Transcript Renal toxicology

Renal toxicology
PHYSIOLOGY
Function

Regulation of electrolytes

Maintenance of acid-base balance

Regulation of BP

Remove wastes from the blood
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Reabsorption of H2O,G,AA
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Produce hormones
Introduction
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True incidence of CKD due to occupational & environmental
exposure is unknown.
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Kidney is especially vulnerable to these exposures & toxins
can be concentrated in kidney.
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These exposure are preventable causes of CKD.
Kidney Diseases
I.
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2.
II.
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2.
Duration
Acute(Weeks)
Chronic(Years)
Location
Glomerular
Non-glomerular(tubular , interstitial)
 The
most common site of injury for toxicants is the
proximal tubule.
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Diagnosis
History
 Physical examination
 Clinical presentation of the renal disease
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Monitoring of exposed workers:
 lack of sensitive and specific tests
 Serial measurement Cr & BUN
Clinical history
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Exposure histories:
◦ Frequency
◦ Intensity
◦ Personal protection
Clinical history & physical examination
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Factors that enhancing nephrotoxicity:
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Age
Genetic
HTN
Diabetes
Gout
Pre-exiting chronic renal disease
Hematuria :
1.
Urinary tract cancer
2.
Papillary necrosis
3.
GN
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1.
2.
Proteinuria:
HMW Proteinuria (albuminuria)
LMW proteinuria (β2-microglobulin & RBP)
Diagnostic Test (U.S. Department of Health )
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correlate with site of possible damage &
detect early renal tubular damage .
glomerular injury (urine albumin)
proximal tubule damage
(RBP, glucosaminidase, alanine amino peptidase)
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distal tubule injury (osmolality)
Limitations
unstable at certain urine pHs
 return to normal levels despite renal damage
 large inter-individual variations
 predictive value of these newer tests has not
been validated.
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Clinical presentation
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Acute renal failure:
ATN
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Chronic renal failure:
Chronic interstitial nephritis
Acute renal dysfunction
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Usually after high-dose exposure
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renal lesion : ATN
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extra renal manifestations usually dominate
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clinical presentation, course of ARF are very
similar in all exposures.
ATN
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Hours to days after exp:
urine output< 500 ml/d.
The urine analysis:
renal tubular cells, muddy brown granular casts,
Pr, RBC,WBC or casts of either cell type: Neg
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BUN ,Cr and electrolyte abnormalities
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After 1-2 weeks: diuresis
ATN
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Treatment
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Hemodialysis and/or hemoperfiision have
almost no role in accelerating the clearance of
occupational and environmental toxins.
These techniques are effective:
 certain alcohols, salicylate, lithium, theophylline
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ARF caused by heavy metals
Divalent metals, Cr, Cd, Hg & vanadium
 Exposure: welding cadmium-plated metals
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Exposure to Cd fumes → cough & progressive
pulmonary distress to ARDS
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RF in form of ATN
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Bilateral cortical necrosis in severe exposure
ARF caused by organic solvents
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Route of absorption: lungs (most common), skin
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Lipophilic & distribute in: fat, liver, BM, blood,
brain & kidney
Organic solvents
A) halogenated Hydrocarbons
carbon tetrachloride (CCL4):
- Acute exposure:
- CNS
GI
-after 7-10d :↓urine output, prerenal azotemia
Organic solvents
Other aliphatic halogenated hydrocarbons:
1-ethylene dichloride (C2H4Cl2):
--less potent than CCl4 as a renal toxicant but greater CNS toxicity
2-Chloroform (CCl3H):
--more nephrotoxic than CCl4
3-Trichloroethylene (C2HCl3):
-- cleaning agent
4-Tetrachloroethane (C2H2Cl4):
--most toxic of halogenated hydrocarbons
5- Ethylene chlorohydrin
--penetrates the skin readily and is absorbed through rubber gloves
B) Nonhalogenated hydrocarbons :
1-Dioxane:
less toxic than halogenated hydrocarbons
2 -Toluene:
-- reversible ATN due to toluene inhalation (glue-sniffing)
3- Ethylene Glycol:
--Mono ethyl ether, mono methyl , butyl ether
--irritants of skin and mucous membranes, CNS depressants.
4-phenol (carbolic acid):
--Local burns, dark urine
ARF caused by Arsine
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semiconductor industry
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Primarily hemotoxic
Firs sign immediately or after a delay up to 24h:
malaise, abd cramps, nausea, vomiting
RF due to ATN secondary to hemoglobinuria
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Hydration, manitol
 Exchange transfusion to prevent further hemolysis
