Lecture 8 Toxic Responses in the Kidney?

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Lecture 8Toxic Responses in the Kidney?
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Anatomical?? arrangement and organization of the
nephrons??? within the kidney

• 1 million nephrons in each human kidney
• Renal blood flow???? (RBF)
• 94 to cortex??
• 5 outer medulla??
• 1 inner medulla

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What causes kidney stones? Kidney stones form
when there is a decrease in urine volume and/or
an excess of stone-forming substances in the
urine. The most common type of kidney stone
contains calcium in combination with either
oxalate or phosphate. Dehydration?? from reduced
fluid intake or strenuous exercise???? without
adequate fluid replacement increases the risk of
kidney stones. High sugar or salt
diets. Kidney stones can also result from
infection in the urinary tract???? these are
known as struvite or infection stones.
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Three Basic functions of the nephron

• Filtration?? at the glomerulus ???
• Tubular reabsorption??????
• Tubular secretion?????
• Amount excreted in urine amount filtered
  reabsorbed secreted by tubules

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Organization of the Glomerulus

• Solute up to 10000 M.W. pass through the filter
  freely
• Diffusion is restricted and ceases around 70000
  M.W. to 100000 M.W.
• For creatinine???? P x GFR UV
• P Plasma, U Urine
• V volume of urine
• GFRglomerulus filtration rate??????

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Tubular reabsorption??????

• Urea??
• Only 30-70 of the filtered load is excreted
• Glucose
• All are reabsorbed
• Calcium
• 60 of the filtered (ionized form) is reabsorbed
• Phosphate 95 reabsorbed
• Uric acid?? mostly reabsorbed
• Amino acids 98 reabsorbed

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Tubular secretion?????

• Foreign substances
• Secretion is active, show saturation kinetics
• Physiological substances
• Metabolic end-products

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Major transport mechanisms for solutes and water
across the renal proximal tubules?????

• 2/3 of the filtered water and sodium are
  reabsorbed per minute
• Amount reabsorbed are influenced by the balance
  of hydrostatic and osmotic forces in the
  peritubular capillaries?????????.
• ? colloid osmotic????? or ? hydrostatic
  pressures??? in peritubular capillaries ? ?
  reabsorption

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Loops of Henle?????

• Run deep into the medulla passing through a
  region of increasing osmolality??? .
• Thin ascending limb??
• Impermeable to water, highly permeable to Sodium
  and chloride and moderately permeable to urea
• NaCl diffuses from tubules back to cortex
• Thick ascending limb
• Distal tubules????

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Major transport pathways in the thick ascending
limb of the loop of Henle

• Reabsorb NaCl from the tubular fluid by
  energy-dependent process
• Impermeable to water
• Luminal fluid becomes hypo-osmotic

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Distal tubules????

• NaCl is reabsorbed
• Early part is impermeable to water
• Permeability of the last part is determined by
  ADH (antidiuretic hormone?????)

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Effects of Nephrotoxins???

• Act on the vascular elements or portion of
  nephron
• Vasoconstriction???? and ischemia??
• Decreased glomerular filtration and tubular
  transport
• Affect the glomerulus directly ? flitration
  dysfunction????
• Affect tubular activities

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Nephrotoxins on kidney function

• Acute toxicity ? alter renal function extensively
• If it is sublethal??? and of short duration ?
  recovery?? to normal function rapidly
• Chronic low dose over long period ? extensive
  renal damage
• Marked changes in renal function may not be
  detected due to the compensatory capacity???? of
  the kidney.

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Common examples of nephrotoxins Heavy metals
such as lead, mercury, cadmium, and arsenic
exposure to these metals is most often
occupational environments. Nonsteroidal
anti-infalmmatory drugs (NSAIDS????????) such as
ibuprofen???(??????) , naproxen??? , and
ketoprofen??? possibly acetaminophen. Certain
antibiotic medications, notably streptomycin???
and gentamicin???? . Organic solvents such as
benzene.
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Heavy Metals

• Exposure to most heavy metals ? renal toxicity
• Necrotic??? proximal tubules containing
  proteinaceous??? casts
• Ischemia produced by vasoconstriction ? ? GFR
• ? dose ? renal failure, renal necrosis, ? BUN
  (Blood urea nitrogen), death
• Protective mechanism against low-dose heavy-metal
  toxicity was exhausted ? cellular damage

