三聚氰胺（酸）对肾脏毒性的动物实验及干预研究
摘要
背景:三聚氰胺(Melamine)是一种三嗪类含氮杂环有机化合物,是重要的有机化工原料。2007年3月至今,美国发生4 000多起猫、狗等宠物中毒死亡事件。美国食品药品管理局调查显示,在回收的宠物食品、死亡动物的尿液结晶和肾脏细胞中都发现有三聚氰胺和三聚氰酸。加拿大安大略省圭尔夫大学(University of Guelph)的研究发现,三聚氰胺和三聚氰酸反应会产生影响肾脏功能的结晶。2008年我国三聚氰胺污染奶粉导致重大公共卫生安全事件,引起国内外广泛关注;婴幼儿进食污染奶粉后发生泌尿系统结石,并导致肾功能损害,严重病例最终导致肾衰或死亡。除了奶粉外,糖果、饼干、鸡蛋等食品也受到三聚氰胺污染的报道。进一步研究发现三聚氰胺遇强酸或强碱时水解,胺基逐步被羟基取代,首先生成三聚氰酸二酰胺,再水解生成三聚氰酸一酰胺,最后水解成三聚氰酸。三聚氰酸也属于三嗪类含氮杂环有机化合物,结构与三聚氰胺相似,是三聚氰胺的衍生物;常用于除草剂、染料、树脂、水池消毒剂等,渗透于人们日常生活和工作。目前,有关三聚氰胺、三聚氰酸、三聚氰胺-三聚氰酸对肾脏的毒性作用和可能的远期并发症尚无深入研究,亦缺乏安全有效的干预措施。
目的:研究三聚氰胺(酸)作用于新生SD大鼠和成年SD大鼠后急、慢性毒性反应,探讨三聚氰胺(酸)对幼年SD大鼠和成年SD大鼠肾脏的损害情况,并对其损害作用进行干预研究。
方法:选取21窝7日龄新生SD大鼠、8窝20日龄幼年SD大鼠和132只成年SD大鼠。将21窝7日龄新生SD大鼠和84只成年大鼠分别随机分为三聚氰胺高剂量组(NM,M),三聚氰胺低剂量组(Nm,m),三聚氰酸高剂量组(NA,A),三聚氰酸低剂量组(Na,a),三聚氰胺-三聚氰酸高剂量组(NMA,MA),三聚氰胺-三聚氰酸低剂量组(Nma,ma)和正常对照组(NN,N);每天给予相应剂量三聚氰胺(酸)灌胃。8窝20日龄幼年SD大鼠和48只成年大鼠分别分为:三聚氰胺-三聚氰酸加金钱草干预组(a,A),三聚氰胺-三聚氰酸加枸橼酸干预组(b,B),三聚氰胺-三聚氰酸加碳酸氢钠干预组(c,C),三聚氰胺-三聚氰酸加自来水组(d,D),三聚氰胺-三聚氰酸自然恢复组(e,E),正常对照组(f,F),其中自然恢复新生组大鼠3窝,自然恢复成年组大鼠18只,a组、A组、b组、B组、c组、C组、d组、D组、f组和F组随机均分。
各实验组分别于灌胃第3天,15天,60天随机处死各剂量组相同数量的大鼠,称取体重、肝、肾重量,并检测血液常规生化指标;观察肝肾脏组织学变化。各干预组于灌胃第30天处死,自然恢复组分别于灌胃后第15天、30天、60天处死相同数量的大鼠;称取体重、肾重量,检测血液常规生化指标;观测肾脏组织学变化。肾脏晶体沉积程度分为阴性(—),弱阳性(+),阳性(++),强阳性(+++)。电镜观察各组肾单位表现。
结果:NN组、Nm组、NM组、Na组、NA组新生鼠体重逐渐增加;NMA组和Nma组体重先增加,然后减轻。N、m、M、a、A组成年鼠体重先增加,然后维持在一个水平,其中M组在近60天时体重逐渐下降;MA组和ma组体重持续减轻。解剖显微镜显示肾脏晶体沉积程度:NM组在60天时为(+);Nm组、NA组、Na组在3天、15天和60天均为(–);NMA组在3天为(+),15天为(++),40天(+++);Nma组在3天和15天均为(–),60天为(++); M组3天为(–),15天为(+),60天为(+++);m组3天和15天均为(–),60天为(+);A组3天和15天均为(—),60天为(++);a组3天和15天均为(—),60天为(+);MA组3天和15天均为(+++);ma组3天为(++),15天为(+++);N组3天、15天和60天均为(–)。电镜观察到含结石的肾小管出现微绒毛减少或消失、粒细胞浸润等炎性反应。NM组、MA组、NMA组、Nma组、M组、A组和ma组随着灌胃时间的延长,肾体重比、尿素氮、肌酐、尿酸值增加;Nm组、NA组、Na组、m组、a组与对照组无差异。各组肝脏HE染色、肝体重比、血谷丙转氨酶值和谷草转氨酶值均无明显异常。
a组、b组、c组、d组、e组、f组、F组体重逐渐增加;A组、B组、C组、D组体重逐渐减少;E组体重先减少后增加。干预组和自然恢复组解剖显微镜显示肾脏晶体程度:b组,c组,d组,e组,f组,F组均为(–);A组为(++);B组为(++);C组为(–);D组为(+);a组为(+);E组15天为(+++),E组30天为(+++),E组60天为(++)。干预组中A组、B组、E组肾体重比明显高于C、D、F组,其中E组随着时间的延长,肾体重比减小。
结论:三聚氰胺(酸)可在大鼠肾脏产生结石,结石产生量与时间、剂量呈正相关;三聚氰胺(酸)可引起血尿素氮、肌酐、尿酸值升高,导致肾功能损害;三聚氰胺(酸)对成年大鼠的毒性大于新生大鼠;三聚氰胺(酸)三聚氰胺毒性大于三聚氰酸;三聚氰胺(酸)混合物毒性大于单体;三聚氰胺(酸)毒性存在个别和窝别差异;三聚氰胺(酸)未见明显肝脏毒性;三聚氰胺(酸)结石可以自行缓慢排出;碱化尿液有助于三聚氰胺(酸)结石排出。
