Renal toxicology

By : Dr ASLANIOCCUPATIONAL MEDICINE

SPECIALIST

PHYSIOLOGY

Regulation of electrolytes

Maintenance of acid-base balance

Regulation of BP

Remove wastes from the blood

Reabsorption of H2O,G,AA

Produce hormones

Function

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.

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

Clinical history

Exposure histories: ◦Frequency◦Intensity◦Personal protection

Clinical history & physical examinationFactors that enhancing

nephrotoxicity:◦Age◦Genetic◦HTN◦Diabetes◦Gout◦Pre-exiting chronic renal disease

Hematuria :

1. Urinary tract cancer

2. Papillary necrosis

3. GN

Proteinuria:

1. HMW Proteinuria (albuminuria)

2. LMW proteinuria (β2-microglobulin & RBP)

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)

Limitations unstable at certain urine pHsreturn to normal levels despite renal

damagelarge inter-individual variationspredictive value of these newer

tests has not been validated.

Clinical presentation Acute renal failure: ATN

Chronic renal failure: Chronic interstitial

nephritis

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.

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

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

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

ARF caused by organic solvents

Route of absorption: lungs (most common), skin

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 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

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

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

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,…

Diagnosis :Measuring blood lead level

EDTA lead mobilization test

Tibial K x-ray fluorescence correlate with bone lead

Cont,…

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

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,…

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,…

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 proteinuriaurinary calculimultiple tubular abnormalitiesCd urine >10 µg/g

Treatment :except removal from the

exposure treatment of osteomalacia

Cont,…

Chronic kidney diseases caused by mercuryExp: Inhalational of Metal fume & ingestion1- ATN 2-Nephrotic syndrome

mercury exposure:Membranous nephropathyminimal-change diseaseanti-GBM

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,…

Beryllium

Exposure: manufacture of electronic tubesfluorescent light bulbsmetal foundries

Absorption: inhalation

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,…

Reproductive Toxicity

Reproductive ToxicityReproductive function

◦Women Who Are Pregnant

◦Women of Child Bearing Age

◦Men

Male:

Spermatogonium

spermatocyte

spermatid mature spermatozoa (3 months)

Hormonal disorder

Hormonal & semen disorder

Oligospermia

Azoospermia

Asthenospermia & teratospermia

Asthenospermia & oligospermia

Adverse Male Reproductive Effects

Female:

Embryonic Fetal

Prenatal death

Major malformation

Minor malformationFunctional defects

1-2w 8w

Difficulty in studying reproductive toxicity in women

◦nature of the female cycle

◦relative frequency spontaneous abortions

◦common occurrence of birth defects in general population

Infertility:

Mens dis:

LBW (< 2500 gr):

Adverse Female Reproductive Effects

Birth defects: Preterm (<37wk):

SAB (fetal loss 20 wk ):

The end