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