BACKROUND: Melamine is a nitrogen-containing heterocyclic triazine compound. It is an important organic chemical raw material. Since mid-March 2007, More than 4000 cats, dogs and other pet were poisoned by pet food in United States. FDA investigation showed that recall pet food, dead animals, urine crystals and renal cells had found melamine and cyanuric acid. University of Guelph study found that melamine and cyanuric acid could produce crystallization which can damage kidney function. Melamine contaminated milk powder caused a significant public health event which aroused wide attention at home and abroad in China in 2008. The babies and infants who ate contaminated baby milk powder were easy to urinary calculi, renal dysfunction, and severe cases eventually lead to renal failure. Until now besides powdered milk, candy, cookies, eggs and other food products also contaminated by melamine which were reported. Melamine hydrolysis when it meets strong acid or alkali solution, amino is gradually replaced by hydroxy, generate cyanuric acid diamide, further hydrolyzed cyanuric an amide, and finally generate cyanuric acid. Cyanruic acid is a derivate of melamine. It is also a nitrogen-containing heterocyclic triazine compound. It commonly used herbicides, dyes, resins, pool disinfectants, etc and closely linked with people's daily life and work. The melamine, cyanuric acid, melamine-cyanuric acid mechanisms and the possible long-term complications, and there was no safe and effective intervention, in-depth study.
OBJECTIVE: Study the acute, chronic toxicity of melamine (cyanuric acid ) to newborn SD rats, young SD rats and adult rats , see the kidney damage and interfere the damage.
METHOD: 21 broods 7-day-old newborn SD rats, 8 broods 20-day-old young SD rats and 132 adult SD rats were selected. Divided the 21 broods 7-day-old newborn SD newborn rats and 84 adult rats into high dose group of melamine (NM, M), low dose group of melamine (Nm, m), high dose group of cyanuric acid (NA, A), low dose group of cyanuric acid (Na, a), high dose group of melamine-cyanuric acid (NMA, MA), low dose group of melamine-cyanuric acid (Nma, ma) and normal control group (NN, N). The corresponding dose of melamine (cyanuric acid) was given by oral gavage everyday. Divided 8 broods 20-day-old young SD rats and 48 adult SD rats into the group of melamine-cyanuric acid treated with christina loosestrife (a, A), the group of melamine-cyanuric acid treated with citrate (b, B), the group of melamine-cyanuric acid treated with sodium bicarbonate (c, C), the group of melamine-cyanuric acid treated with tap water (d, D), melamine-cyanuric acid spontaneous recovery group (e, E) and normal control group (f, F). The spontaneous recovery group of young rats were 3 broods and adult rats was 18. The a group, A group, b group, B group, c group, C group,d group, D group, f group, F group were divided randomly.