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Chronic kidney diseases caused by lead
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Exposure: ingestion of leaded paint, battery manufacturing,
mining, combustion of leaded gasoline
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Absorbed by GI (adults:10% , children:50%) & lungs
Concentrated in bone (90%) & kidneys
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Chronic lead exposure→ ( fanconi-type syndrome)
After 5-30y : progressive tubular atrophy & interstitial
fibrosis
Cont,…
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Mechanisms of gout :
1-↓urine clearance of uric acid
2- crystallization at low urate concentration
3- lead-induced formation of guanine crystals
Mechanisms of HTN:
 acute lead intoxication
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1-↑ intracellular Ca
2-inhibition Na+,K+ ATPase
3-direct vasoconstriction
4-alteration in RAA axis
Cont,…
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Classic presentation of lead nephropathy:
CKD+ HTN+ gout.
CKD+ low-grade proteinuria , ( without gout or HTN )
U/A 24 hr: 1-2 g
Ultrasonography :small, contracted kidneys
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Renal biopsy :tubular atrophy, interstitial fibrosis, and
minimal inflammatory infiltrates.
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Electron microscopy :
intranuclear inclusion bodies usually are present in the
early stages of lead exposure but often are absent after
chronic exposure or after lead chelation.
Cont,…
Diagnosis :
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Measuring blood lead level
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EDTA lead mobilization test
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Tibial K x-ray fluorescence correlate with bone lead
Chronic kidney diseases caused by cadmium
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Exposure:
Cd-sulfide in ores of zinc, lead, and copper.
 nickel-cadmium batteries, pigments, glass, metal alloys, and
electrical equipment.
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40% - 80% of Cd is stored in: liver, kidneys (1/3)
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Cd is a contaminant of tobacco smoke.
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Only 25% of ingested Cd is absorbed.
Cont,…
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Cd blood rises then falls because it taken by the liver.
RBC & soft tissues: Cd-metallothionein.
 This complex is filtered at the glomerulus, undergoes
endocytosis in the prox.T, and is later degraded in
the lysosomes.
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The adverse effects of Cd on the Prox.T:
 Unbound Cd, that interfere with zinc-dependent
enzymes.
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Cont,…
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Target organs : kidney & lung
fanconi syndrome
 Hypercalciuria with normocalcemia,
hyperphosphaturia→ osteomalacia, pseudofx,
nephrolithiasis
 Uretral colic from calculi in 40%
 Itai-itai dx : painful bone dx with pseudofx in japan
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Cont,…
Possible causes of osteomalacia:
1- a direct effect of cd on bone
2- ↓renal tubular reabsoroption of Ca & P
3- ↑PTH & ↓ hydroxylation of vit D
Cont,…
Renal cadmium toxicity
 low-molecular-weight proteinuria
 urinary calculi
 multiple tubular abnormalities
 Cd urine >10 µg/g
Treatment :
 except removal from the exposure
 treatment of osteomalacia
Chronic kidney diseases caused by mercury
Exp: Inhalational of Metal fume & ingestion
1- ATN
2-Nephrotic syndrome
mercury exposure:
 Membranous nephropathy
 minimal-change disease
 anti-GBM
Cont,…
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Clinical presentation of ATN: extrarenal manifestations
Dx: history of exposure
glomerular disease such as membranous nephropathy??
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blood and urine mercury concentrations do not
correlate with renal disease.
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Spontaneous resolution of the proteinuria following
removal from the source of mercury exposure is
consistent with mercury-mediated glomerular disease.
Beryllium
Exposure:
 manufacture of electronic tubes
 fluorescent light bulbs
 metal foundries
Absorption:
 inhalation
Cont,…
manifestation of berylliosis :
 systemic granulomatous disease:
 lungs, bone, bone marrow, liver, lymph nodes, …
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kidneys:
granulomas and interstitial fibrosis.
Hypercalciuria, Hyperuricemia ,urinary tract stones.(30%)
PTH depressed,
Reproductive Toxicity
Reproductive Toxicity
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Reproductive function
◦ Women Who Are Pregnant
◦ Women of Child Bearing Age
◦ Men
 Male:
Spermatogonium
spermatid
months)
spermatocyte
mature spermatozoa (3
Adverse Male Reproductive Effects
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Hormonal disorder
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Hormonal & semen disorder
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Oligospermia
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Azoospermia
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Asthenospermia & teratospermia
Asthenospermia & oligospermia
Female:
Embryonic
1-2w
Prenatal
death
Fetal
8w
Major
malformation
Minor malformation
Functional defects
Difficulty in studying reproductive toxicity in
women
◦ nature of the female cycle
◦ relative frequency spontaneous abortions
◦ common occurrence of birth defects in general
population
Adverse Female Reproductive Effects
 Infertility:
 Mens
 LBW
dis:
(< 2500 gr):
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Birth defects:
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Preterm (<37wk):
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SAB (fetal loss 20 wk ):