1. OCCUPATIONAL MEDICINE SPECIALIST
Renal toxicology
By : Dr ASLANI
OCCUPATIONAL MEDICINE SPECIALIST

2. PHYSIOLOGY

3. Function Regulation of electrolytes Maintenance of acid-base balance
Regulation of BP
Remove wastes from the blood
Reabsorption of H2O,G,AA
Produce hormones

4. 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.

5. Kidney Diseases Duration Acute(Weeks) Chronic(Years) Location
Glomerular
Non-glomerular(tubular , interstitial)
The most common site of injury for toxicants is the proximal tubule.

6. Diagnosis History Physical examination
Clinical presentation of the renal disease
Monitoring of exposed workers:
lack of sensitive and specific tests
Serial measurement Cr & BUN

7. Clinical history Exposure histories: Frequency Intensity
Personal protection

8. Clinical history & physical examination
Factors that enhancing nephrotoxicity:
Age
Genetic
HTN
Diabetes
Gout
Pre-exiting chronic renal disease

9. Hematuria : Proteinuria: Papillary necrosis GN
Urinary tract cancer
Papillary necrosis GN
Proteinuria:
HMW Proteinuria (albuminuria)
LMW proteinuria (β2-microglobulin & RBP)

10. 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)

12. 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.

13. Clinical presentation
Acute renal failure:
ATN
Chronic renal failure:
Chronic interstitial nephritis

14. 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.

15. 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

16. 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
For these techniques to be effective, tox­ins must have a low apparent volume of distribution and molecular weight, a low affinity for plasma proteins, and low tissue-binding properties. For example, charcoal
hemoperfiision can result in almost complete removal of circulating paraquat, but because of high tissue binding, only small amounts of total-body paraquat are removed. Consequendy, hemoperfiision does not affect the progno­sis in paraquat poisoning.

17. 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

18. ARF caused by organic solvents
Route of absorption: lungs (most common), skin
Lipophilic & distribute in: fat, liver, BM, blood, brain & kidney

19. Organic solvents A) halogenated Hydrocarbons
carbon tetrachloride (CCL4):
- Acute exposure:
- CNS GI
-after 7-10d :↓urine output, prerenal azotemia
Ccl4:Household cleaning, fire extinguishing(pyeren)
Irritation mucous,several days symptom free then acute abdoman.

20. 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
1. As solvents for oils, waxes, rubber & resines, as insecticide & fumigant, in fire extinguishers & household cleaning fluids
3. Anesthetic agent
5. It is far more toxic than any of the other aliphatic haloge­nated hydrocarbons

21. 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
Vapor pressure is low : respiratory overexp is rare. --insidious toxicity by large amount inhalation without warning
--hours after exposure → acute abdoman,anorexia, nausea, vomiting, jaundice (uncommon), ↓ urine output on 3th day
2. Metabolic acidosis, hippuric acid production, net acid excretion, k, Na –
3. with resulting symptoms of headache, drowsiness, weakness, slurred speech, staggering gait, and blurred vision. The renal injury caused by these ethers is not related to the oxalic aciduria
4. albumin,RBC, cast urine.+ GI, headache, vertigo, hypothermia , convulsion, phenol:::hydroquinone:::oxidized to colored substance(carboluria) Prolonged exp: pr uria,
5- hyperpyrexia, vascular collapse, subtoxic: reversible prox.T , phosphatouria
6- Dinitrophenol:Renal faiure: direct effect agent or metabolic disorder
--metabolic acidosis in abusers due to a) overproduction of hyppuric acid & b) ↓excretion of net acid (NH4+)
-- Na & K depletion
--may resemble an acute abd emergency

22. ARF caused by Arsine semiconductor industry Primarily hemotoxic
Firs 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

23. 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
Organic lead is not nephrotoxic, but its combustion products are.

24. Cont,… Mechanisms of gout : Mechanisms of HTN: acute lead intoxication
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
50% lead nephropathy had gout.
Lead cause gout & RF both.

25. 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
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.
proteinuria (1+,2+), without cells or cellular casts.

26. Cont,… Diagnosis : Measuring blood lead level
EDTA lead mobilization test
Tibial K x-ray fluorescence correlate with bone lead

27. 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 (1/3)
Cd is a contaminant of tobacco smoke.
Only 25% of ingested Cd is absorbed.

28. 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.
low-molecular-weight polypeptide.

29. 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

30. 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

31. 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

32. 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
occupational studies have not been able to find an association between mercury exposure and proteinuria.

33. 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.
In severe cases of mercury toxicity with anuric renal failure, the use of hemodialysis with the prefilter infusion of DMSA has been reported to increase the removal of inorganic mercury.

34. Beryllium Exposure: manufacture of electronic tubes
fluorescent light bulbs
metal foundries
Absorption:
inhalation
through the gut is very poor

35. 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,
increased calcium absorption through the gut similar to that encountered in sarcoidosis

36. Reproductive Toxicity

37. Reproductive Toxicity
Reproductive function
Women Who Are Pregnant
Women of Child Bearing Age
Men

38. Male: Spermatogonium spermatocyte
spermatid mature spermatozoa (3 months)

39. Adverse Male Reproductive Effects
Hormonal disorder
Hormonal & semen disorder
Oligospermia
Azoospermia
Asthenospermia & teratospermia
Asthenospermia & oligospermia

40. Female: Embryonic Fetal 8w 1-2w Minor malformation Major Prenatal
Functional defects
Major
malformation
Prenatal
death

41. Difficulty in studying reproductive toxicity in women
nature of the female cycle
relative frequency spontaneous abortions
common occurrence of birth defects in general population

42. Adverse Female Reproductive Effects
Infertility:
Mens dis:
LBW (< 2500 gr):

43. Birth defects:
Preterm (<37wk):
SAB (fetal loss 20 wk ):

46. The end