The same number of rats in model groups was killed after intragastric administration 3 days, 15 days and 60 days. The body weight, liver and kidney weight were collected. The convention biochemistry target of blood was examined. The liver and kidney histology change observed. The intervention groups were killed after intragastric administration 30 days. The same number of rats in spontaneous recovery group was killed after intragastric administration 15 days, 30 days and 60 days. The body weight and kindy weight were collected. The convention biochemistry target of blood was examined. The kidney histology change was observed. According to the number of renal calculus, we divided them into negative (–), weakly positive (+), positive (++) and strong positive (+++). Electron microscopy observed each group of rats’renal unit.
RESULT: The body weight of NN group, NM group, Nm group NA group, Na group newborn rats increased continuously. NMA group and Nma group body weight first increased, and then decreased. The body weight of M group, m group, A group, a group adult groups increased gradually, and then maintained at a lever. The body weight of M group began to reduce nearly 60 days. The body weight of MA group and ma group reduced gradually. The number of the model groups’kidney crystal under anatomical microscope was that 3 days of NMA group was (+), 15 days (++), 60 days (+++); Nma group of 3 days and 15 days all were (–), 60 days (+++). NM group of 60 days was (+); the other newborn groups were (–) at each time points; 3 days of M group was (–), 15 days (+), 60 days (+++); m group of 3 days and 15 days were (–), 60 days (+); A group of 3 days and 15 days were (–), 60 days ( ++); a group of 3 days and 15 days were (–), 60 days (+); MA group of 3 days and 15 days were (+++); 3 days of ma group was (++), 15 days (+++); N group was (–). The electron microscope demonstrated that the tubules which contained stones microvilli reduced or disappeared, granulocyte infiltration and other inflammatory response. In the model groups, the kidney weight/body weight, urea nitrogen, creatinine, uric acid value increased in NMA group, Nma group, NM group, MA group, ma group, M group and A group with administration time extension; and the Nm group, NA group, Na group, m group, A group and a group were similar to control group. HE staining of liver, liver weight /body weight, serum alanine aminotransferase and aspartate aminotransferase values were not significantly abnormal in each group.
The body weight of a group, b group, c group, d group, e group, f group increased continuously. The body weight of A, B, C, D group reduced gradually. E group body weight first decreased, and then increased. The body weight of F group increased continuously. The number of the intervention groups’kidney calculus under anatomical microscope was that the a group, b group, c group, d group, e group, f group and F group were (–);A group was (++); B group was (++); C group was (–); D group was (+); E group of 15 days was (+++), 30 days (+++), 60 days (++). A, B, F groups’kidney weight/body weight value was much higher than C, D, E group. The kidney weight/body weight value decreased with time extension.
CONCLUSION: Melamine (cyanuric acid) could produce insoluble calculus in rat kidney and the number of melamine (cyanuric acid) calculus was positively correlated with dose and time. Melamine (cyanuric acid) can cause blood urea nitrogen, creatinine, uric acid levels rise, leading to renal dysfunction. The toxicity of melamine (cyanuric acid) was greater in adult rats than in newborn. The toxicity of melamine was greater than cyanuric acid. Melamine (cyanuric acid) mixture toxicity was greater than the monomer. Melamine (cyanuric acid) toxicity had individual differences and brood diffenences. Melamine (cyanuric acid) did not have significant liver toxicity. Melamine (cyanuric acid) calculus can be discharged slowly. Alkaline urine could help melamine (cyanuric acid) calculus discharged.