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Heavy Metal (II)

• Mercury
• Elemental, inorganic and organic mercury are
  nephrotoxic
• Low dose ? affect proximal tubule ? secret
  organic ions
• Platinum
• A complication of cisplatin (an antitumor drug)
  therapy
• Damage to proximal tubule, ion loss ? not able to
  produce concentrated urine
• Alter GFR, affect distal tubule and collecting
  duct functions

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Heavy Metals (III)

• Cadmium
• Toxicity ? ? synthesis of metal binding protein
  metallothionein in liver
• The complex ? toxicity to other organs but ?
  nephrotoxicity
• Toxicity is localized to proximal tubule ? ?
  reabsorption, ion loss (phosphate)
• Presence of low and high M.W. proteins in urine
  (GFR defects)
• Other Metals
• Toxicity observed for chromium (potassium
  dichromate), arsenic, gold, iron, antimony,
  thallium and lead

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Halogenated Hydrocarbons???

• Both hepatotoxic??? and nephrotoxic
• Nephrotoxic metabolites produced
• Directly by the kidney
• Produced in the liver and transported to the
  kidney
• Non-nephrotoxic metabolite produced in the liver
  then transported to the kidney ? further
  biotransformation ? nephrotoxin

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Carbon Tetrachloride???? and Chloroform??

• Damage primarily to proximal tubules, secondarily
  to the entire nephron
• Proximal tubular necrosis
• Glucosurea, aminoacidurea, proteinurea and ?
  secretion of organic ions
• Glomerular or distal tubular functions are not
  apparently affected
• At high dose ? renal necrosis, renal failure, ?
  BUN, dealth

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Hexachlorobutadiene?????

• Widespread environmental pollutant
• Potent nephrotoxic with little hepatic toxicity
• Low dose ? affect proximal tubules
• Failure to reabsorb tubular filtrate (glucosurea,
  proteinurea, aminoacidurea)
• ? secretion of organic ions
• Necrotic proximal tubules
• High dose ? renal failure, renal necrosis, ? BUN,
  death

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Other halogenated hydrocarbons

• Bromobenzene
• Hepatoxic and nephrotoxic
• Nephrotoxic metabolites from liver ? to kidney ?
  damage the kidney tissue directly
• 2-Bromoethylamine (BEA)
• Necrosis of loop of Henle and collecting duct
• Sclerosis of juxtamedullary glomeruli and urinary
  concentration defects
• Methoxyflurane
• Produce medullary necrosis and renal failure
• Not able to produce concentrated urine, ion loss,
  ? BUN and renal failure

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Analgesics???

• In humans, chronic ingestion of high doses of
  analgesics (aspirin????, phenacetin???? ,
  acetaminophen??????) ? medullary interstitial
  inflammation, fibrosis, renal failure.
• Vasoconstriction of the vasa recta???? ? ischemic
  medullary damage
• Neprotoxic metabolites produced by liver ?
  transport to kidney ? cortical tissue damage

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Antibiotics???

• Certain antibiotics (neomycin, gentamicin,
  tobramycin, netilmicin, kanamycin, amikacin and
  streptomycin) possess aminoglycoside side chains
  ? nephrotoxic
• Damage primarily at the proximal convoluted
  tubule and glomerulus.
• Changes in the endothelial pore size ? filtration
  dysfunction
• Tetracyclines??? ? medullary toxins
• Failure to produce concentrated urine
• Glucosuria??, aminoaciduria???? , proteinuria???

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Environment contaminants

• Herbicides???
• Affect renal capacity to secrete organic ions
• Polychlorinated Biphenyls???? (PCB) and
  Polybrominated Biphenyls???? (PBB)
• Enhance drug metabolizing enzyme systems in
  kidneys ? potential hazard
• Tetrachlorodibenzo-?-dioxin??? (TCDD)
• Enhance renal drug metabolizing enzymes, but no
  direct effect on the kidneys shown
• Mycotoxins????
• In contaminated animal and human foods ?
  proximal tubular dysfunction and ?organic ion
  transport