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Routes of absorption, distribution and excretion of toxicants in the body
Human kidney
Each:
~170g, 10cm long,
6cm wide
Paired:
0.4% body mass
20-25% cardiac
output
Fig. 5.1
RENAL TOXICOLOGY
Nephron – functional unit of mammalian kidney
(single layer of epithelial cells)
Kidney functions
1. Maintenance of homeostasis
maintenance of ion concentrations (e.g. Na+, K+, Cl-)
maintenance of ECF volume
maintenance of ECF osmolality
2. Elimination of metabolic wastes and xenobiotics
removal of metabolic end products (e.g. urea, HCO3-)
removal of foreign substances and by-products
(e.g. metals, penicillin)
3. Hormonal regulation
synthesis of erythropoietin (stimulates production of RBC)
synthesis of renin (if P02 low, if blood volume low)
1,25-dihydro-vitamin
Eckert, Fig. 14.18
Fig.14.1
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URINE FORMATION
1. Glomerular filtration
up to 25% of arriving water & salts
water, salts, glucose, urea, etc.
non-selective except excludes:
RBC & large plasma proteins
2. Tubular reabsorption
~99% water, most salts, glucose reabsorbed
mostly in proximal tubule
by active transport (e.g. NaCl)
or passive diffusion (e.g. water)
3. Tubular secretion
K+, H+, HCO3-, foreign substances
selective
active transport
Table ‘14.1’
Eckert Fig. 14.21
Table 14.1
URINE FORMATION
1. Glomerular
filtration
2. Tubular
reabsorption
* Glomerular filtration rate : 125 ml/min = 180 L/24hours
3. Tubular secretion
Eckert Fig. 14.21
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GLOMERULAR FILTRATION (GFR)
Fig. 14. 20, 21
Targets of toxicants:
1. Renal vasculature
2. glomerulus
Table ‘14.1’
Mechanisms of reduction of the glomerular filtration rate (GFR)
Tubular reabsorption
movement of ions, water and other solutes along the renal tubule
GFR depends on:
1. Adequate blood flow to the
glomerulus
2. Adequate glomerular
capillary pressure
3. Glomerular permeability
4. Low intratubular pressure
Targets of toxicants:
3. Renal tubule
(proximal tubule)
Eckert Fig. 14. 28
Fig.14.4
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Mechanisms of glomerular and tubular proteinuria
Nephrotoxicity
alterations in cytoskeleton and in normal distribution of membrane proteins
Low molecular wt proteins are
normally reabsorbed by
endocytosis (EL=endosome,
L=lysosome); catabolism to
aa
Endocytosis may be impaired
(proteins appear in urine)
In mild glomerular injury, large
proteins are absorbed
In severe glomerular injury,
proteins appear in urine
Fig. 14.9
Response of the nephron to a nephrotoxic insult – repair mechanisms
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Covalent and noncovalent binding and oxidative stress mechanisms of cell injury
Assessment of renal function and symptoms of renal toxicity
A. Urine volume
pathology: anuria, polyuria
B. Urine composition (electrolytes, glucose, protein, pH, osmolality)
pathology: e.g.glucosuria, proteinuria, presence of specific enzymes
(e.g. LDH released from dead cells,alkaline phosphatase relased
from brush border pf kidney cells)
presence of blood in urine
C. Serum chemistry
pathology: BUN (blood urea nitrogen)
D. Anatomy
pathology : structural anomalies
Tests used in humans
• Non invasive (urine or blood chemistry)
• Invasive (GFR, biopsy, scans, systemic pressure,…)
• Post mortem (histopathology)
Nephrotoxicants
Use of histopathology to diagnose
nephrotoxcity
1. Heavy metals
(Hg, Cd, Pb, Pt, Cr, As)
Effects on renal vasculature
vasoconstriction (leads to lower GFR)
ischemia
Direct cell toxicity
great vulnerability of proximal tubule
2. Organochlorines (CCl4, chloroform, hexachlorobenzene,..)
(N.B. bioactivation of several OCs in liver)
3. Drugs
analgesics (e.g.acetaminophen)
anasthetics (e.g. methoxyflurane – transformed into oxalate
and F-)
antibiotics
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METALS
Natural elements present in environmental compartments. Their availability and
Distribution are modified by human activities. Speciation greatly influences the
toxicity of a given metal. Some metals are essential elements,
others do not have a biological function.
Essential metals: (8)
Co, Cu, Mn, Mo, Fe, Zn, Se, Mg
N.B. U-shaped dose-response curve
Non essential metals:
Cd, Ni, Hg, Pb, As,…
Differences in half life:
Cd and Pb – half life 20-30 years
As or Cr – hours to days
Metal speciation:
Metal species vs toxicity vs biotransformation enzymes vs pH
As3+ >> As5+
Cr3+ << Cr6+
6