目的:研究三聚氰胺(酸)作用于新生SD大鼠和成年SD大鼠后急、慢性毒性反应,探讨三聚氰胺(酸)对幼年SD大鼠和成年SD大鼠肾脏的损害情况,并对其损害作用进行干预研究。
方法:选取21窝7日龄新生SD大鼠、8窝20日龄幼年SD大鼠和132只成年SD大鼠。将21窝7日龄新生SD大鼠和84只成年大鼠分别随机分为三聚氰胺高剂量组(NM,M),三聚氰胺低剂量组(Nm,m),三聚氰酸高剂量组(NA,A),三聚氰酸低剂量组(Na,a),三聚氰胺-三聚氰酸高剂量组(NMA,MA),三聚氰胺-三聚氰酸低剂量组(Nma,ma)和正常对照组(NN,N);每天给予相应剂量三聚氰胺(酸)灌胃。8窝20日龄幼年SD大鼠和48只成年大鼠分别分为:三聚氰胺-三聚氰酸加金钱草干预组(a,A),三聚氰胺-三聚氰酸加枸橼酸干预组(b,B),三聚氰胺-三聚氰酸加碳酸氢钠干预组(c,C),三聚氰胺-三聚氰酸加自来水组(d,D),三聚氰胺-三聚氰酸自然恢复组(e,E),正常对照组(f,F),其中自然恢复新生组大鼠3窝,自然恢复成年组大鼠18只,a组、A组、b组、B组、c组、C组、d组、D组、f组和F组随机均分。
各实验组分别于灌胃第3天,15天,60天随机处死各剂量组相同数量的大鼠,称取体重、肝、肾重量,并检测血液常规生化指标;观察肝肾脏组织学变化。各干预组于灌胃第30天处死,自然恢复组分别于灌胃后第15天、30天、60天处死相同数量的大鼠;称取体重、肾重量,检测血液常规生化指标;观测肾脏组织学变化。肾脏晶体沉积程度分为阴性(—),弱阳性(+),阳性(++),强阳性(+++)。电镜观察各组肾单位表现。
结果:NN组、Nm组、NM组、Na组、NA组新生鼠体重逐渐增加;NMA组和Nma组体重先增加,然后减轻。N、m、M、a、A组成年鼠体重先增加,然后维持在一个水平,其中M组在近60天时体重逐渐下降;MA组和ma组体重持续减轻。解剖显微镜显示肾脏晶体沉积程度:NM组在60天时为(+);Nm组、NA组、Na组在3天、15天和60天均为(–);NMA组在3天为(+),15天为(++),40天(+++);Nma组在3天和15天均为(–),60天为(++); M组3天为(–),15天为(+),60天为(+++);m组3天和15天均为(–),60天为(+);A组3天和15天均为(—),60天为(++);a组3天和15天均为(—),60天为(+);MA组3天和15天均为(+++);ma组3天为(++),15天为(+++);N组3天、15天和60天均为(–)。电镜观察到含结石的肾小管出现微绒毛减少或消失、粒细胞浸润等炎性反应。NM组、MA组、NMA组、Nma组、M组、A组和ma组随着灌胃时间的延长,肾体重比、尿素氮、肌酐、尿酸值增加;Nm组、NA组、Na组、m组、a组与对照组无差异。各组肝脏HE染色、肝体重比、血谷丙转氨酶值和谷草转氨酶值均无明显异常。
a组、b组、c组、d组、e组、f组、F组体重逐渐增加;A组、B组、C组、D组体重逐渐减少;E组体重先减少后增加。干预组和自然恢复组解剖显微镜显示肾脏晶体程度:b组,c组,d组,e组,f组,F组均为(–);A组为(++);B组为(++);C组为(–);D组为(+);a组为(+);E组15天为(+++),E组30天为(+++),E组60天为(++)。干预组中A组、B组、E组肾体重比明显高于C、D、F组,其中E组随着时间的延长,肾体重比减小。
结论:三聚氰胺(酸)可在大鼠肾脏产生结石,结石产生量与时间、剂量呈正相关;三聚氰胺(酸)可引起血尿素氮、肌酐、尿酸值升高,导致肾功能损害;三聚氰胺(酸)对成年大鼠的毒性大于新生大鼠;三聚氰胺(酸)三聚氰胺毒性大于三聚氰酸;三聚氰胺(酸)混合物毒性大于单体;三聚氰胺(酸)毒性存在个别和窝别差异;三聚氰胺(酸)未见明显肝脏毒性;三聚氰胺(酸)结石可以自行缓慢排出;碱化尿液有助于三聚氰胺(酸)结石排出。
BACKROUND: Melamine is a nitrogen-containing heterocyclic triazine compound. It is an important organic chemical raw material. Since mid-March 2007, More than 4000 cats, dogs and other pet were poisoned by pet food in United States. FDA investigation showed that recall pet food, dead animals, urine crystals and renal cells had found melamine and cyanuric acid. University of Guelph study found that melamine and cyanuric acid could produce crystallization which can damage kidney function. Melamine contaminated milk powder caused a significant public health event which aroused wide attention at home and abroad in China in 2008. The babies and infants who ate contaminated baby milk powder were easy to urinary calculi, renal dysfunction, and severe cases eventually lead to renal failure. Until now besides powdered milk, candy, cookies, eggs and other food products also contaminated by melamine which were reported. Melamine hydrolysis when it meets strong acid or alkali solution, amino is gradually replaced by hydroxy, generate cyanuric acid