renal toxicology. physiology regulation of electrolytes maintenance of acid-base balance ...
TRANSCRIPT
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Renal toxicology
By : Dr ASLANIOCCUPATIONAL MEDICINE
SPECIALIST
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PHYSIOLOGY
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Regulation of electrolytes
Maintenance of acid-base balance
Regulation of BP
Remove wastes from the blood
Reabsorption of H2O,G,AA
Produce hormones
Function
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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. Duration1. Acute(Weeks)2. Chronic(Years)
II. Location1. Glomerular2. Non-glomerular(tubular , interstitial)
The most common site of injury for toxicants is the proximal tubule.
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Diagnosis HistoryPhysical examinationClinical presentation of the renal
disease
Monitoring of exposed workers:lack of sensitive and specific testsSerial measurement Cr & BUN
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Clinical history
Exposure histories: ◦Frequency◦Intensity◦Personal protection
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Clinical history & physical examinationFactors that enhancing
nephrotoxicity:◦Age◦Genetic◦HTN◦Diabetes◦Gout◦Pre-exiting chronic renal disease
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Hematuria :
1. Urinary tract cancer
2. Papillary necrosis
3. GN
Proteinuria:
1. HMW Proteinuria (albuminuria)
2. 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 pHsreturn to normal levels despite renal
damagelarge inter-individual variationspredictive 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 dysfunctionUsually 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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ATNHours 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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ATNTreatment
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 & vanadiumExposure: 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 Arsinesemiconductor industry
Primarily hemotoxic Firs sign immediately or after a delay up to
24h:malaise, abd cramps, nausea, vomitingRF due to ATN secondary to hemoglobinuria
Hydration, manitolExchange 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%) & kidneys
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 4-alteration in RAA axis
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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
Renal biopsy :tubular atrophy, interstitial fibrosis, and minimal inflammatory infiltrates.
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,…
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Diagnosis :Measuring blood lead level
EDTA lead mobilization test
Tibial K x-ray fluorescence correlate with bone lead
Cont,…
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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 (1/3)
Cd is a contaminant of tobacco smoke.
Only 25% of ingested Cd is absorbed.
Chronic kidney diseases caused by cadmium
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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.
The adverse effects of Cd on the Prox.T:Unbound Cd, that interfere with zinc-
dependent enzymes.
Cont,…
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Target organs : kidney & lung
fanconi syndromeHypercalciuria with normocalcemia,
hyperphosphaturia→ osteomalacia, pseudofx, nephrolithiasis
Uretral colic from calculi in 40%Itai-itai dx : painful bone dx with
pseudofx in japan
Cont,…
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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,…
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Renal cadmium toxicity low-molecular-weight proteinuriaurinary calculimultiple tubular abnormalitiesCd urine >10 µg/g
Treatment :except removal from the
exposure treatment of osteomalacia
Cont,…
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Chronic kidney diseases caused by mercuryExp: Inhalational of Metal fume & ingestion1- ATN 2-Nephrotic syndrome
mercury exposure:Membranous nephropathyminimal-change diseaseanti-GBM
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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.
Cont,…
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Beryllium
Exposure: manufacture of electronic tubesfluorescent light bulbsmetal foundries
Absorption: inhalation
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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,
Cont,…
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Reproductive Toxicity
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Reproductive ToxicityReproductive function
◦Women Who Are Pregnant
◦Women of Child Bearing Age
◦Men
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Male:
Spermatogonium
spermatocyte
spermatid mature spermatozoa (3 months)
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Hormonal disorder
Hormonal & semen disorder
Oligospermia
Azoospermia
Asthenospermia & teratospermia
Asthenospermia & oligospermia
Adverse Male Reproductive Effects
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Female:
Embryonic Fetal
Prenatal death
Major malformation
Minor malformationFunctional defects
1-2w 8w
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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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Infertility:
Mens dis:
LBW (< 2500 gr):
Adverse Female Reproductive Effects
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Birth defects: Preterm (<37wk):
SAB (fetal loss 20 wk ):
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The end