Download Renal toxicology

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‫دکتر رامازینی در سال ‪ 1633‬میالدی در ایتالیا بدنیا آمد و بعلت خدمات‬
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‫و بیماری وی وجود داشته باشد‬
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Renal toxicology
By:Dr.Bahrami
Occupational Medicine specialist
95‫اذر‬
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PHYSIOLOGY
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Function

Regulation of electrolytes

Maintenance of acid-base balance

Regulation of BP

Remove wastes from the blood

Reabsorption of H2O,G,AA

Produce hormones
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Introduction

True incidence of CKD due to occupational & environmental
exposure is unknown.

Kidney is especially vulnerable to these exposures & toxins
can be concentrated in kidney.

These exposure are preventable causes of CKD.
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Kidney Diseases
I.
1.
2.
II.
1.
2.
Duration
Acute(Weeks)
Chronic(Years)
Location
Glomerular
Non-glomerular(tubular , interstitial)
 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

Monitoring of exposed workers:
 lack of sensitive and specific tests
 Serial measurement Cr & BUN
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Clinical history

Exposure histories:
◦ Frequency
◦ Intensity
◦ Personal protection
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Clinical history & physical examination

Factors that enhancing nephrotoxicity:
◦
◦
◦
◦
◦
◦
Age
Genetic(G6PD)
HTN
Diabetes
Gout
Pre-exiting chronic renal disease
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Hematuria :
1.
Urinary tract cancer
2.
Papillary necrosis
3.
GN

1.
2.
Proteinuria:
HMW Proteinuria (albuminuria)
LMW proteinuria (β2-microglobulin & RBP)
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Diagnostic Test (U.S. Department of Health )



correlate with site of possible damage &
detect early renal tubular damage .
glomerular injury (urine albumin)
proximal tubule damage
(RBP, glucosaminidase, alanine amino peptidase)

distal tubule injury (osmolality)
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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

Acute renal failure:
ATN

Chronic renal failure:
Chronic interstitial nephritis
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Acute renal dysfunction

Usually after high-dose exposure

renal lesion : ATN

extra renal manifestations usually dominate

clinical presentation, course of ARF are very
similar in all exposures.
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ATN


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

BUN ,Cr and electrolyte abnormalities

After 1-2 weeks: diuresis
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ATN

Treatment

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


Exposure to Cd fumes → cough & progressive
pulmonary distress to ARDS

RF in form of ATN

Bilateral cortical necrosis in severe exposure
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ARF caused by organic solvents

Route of absorption: lungs (most common), skin

Lipophilic & distribute in: fat, liver, BM, blood,
brain & kidney
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Organic solvents
A) halogenated Hydrocarbons
carbon tetrachloride (CCL4):
- Acute exposure:
- CNS
GI
-after 7-10d :↓urine output, prerenal azotemia
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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
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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
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ARF caused by Arsine

semiconductor industry

Primarily hemotoxic
First sign immediately or after a delay up to 24h:
malaise, abd cramps, nausea, vomiting
RF due to ATN secondary to hemoglobinuria



Hydration, manitol
 Exchange transfusion to prevent further hemolysis

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Chronic kidney diseases caused by lead

Exposure: ingestion of leaded paint, battery manufacturing,
mining, combustion of leaded gasoline

Absorbed by GI (adults:10% , children:50%) & lungs
Concentrated in bone (90%) & kidney



Chronic lead exposure→ ( fanconi-type syndrome)
After 5-30y : progressive tubular atrophy & interstitial
fibrosis
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Cont,…

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

1-↑ intracellular Ca
2-inhibition Na+,K+ ATPase
3-direct vasoconstriction
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Cont,…
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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Cont,…
Diagnosis :

Measuring blood lead level

EDTA lead mobilization test

Tibial K x-ray fluorescence correlate with bone lead
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Chronic kidney diseases caused by cadmium

Exposure:
Cd-sulfide in ores of zinc, lead, and copper.
 nickel-cadmium batteries, pigments, glass, metal alloys, and
electrical equipment.


40% - 80% of Cd is stored in: liver, kidneys

Cd is a contaminant of tobacco smoke.

Only 25% of ingested Cd is absorbed.
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Cont,…

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.

The adverse effects of Cd on the Prox.T:
 Unbound Cd, that interfere with zinc-dependent
enzymes.

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Cont,…

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
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Cont,…
Renal cadmium toxicity
 low-molecular-weight proteinuria
 urinary calculi
 multiple tubular abnormalities
 Cd urine >10 µg/gcr
Treatment :
 except removal from the exposure
 treatment of osteomalacia
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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
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Cont,…


Clinical presentation of ATN: extrarenal manifestations
Dx: history of exposure
glomerular disease such as membranous nephropathy??

blood and urine mercury concentrations do not
correlate with renal disease.

Spontaneous resolution of the proteinuria following
removal from the source of mercury exposure is
consistent with mercury-mediated glomerular disease.
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Beryllium
Exposure:
 manufacture of electronic tubes
 fluorescent light bulbs
 metal foundries
Absorption:
 inhalation
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Cont,…
manifestation of berylliosis :
 systemic granulomatous disease:
 lungs, bone, bone marrow, liver, lymph nodes, …




kidneys:
granulomas and interstitial fibrosis.
Hypercalciuria, Hyperuricemia ,urinary tract stones.(30%)
PTH depressed,
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Reproductive Toxicity
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Reproductive Toxicity

Reproductive function
◦ Women Who Are Pregnant
◦ Women of Child Bearing Age
◦ Men
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 Male:
Spermatogonium
spermatid
spermatocyte
mature spermatozoa (3 m)
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Adverse Male Reproductive Effects

Hormonal disorder

Hormonal & semen disorder

Oligospermia

Azoospermia


Asthenospermia & teratospermia
Asthenospermia & oligospermia
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Female:
Embryonic
1-2w
Prenatal
death
Fetal
8w
Major
malformation
Minor malformation
Functional defects
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Difficulty in studying reproductive toxicity in
women
◦ nature of the female cycle
◦ relative frequency spontaneous abortions
◦ common occurrence of birth defects in general
population
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Adverse Female Reproductive Effects
 Infertility:
 Mens
 LBW
dis:
(< 2500 gr):
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
Birth defects:

Preterm (<37wk):

SAB (fetal loss 20 wk ):
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