diamide, further hydrolyzed cyanuric an amide, and finally generate cyanuric acid. Cyanruic acid is a derivate of melamine. It is also a nitrogen-containing heterocyclic triazine compound. It commonly used herbicides, dyes, resins, pool disinfectants, etc and closely linked with people's daily life and work. The melamine, cyanuric acid, melamine-cyanuric acid mechanisms and the possible long-term complications, and there was no safe and effective intervention, in-depth study.
OBJECTIVE: Study the acute, chronic toxicity of melamine (cyanuric acid ) to newborn SD rats, young SD rats and adult rats , see the kidney damage and interfere the damage.
METHOD: 21 broods 7-day-old newborn SD rats, 8 broods 20-day-old young SD rats and 132 adult SD rats were selected. Divided the 21 broods 7-day-old newborn SD newborn rats and 84 adult rats into high dose group of melamine (NM, M), low dose group of melamine (Nm, m), high dose group of cyanuric acid (NA, A), low dose group of cyanuric acid (Na, a), high dose group of melamine-cyanuric acid (NMA, MA), low dose group of melamine-cyanuric acid (Nma, ma) and normal control group (NN, N). The corresponding dose of melamine (cyanuric acid) was given by oral gavage everyday. Divided 8 broods 20-day-old young SD rats and 48 adult SD rats into the group of melamine-cyanuric acid treated with christina loosestrife (a, A), the group of melamine-cyanuric acid treated with citrate (b, B), the group of melamine-cyanuric acid treated with sodium bicarbonate (c, C), the group of melamine-cyanuric acid treated with tap water (d, D), melamine-cyanuric acid spontaneous recovery group (e, E) and normal control group (f, F). The spontaneous recovery group of young rats were 3 broods and adult rats was 18. The a group, A group, b group, B group, c group, C group,d group, D group, f group, F group were divided randomly.
The same number of rats in model groups was killed after intragastric administration 3 days, 15 days and 60 days. The body weight, liver and kidney weight were collected. The convention biochemistry target of blood was examined. The liver and kidney histology change observed. The intervention groups were killed after intragastric administration 30 days. The same number of rats in spontaneous recovery group was killed after intragastric administration 15 days, 30 days and 60 days. The body weight and kindy weight were collected. The convention biochemistry target of blood was examined. The kidney histology change was observed. According to the number of renal calculus, we divided them into negative (–), weakly positive (+), positive (++) and strong positive (+++). Electron microscopy observed each group of rats’renal unit.
