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Renal toxicology

Renal toxicology. By : Dr ASLANI OCCUPATIONAL MEDICINE SPECIALIST. PHYSIOLOGY. Function. Regulation of electrolytes Maintenance of acid-base balance Regulation of BP Remove wastes from the blood Reabsorption of H2O,G,AA Produce hormones. Introduction.

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Renal toxicology

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  1. 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. Aghaee2a@gmail.com

  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: • 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)

  11. 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.

  12. Clinical presentation • Acute renal failure: ATN • Chronic renal failure: Chronic interstitial nephritis

  13. 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.

  14. 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

  15. 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

  16. 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

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

  18. Organic solvents A) halogenated Hydrocarbons carbon tetrachloride (CCL4): - Acute exposure: - CNS GI -after 7-10d :↓urine output, prerenalazotemia

  19. 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

  20. 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

  21. 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

  22. 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

  23. Cont,… • Mechanisms of gout : 1-↓urine clearance of uric acid 2- crystallization at low urate concentration 3- lead-induced formation of guanine crystals • Mechanisms ofHTN: • acute lead intoxication 1-↑ intracellular Ca 2-inhibition Na+,K+ ATPase 3-direct vasoconstriction 4-alteration in RAA axis

  24. 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 : • intranuclearinclusion bodies usually are present in the early stages of lead exposure but often are absent after chronic exposure or after lead chelation.

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

  26. 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.

  27. 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.

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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.

  33. Beryllium Exposure: • manufacture of electronic tubes • fluorescent light bulbs • metal foundries Absorption: • inhalation

  34. 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,

  35. Reproductive Toxicity

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

  37. Male: Spermatogoniumspermatocyte spermatid mature spermatozoa (3 months)

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

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

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

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

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

  43. Theend

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