Download - Lecture 8 Toxic Responses in the Kidney 肾
Lecture 8
Toxic Responses in the Kidney 肾
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
肾小球
肾亨利氏环
近端小管
远球小管
What causes kidney stones?
Kidney stones form when there is a decrease in urine 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.
Three Basic functions of the nephron
1. Filtration 过滤 at the glo
merulus 肾小球 2. Tubular reabsorption 肾
小管重吸收 3. Tubular secretion 肾小管
分泌
• Amount excreted in urine = amount filtered + reabsorbed + secreted by tubules
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
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
Tubular secretion 肾小管分泌 • Foreign substances
– Secretion is active, show saturation kinetics
• Physiological substances– Metabolic end-products
Major transport mechanisms for solutes and water across the renal proximal tubules 肾近
端小管 • 2/3 of the filtered water a
nd 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
Loops of Henle 肾亨利氏环 • Run deep into the medulla passing through a reg
ion 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
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
Distal tubules 远球小管 • NaCl is reabsorbed• Early part is impermea
ble to water• Permeability of the last
part is determined by ADH (antidiuretic hormone 抗利尿激素 )
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 tra
nsport– Affect the glomerulus directly flitration dysf
unction 功能障碍 – Affect tubular activities
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.
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.
Heavy Metals
• Exposure to most heavy metals renal toxicity– Necrotic 坏死的 proximal tubules containing proteina
ceous 蛋白质 casts
– Ischemia produced by vasoconstriction GFR dose renal failure, renal necrosis, BUN (Blood u
rea nitrogen), death
• Protective mechanism against low-dose heavy-metal toxicity was exhausted cellular damage
Heavy Metal (II)
• Mercury– Elemental, inorganic and organic mercury are nephrot
oxic– Low dose affect proximal tubule secret organic io
ns
• Platinum– A complication of cisplatin (an antitumor drug) therapy– Damage to proximal tubule, ion loss not able to pro
duce concentrated urine– Alter GFR, affect distal tubule and collecting duct func
tions
Heavy Metals (III)
• Cadmium– Toxicity synthesis of metal binding protein metallo
thionein in liver– The complex toxicity to other organs but nephrotox
icity– Toxicity is localized to proximal tubule reabsorptio
n, 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
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 ki
dney– Non-nephrotoxic metabolite produced in the li
ver then transported to the kidney further biotransformation nephrotoxin
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
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
Other halogenated hydrocarbons
• Bromobenzene– Hepatoxic and nephrotoxic– Nephrotoxic metabolites from liver to kidney da
mage the kidney tissue directly• 2-Bromoethylamine (BEA)
– Necrosis of loop of Henle and collecting duct– Sclerosis of juxtamedullary glomeruli and urinary conc
entration defects• Methoxyflurane
– Produce medullary necrosis and renal failure– Not able to produce concentrated urine, ion loss, BU
N and renal failure
Analgesics 止痛药 • In humans, chronic ingestion of high doses of anal
gesics (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
Antibiotics 抗生素 • Certain antibiotics (neomycin, gentamicin, tobra
mycin, netilmicin, kanamycin, amikacin and streptomycin) possess aminoglycoside side chains nephrotoxic– Damage primarily at the proximal convoluted tubule a
nd glomerulus.– Changes in the endothelial pore size filtration dysfu
nction• Tetracyclines 四环素 medullary toxins
– Failure to produce concentrated urine– Glucosuria 糖尿 , aminoaciduria 氨基酸尿 , protein
uria 蛋白尿
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 poten
tial hazard
• Tetrachlorodibenzo--dioxin 二恶英 (TCDD)– Enhance renal drug metabolizing enzymes, but no direct effect o
n the kidneys shown
• Mycotoxins 霉菌毒素 – In contaminated animal and human foods proximal tubular dy
sfunction and organic ion transport