RESULT: The body weight of NN group, NM group, Nm group NA group, Na group newborn rats increased continuously. NMA group and Nma group body weight first increased, and then decreased. The body weight of M group, m group, A group, a group adult groups increased gradually, and then maintained at a lever. The body weight of M group began to reduce nearly 60 days. The body weight of MA group and ma group reduced gradually. The number of the model groups’kidney crystal under anatomical microscope was that 3 days of NMA group was (+), 15 days (++), 60 days (+++); Nma group of 3 days and 15 days all were (–), 60 days (+++). NM group of 60 days was (+); the other newborn groups were (–) at each time points; 3 days of M group was (–), 15 days (+), 60 days (+++); m group of 3 days and 15 days were (–), 60 days (+); A group of 3 days and 15 days were (–), 60 days ( ++); a group of 3 days and 15 days were (–), 60 days (+); MA group of 3 days and 15 days were (+++); 3 days of ma group was (++), 15 days (+++); N group was (–). The electron microscope demonstrated that the tubules which contained stones microvilli reduced or disappeared, granulocyte infiltration and other inflammatory response. In the model groups, the kidney weight/body weight, urea nitrogen, creatinine, uric acid value increased in NMA group, Nma group, NM group, MA group, ma group, M group and A group with administration time extension; and the Nm group, NA group, Na group, m group, A group and a group were similar to control group. HE staining of liver, liver weight /body weight, serum alanine aminotransferase and aspartate aminotransferase values were not significantly abnormal in each group.
The body weight of a group, b group, c group, d group, e group, f group increased continuously. The body weight of A, B, C, D group reduced gradually. E group body weight first decreased, and then increased. The body weight of F group increased continuously. The number of the intervention groups’kidney calculus under anatomical microscope was that the a group, b group, c group, d group, e group, f group and F group were (–);A group was (++); B group was (++); C group was (–); D group was (+); E group of 15 days was (+++), 30 days (+++), 60 days (++). A, B, F groups’kidney weight/body weight value was much higher than C, D, E group. The kidney weight/body weight value decreased with time extension.
CONCLUSION: Melamine (cyanuric acid) could produce insoluble calculus in rat kidney and the number of melamine (cyanuric acid) calculus was positively correlated with dose and time. Melamine (cyanuric acid) can cause blood urea nitrogen, creatinine, uric acid levels rise, leading to renal dysfunction. The toxicity of melamine (cyanuric acid) was greater in adult rats than in newborn. The toxicity of melamine was greater than cyanuric acid. Melamine (cyanuric acid) mixture toxicity was greater than the monomer. Melamine (cyanuric acid) toxicity had individual differences and brood diffenences. Melamine (cyanuric acid) did not have significant liver toxicity. Melamine (cyanuric acid) calculus can be discharged slowly. Alkaline urine could help melamine (cyanuric acid) calculus discharged.
引文
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[3] Baynes RE, Smith G, Mason SE,et al. Pharmacokinetics of melamine in pigs following intravenous administration[J]. Food Chem Toxicol. 2008, 46(3): 1196-1200.
[4] Gangyi Liu , Shuijun Li , Jingying Jia,et al. Pharmacokinetic study of melamine in rhesus monkey after a single oral administration of a tolerable daily intake dose[J]. Regulatory Toxicology and Pharmacology.2010,56:193-196.
[5] Na Guan, Qingfeng Fan, Jie Ding, et al. Melamine-Contaminated Powdered Formula and Urolithiasis in Young Children[J]. N Engl J Med. 2009, 360(11):1067-1074.
[6] Hammond BG, Barbee SJ, Inoue T, et al. A review of toxicology studies on cyanurate and its chlorinated derivatives[J]. Environ Health Perspect.1986, 69: 287–292.
[7] Hodge HC, Panner BJ, Downs WL, et al.Toxicity of sodium cyanurate[J]. Toxicol. Appl. Pharmacol. 1965,7:667–674.
[8] Lam CW, Lan L, Che X, Tam S, et al. Diagnosis and spectrum of melamine-related renal disease: Plausible mechanism of stone formation in humans[J].Clin Chim Acta, 2009, 402(1-2):150-155.
[9] Brown CA, Jeong KS, Poppenga RH, et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007[J]. J Vet Diagn Invest. 2007, 19(5): 525-531.
[10] SAleksandrian AV. Toxicity and sanitay standardization of melamine cyanurate (experimental data) [J]. Gig Tr Prof Zabol, 1986, (1): 44-45.
[11] Takahiro Kobayashi, Atsushi Okada, Yasuhiro Fujii, et al. The mechanism of renal stone formation and renal failure induced by administration of melamine and cyanuric acid[J]. Urol Res. 2010, 38(2):117-25.
