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1 دکتر رامازینی در سال 1633میالدی در ایتالیا بدنیا آمد و بعلت خدمات ارزنده اش در طب کاربعنوان (( پدر طب کار)) نامیده شد. او نخستین فردی است که به پزشکان توصیه کرد : درضمن پرسشهای خود ازبیمار،شغل او را نیزمورد پرسش قراردهند،زیرااومعتقدبود که ممکن است ارتباطی نزدیک بین شغل فرد و بیماری وی وجود داشته باشد 2 Renal toxicology By:Dr.Bahrami Occupational Medicine specialist 95اذر 3 PHYSIOLOGY 4 Function Regulation of electrolytes Maintenance of acid-base balance Regulation of BP Remove wastes from the blood Reabsorption of H2O,G,AA Produce hormones 5 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. 6 Kidney Diseases I. 1. 2. II. 1. 2. Duration Acute(Weeks) Chronic(Years) Location Glomerular Non-glomerular(tubular , interstitial) most common site of injury for toxicants is the proximal tubule 7 Diagnosis History Physical examination Clinical presentation of the renal disease Monitoring of exposed workers: lack of sensitive and specific tests Serial measurement Cr & BUN 8 Clinical history Exposure histories: ◦ Frequency ◦ Intensity ◦ Personal protection 9 Clinical history & physical examination Factors that enhancing nephrotoxicity: ◦ ◦ ◦ ◦ ◦ ◦ Age Genetic(G6PD) HTN Diabetes Gout Pre-exiting chronic renal disease 10 Hematuria : 1. Urinary tract cancer 2. Papillary necrosis 3. GN 1. 2. Proteinuria: HMW Proteinuria (albuminuria) LMW proteinuria (β2-microglobulin & RBP) 11 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 13 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. 14 Clinical presentation Acute renal failure: ATN Chronic renal failure: Chronic interstitial nephritis 15 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. 16 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 17 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 18 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 19 ARF caused by organic solvents Route of absorption: lungs (most common), skin Lipophilic & distribute in: fat, liver, BM, blood, brain & kidney 20 Organic solvents A) halogenated Hydrocarbons carbon tetrachloride (CCL4): - Acute exposure: - CNS GI -after 7-10d :↓urine output, prerenal azotemia 21 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 22 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 23 ARF caused by Arsine semiconductor industry Primarily hemotoxic First 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 24 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%) & kidney Chronic lead exposure→ ( fanconi-type syndrome) After 5-30y : progressive tubular atrophy & interstitial fibrosis 25 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 26 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 27 Cont,… Diagnosis : Measuring blood lead level EDTA lead mobilization test Tibial K x-ray fluorescence correlate with bone lead 28 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 Cd is a contaminant of tobacco smoke. Only 25% of ingested Cd is absorbed. 29 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. 30 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 31 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 32 Cont,… Renal cadmium toxicity low-molecular-weight proteinuria urinary calculi multiple tubular abnormalities Cd urine >10 µg/gcr Treatment : except removal from the exposure treatment of osteomalacia 33 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 34 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. 35 Beryllium Exposure: manufacture of electronic tubes fluorescent light bulbs metal foundries Absorption: inhalation 36 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, 37 Reproductive Toxicity 38 Reproductive Toxicity Reproductive function ◦ Women Who Are Pregnant ◦ Women of Child Bearing Age ◦ Men 39 Male: Spermatogonium spermatid spermatocyte mature spermatozoa (3 m) 40 Adverse Male Reproductive Effects Hormonal disorder Hormonal & semen disorder Oligospermia Azoospermia Asthenospermia & teratospermia Asthenospermia & oligospermia 41 Female: Embryonic 1-2w Prenatal death Fetal 8w Major malformation Minor malformation Functional defects 42 Difficulty in studying reproductive toxicity in women ◦ nature of the female cycle ◦ relative frequency spontaneous abortions ◦ common occurrence of birth defects in general population 43 Adverse Female Reproductive Effects Infertility: Mens LBW dis: (< 2500 gr): 44 Birth defects: Preterm (<37wk): SAB (fetal loss 20 wk ): 45 46 47 48