Renal toxicology By : Dr ASLANI - PowerPoint Presentation

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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 balanceRegulation of BP Remove wastes from the bloodReabsorption 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

DurationAcute(Weeks)Chronic(Years)LocationGlomerular

Non-

glomerular

(tubular , interstitial)

The most common site of injury for toxicants is the proximal tubule.

Aghaee2a@gmail.com

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Diagnosis

HistoryPhysical examinationClinical presentation of the renal diseaseMonitoring of exposed workers:lack of sensitive and specific testsSerial measurement Cr & BUN

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Clinical history

Exposure histories: FrequencyIntensityPersonal protection

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Clinical history & physical examination

Factors that enhancing nephrotoxicity:AgeGeneticHTNDiabetesGoutPre-exiting chronic renal disease

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Hematuria

: Urinary tract cancerPapillary necrosis

GN

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 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: ATNChronic renal failure: Chronic interstitial nephritis

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Acute renal dysfunction

Usually after high-dose exposurerenal lesion : ATNextra renal manifestations usually dominateclinical 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: NegBUN ,Cr and electrolyte abnormalities After 1-2 weeks: diuresis

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ATN

TreatmentHemodialysis 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 metalsDivalent metals, Cr, Cd, Hg & vanadiumExposure: welding cadmium-plated metalsExposure 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 solventsRoute of absorption: lungs (most common), skinLipophilic & distribute in: fat, liver, BM, blood, brain & kidney

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Organic

solventsA) 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 agent4-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 hydrocarbons2 -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 industryPrimarily hemotoxic Firs sign immediately or after a delay up to 24h:malaise, abd cramps, nausea, vomitingRF due to ATN secondary to hemoglobinuriaHydration, 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 gasolineAbsorbed by GI (adults:10% , children:50%) & lungsConcentrated 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 crystalsMechanisms 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 kidneysRenal 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 levelEDTA lead mobilization testTibial K x-ray fluorescence correlate with bone leadCont,…

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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, nephrolithiasisUretral colic from calculi in 40%Itai-itai dx : painful bone dx with pseudofx in japanCont,…

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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 DCont,…

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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 osteomalaciaCont,…

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Chronic kidney diseases caused by mercury

Exp: Inhalational of Metal fume & ingestion1- ATN 2-Nephrotic syndromemercury exposure:Membranous nephropathyminimal-change diseaseanti-GBM

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Clinical presentation of ATN: extrarenal manifestations Dx

: history of exposureglomerular 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 foundriesAbsorption: 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 Toxicity

Reproductive functionWomen Who Are PregnantWomen of Child Bearing AgeMen

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Male:

Spermatogonium spermatocyte spermatid mature spermatozoa (3 months)

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Hormonal disorder

Hormonal & semen disorderOligospermia

Azoospermia

Asthenospermia

&

teratospermia

Asthenospermia

&

oligospermia

Adverse Male Reproductive

Effects

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Female:

Embryonic

Fetal

Prenatal

death

Major

malformation

Minor malformation

Functional defects

1-2w

8w

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Difficulty in studying

reproductive toxicity in womennature of the female cyclerelative 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