Lecture 8 Toxic Responses in the Kidney 肾

1. Lecture 8Toxic Responses in the Kidney肾

2. Anatomical解剖arrangement and organization of the nephrons肾单位within the kidney • 1 million nephrons in each human kidney • Renal blood flow肾血流量(RBF) • 94% to cortex皮质 • 5% outer medulla髓质 • 1% inner medulla

4. 近端小管 远球小管 肾小球 肾亨利氏环

7. What causes kidney stones? Kidney stones form when there is a decrease inurine volume and/or an excess of stone-forming substances in the urine. The most common type of kidney stone contains calcium in combination with either oxalate or phosphate. Dehydration脱水from reduced fluid intake or strenuous exercise剧烈运动without adequate fluid replacement increases the risk of kidney stones. High sugar or salt diets. Kidney stones can also result from infection in the urinary tract尿道感染; these are known as struvite or infection stones.

8. Three Basic functions of the nephron • Filtration过滤at the glomerulus 肾小球 • Tubular reabsorption肾小管重吸收 • Tubular secretion肾小管分泌 • Amount excreted in urine = amount filtered + reabsorbed + secreted by tubules

9. Organization of the Glomerulus • Solute up to 10000 M.W. pass through the filter freely • Diffusion is restricted and ceases around 70000 M.W. to 100000 M.W. • For creatinine肌氨酸酐P x GFR = UV P: [Plasma], U: [Urine] V: volume of urine GFR=glomerulus filtration rate肾小球滤过率

10. Tubular reabsorption肾小管重吸收 • Urea尿素 • Only 30-70% of the filtered load is excreted • Glucose • All are reabsorbed • Calcium • 60% of the filtered (ionized form) is reabsorbed • Phosphate – 95% reabsorbed • Uric acid尿酸– mostly reabsorbed • Amino acids – 98% reabsorbed

11. Tubular secretion肾小管分泌 • Foreign substances • Secretion is active, show saturation kinetics • Physiological substances • Metabolic end-products

12. Major transport mechanisms for solutes and water across the renal proximal tubules肾近端小管 • 2/3 of the filtered water and sodium are reabsorbed per minute • Amount reabsorbed are influenced by the balance of hydrostatic and osmotic forces in the peritubular capillaries肾小管周围毛细血管. •  colloid osmotic胶体渗透压 or  hydrostatic pressures水压力 in peritubular capillaries   reabsorption

13. Loops of Henle肾亨利氏环 • Run deep into the medulla passing through a region of increasing osmolality渗透压. • Thin ascending limb升支 • Impermeable to water, highly permeable to Sodium and chloride and moderately permeable to urea • NaCl diffuses from tubules back to cortex • Thick ascending limb • Distal tubules远球小管

14. Major transport pathways in the thick ascending limb of the loop of Henle • Reabsorb NaCl from the tubular fluid by energy-dependent process • Impermeable to water • Luminal fluid becomes hypo-osmotic

15. Distal tubules远球小管 • NaCl is reabsorbed • Early part is impermeable to water • Permeability of the last part is determined by ADH (antidiuretic hormone抗利尿激素)

16. Effects of Nephrotoxins肾毒素 • Act on the vascular elements or portion of nephron • Vasoconstriction血管收缩and ischemia缺血 • Decreased glomerular filtration and tubular transport • Affect the glomerulus directly  flitration dysfunction功能障碍 • Affect tubular activities

17. Nephrotoxins on kidney function • Acute toxicity  alter renal function extensively • If it is sublethal亚致死and of short duration  recovery复苏to normal function rapidly • Chronic low dose over long period  extensive renal damage • Marked changes in renal function may not be detected due to the compensatory capacity代偿能力of the kidney.

18. Common examples of nephrotoxins Heavy metals such as lead, mercury, cadmium, and arsenic; exposure to these metals is most often occupational environments. Nonsteroidal anti-infalmmatory drugs (NSAIDS非甾体类抗炎药物) such as ibuprofen布洛芬(抗炎、镇痛药), naproxen萘普生, and ketoprofen酮洛芬possibly acetaminophen. Certain antibiotic medications, notably streptomycin链霉素and gentamicin庆大霉素. Organic solvents such as benzene.

