total circulating volume of blood passes every ___ minutes

6

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10

2 capillary beds of kidney

  1. glomerular

  2. Peritubular

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11

What in the kidney can lead to precipitation of various substances

intratubular pH

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12

How many nephrons does each kidney have

1 million

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13

T or F Nephrons can regenerate

F - only repair themselves

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14

What happens when nephrons are starved of blood for too long

die

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15

Collecting ducts

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

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16

Main reason kidneys are resistant to damage

Have large functional reserve - can survive with 1 kidney

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17

What does kidney do to take over function of lost nephrons

Hypertrophy- grow in size Occurs when you lose a kidney

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18

3 parts of nephron

glomerulus tubules collecting duct

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19

What is glomerular filtration

Blood will flow through bowmans capsule into proximal tubule

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20

What happens after glomerular filtration

tubular reabsorption and secretion

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21

How much is filtered and reabsorbed per day

180L filtered 178.5 reabsorbed

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22

Capillary pressure in glomerulus

high

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23

What kind of filter is glomerulus

macromolecular

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24

3 forces acting on glomerulus

Hydrostatic pressure Osmotic pressure Pressure inside bowmans capsule

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25

Hydrostatic pressure of glomerulus

forces fluid out

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26

Osmotic pressure

opposing pressure Due to plasma proteins - will retain fluid inside

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27

Pressure inside bowmans capsule

opposing pressure

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28

Net pressure in glomerulus

Net outward pressure of 10mmhg - fluid leaves vessels

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29

Pressure of blood flowing through glomerulus is altered due to what

amount of salt detected in the distal convoluted tubule

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30

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

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31

What are glomerular capillaries surrounded by

Podocytes

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32

Role of basement membrane in glomerular capillaries

Acts as filter since capillaries are full of holes

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33

Role of podocytes

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

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34

Action of podocytes

Make and determine the filtration properties of the basement membrane

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35

3 layers of glomerular capillary

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

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36

% of fluid that gets filtered into capsule

20%

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37

Where is does most reabsorption occur

Proximal tubule

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38

Most vulnerable area of nephrone

proximal tubule

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39

Kind of transport in proximal tubule

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

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40

Where does active transport occur in proximal tubule

At basolateral membrane

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41

Where are co transport mechanisms for sodium in proximal tubule

at luminal membrane

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42

Proximal tubule absorbs what % of filtered solutes and water

60-80%

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43

Proximal tubule requirement

high ATP this makes it more vulnerable

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44

Where are renal p450s

proximal tubule this makes it more vulnerable

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45

Action of toxins at proximal tubule

Block ATP production Block enzymes/transporters Impair blood flow

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46

Main actions at loop of henle

reabsorption of electrolytes where urine is concentrated

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47

How is urine concentrated at loop of henle

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

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48

Cause of Acute renal failure - Intrarenal failure

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

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49

Cause of Acute renal failure - Prerenal failure

Sudden and severe drop BP

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50

Cause of Acute renal failure - Postrenal failure

Sudden obstruction of urine flow

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51

90% of blood flow goes to

renal cortex (where nephrons are)

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52

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

Medulla and papillae

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53

What happens to toxin that is secreted unchanged

Will become more concentrated as it gets through the nephron

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54

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

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55

Acute tubular necrosis

Death of cells at different regions along the nephron

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56

Evidence of acute tubular necrosis

Casts - dead epithelial cells that clump up and clog tubules

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57

Main problems in bowmans capsule and glomerulus

Immune complex deposition

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58

Immune complex deposition

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

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59

Where does immune complex deposition often occur

bowmans capsule and glomerulus

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60

What does complex of antibodies do (immune complex deposition)

attract immune mediators - inflammatory response

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61

What do circulating immune complexes do

stick to basement membrane when they are filtered cause immune response

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62

What toxicant causes immune complex deposition

Chronic mercury exposure

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63

What anti body is present during chronic mercury exposure

IgG throughout the basement membrane of glomerulus

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64

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

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65

3 parts of immune response intiated by immune complex deposition

  1. inflammation

  2. Complement activation

  3. Recruitment of neutrophils

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66

What can antigen-antibody complexes damage

Podocytes - effacement

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67

Most common place for toxins to damage kidney

proximal tubule

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68

Main toxins that can effect proximal tubule

Antibiotics Anticancer drugs Mycotoxins Heavy metals

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69

Mycotoxin orellanine

fungus mushroom nephrotoxin

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70

What does mycotoxin orellanine produce

free radical production

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71

What does mycotoxin orellanine do to body

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

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72

Kidney failure due to mycotoxin orellanine can go 2 ways

  1. acute and recover

  2. Progress to chronic failure

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73

Kidneys infected with mycotoxin orellanine will show

tubular degeneration Distortion and necrosis

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74

Proximal tubule will concentrate which substances

Mercury cadmium antibiotics : neomycin gentamycin streptomycin

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75

Type of antibiotics that effect proximal tubule

Aminoglycosides

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76

Example of aminoglycoside

Gentamycin

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77

Where do antibiotics go once reach proximal tubule

reabsorbed binds to anionic lipids

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78

What happens to antibiotics after binding to anionic lipids

taken up into lysosomes via endocytosis

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79

What happens once antibiotics are inside lysosome

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

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80

How do antibiotics cause tubular necrosis

Ruptured lysosomes release free radicals that cause damage to cell

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81

Common name for ethylene glycol

Antifreeze

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82

Where is ethylene glycol toxic

proximal tubules

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83

What happens to proximal tubule when ethylene glycol is ingested

immediate toxicity to tubular epithelial cells (renal tubular necrosis)

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84

Metabolism of ethylene glycol

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

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85

Why would ethylene glycol be ingested

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

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86

Ethylene glycol metabolized by what (how is this toxic)

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

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87

Where is oxalic acid found naturally

Variety of plants - leaves of rhubarb

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88

Where is nephrotoxicty caused by melamine and cisplatin

distal tubule

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89

crystal deposition due to melamine causes

tubular necrosis hemorrhage inflamamtion

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90

Toxicity of cisplatin necrosis

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

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91

Cisplatin mechanism of apoptosis

alters function of mitochondria Will now release enzymes for apoptosis

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92

What causes damage in loop of henle

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

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93

How does fluoride cause damage to loop of henle

Decr NaCl reabsorption in distal portion of nephron

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94

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

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95

What toxicant effects medulla

NSAIDS (acute) and mixtures of analgesics (chronic)

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96

Action of NSAIDS

block COX 1 and COX2

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97

How to NSAIDS effect medulla

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

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98

Cox2 housekeeping roles

Make vasodilator prostaglandins

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99

Action of vasodilator prostaglandins

maintain flow through afferent arteriole to maintain normal GFR

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100

What happens when vasodilator prostanglandins blocked

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

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