Download 远球小管

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
近端小管
远球小管
肾小球
肾亨利氏环
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
glomerulus 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
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
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
Major transport pathways in the thick
ascending limb of the loop of Henle
• Reabsorb NaCl
from the tubular
fluid by energydependent process
• Impermeable to
water
• Luminal fluid
becomes hypoosmotic
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)
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
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
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 heavymetal toxicity was exhausted  cellular damage
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
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
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
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 
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
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
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
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