19. Heavy Metals • Exposure to most heavy metals  renal toxicity • Necrotic坏死的proximal tubules containing proteinaceous蛋白质casts • Ischemia produced by vasoconstriction   GFR •  dose  renal failure, renal necrosis,  BUN (Blood urea nitrogen), death • Protective mechanism against low-dose heavy-metal toxicity was exhausted  cellular damage

20. Heavy Metal (II) • Mercury • Elemental, inorganic and organic mercury are nephrotoxic • Low dose  affect proximal tubule  secret organic ions • Platinum • A complication of cisplatin (an antitumor drug) therapy • Damage to proximal tubule, ion loss  not able to produce concentrated urine • Alter GFR, affect distal tubule and collecting duct functions

21. Heavy Metals (III) • Cadmium • Toxicity   synthesis of metal binding protein metallothionein in liver • The complex  toxicity to other organs but  nephrotoxicity • Toxicity is localized to proximal tubule   reabsorption, ion loss (phosphate) • Presence of low and high M.W. proteins in urine (GFR defects) • Other Metals • Toxicity observed for chromium (potassium dichromate), arsenic, gold, iron, antimony, thallium and lead

22. Halogenated Hydrocarbons卤化烃 • Both hepatotoxic肝毒性and nephrotoxic • Nephrotoxic metabolites produced • Directly by the kidney • Produced in the liver and transported to the kidney • Non-nephrotoxic metabolite produced in the liver then transported to the kidney  further biotransformation  nephrotoxin

23. Carbon Tetrachloride四氯化碳and Chloroform氯仿 • Damage primarily to proximal tubules, secondarily to the entire nephron • Proximal tubular necrosis • Glucosurea, aminoacidurea, proteinurea and  secretion of organic ions • Glomerular or distal tubular functions are not apparently affected • At high dose  renal necrosis, renal failure,  BUN, dealth

24. Hexachlorobutadiene六氯丁二烯 • Widespread environmental pollutant • Potent nephrotoxic with little hepatic toxicity • Low dose  affect proximal tubules • Failure to reabsorb tubular filtrate (glucosurea, proteinurea, aminoacidurea) •  secretion of organic ions • Necrotic proximal tubules • High dose  renal failure, renal necrosis,  BUN, death

25. Other halogenated hydrocarbons • Bromobenzene • Hepatoxic and nephrotoxic • Nephrotoxic metabolites from liver  to kidney  damage the kidney tissue directly • 2-Bromoethylamine (BEA) • Necrosis of loop of Henle and collecting duct • Sclerosis of juxtamedullary glomeruli and urinary concentration defects • Methoxyflurane • Produce medullary necrosis and renal failure • Not able to produce concentrated urine, ion loss,  BUN and renal failure

26. Analgesics止痛药 • In humans, chronic ingestion of high doses of analgesics (aspirin阿司匹林, phenacetin非那西丁, acetaminophen对乙酰氨基酚)  medullary interstitial inflammation, fibrosis, renal failure. • Vasoconstriction of the vasa recta直小血管  ischemic medullary damage • Neprotoxic metabolites produced by liver  transport to kidney  cortical tissue damage

27. Antibiotics抗生素 • Certain antibiotics (neomycin, gentamicin, tobramycin, netilmicin, kanamycin, amikacin and streptomycin) possess aminoglycoside side chains  nephrotoxic • Damage primarily at the proximal convoluted tubule and glomerulus. • Changes in the endothelial pore size  filtration dysfunction • Tetracyclines四环素 medullary toxins • Failure to produce concentrated urine • Glucosuria糖尿, aminoaciduria氨基酸尿, proteinuria蛋白尿

28. Environment contaminants • Herbicides除草剂 • Affect renal capacity to secrete organic ions • Polychlorinated Biphenyls多氯联苯(PCB) and Polybrominated Biphenyls多溴联苯(PBB) • Enhance drug metabolizing enzyme systems in kidneys  potential hazard • Tetrachlorodibenzo--dioxin二恶英(TCDD) • Enhance renal drug metabolizing enzymes, but no direct effect on the kidneys shown • Mycotoxins霉菌毒素 • In contaminated animal and human foods  proximal tubular dysfunction and organic ion transport