[1]叶章群.泌尿系结石研究现况与展望[J].中华实验外科志.2005,22 (3):261-262.
[2]于晓鹏,张进,孙亚青.泌尿结石抑制物的研究进展[J].现代医药卫生. 2006, 22 (18):2814-2815.
[3]欧阳健明.枸橼酸盐抑制泌尿系结石形成的化学基础[J].无机化学学报,2004,20(12):1377-1382.
[4] Pak CYC.Citrate and renal calculi:An update[J].Miner Electrolyte Metab,1994,20:371-377.
[5]曹萍,褚小兰,范崔生.金钱草类中药的研究概况[J].江西医学院学报.2005, 45(1): 110-113.
[6]孙宁,沈颖,孙嫱,等.婴幼儿三聚氰胺相关泌尿系结石并发急性肾衰竭诊疗分析[J].中华儿科杂志. 2008, 46(11):810-815.
[7]陈兴发.三聚氰胺致婴幼儿泌尿系结石的诊断和治疗[J].现代泌尿外科杂志。2009,14(3):166-168.
[8]沈颖,孙宁,蒋也平,等.《与食用受污染三鹿牌婴幼儿配方奶粉相关的婴幼儿泌尿系统结石诊疗方案》解读[J].中华儿科杂志.2008,46(11):816-819.
[1] Niconletta JA and Lande MB. Medical evaluation and treatment of urolithiasis[J]. Pediatr Clin North Am, 2006,53:4-7.
[2] Coward RJ, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK[J]. Arch Dis Child, 2003;88:962–965.
[3] Alon US, Zimmerman H, Alon M. Evaluation and treatment of pediatric idiopathic urolithiasis-revisited[J]. Pediatr Nephrol, 2004,19:516–520.
[4]叶章群,邓耀良.泌尿系结石[J].北京:人民卫生出版社,2003,57-92.
[5] Hee Yeon Cho, Bum Hee Lee, Hyun Jin Choi. Renal manifestations of Dent disease and Lowe syndrome[J]. Pediatr Nephrol,2008,23:243–249.
[6] Cameron MA, Pak CYC. Approach to the patient with the first episode of nephrolithiasis[J]. Clin Rev Bone Miner Metab, 2004,2:265–278.
[7] Reddy ST, Wang CY, Sakhaee K, et al. Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism [J].Am J Kidney Dis, 2002,40:265–274.
[8] Edin-Liljegren A, Hedelin HH, Grenabo L, et al. Impact of Escherichia coli on urine citrate and urease-induced crystallization[J]. Scanning Microsc, 1995,9:901–905.
[9] Ernst Leumann,Bernd Hoppe.The Primary Hyperoxalurias[J].J Am Soc Nephrol, 2001,12:1986-1993.
[10] 1Asplin JR Hyperoxaluric calcium nephrolithiasis[J]. Endocrinol Metab Clin N Am, 2002, 31:927–949.
[11] Sorensen CM, Chandhoke PS. Hyperuricosuric calcium nephrolithiasis[J]. Endocrinol Metab Clin North Am,2002,31:915–925.
[12] Zerwekh JE, Holt K, Pak CY Natural urinary macromolecular inhibitors: Attenuation of inhibitory activity by urate salts[J]. Kidney Int,1983,23:838–841.
[13] Kraus SJ, Lebowitz RL, Royal SA. Renal calculi in children: imaging features that lead to diagnoses: a pictorial essay[J]. Pediatr Radiol ,1999,29(8):624–630.
[14] Feliubadalo L, Font M, Purroy J, et al. Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo, + AT) of rBAT[J]. Nat Genet, 1999,23(1):52-57.
[15] Thomas Knoll. Antonia Z_llner.Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up[J].Pediatr Nephrol,2005,20:19–24.
[16] Milliner DS. Urolithiasis. Pediatric nephrology.Philadelphia[J]: Lippincott Williams& Wilkins. 2004, p: 1091–1111.
[17] Gearhart JR, Herzberg GZ, Jeffs RD .Childhood urolithiasis: experiences and advances[J]. Pediatrics,1991,87:445–450.
[18] Vesna D. Stojanovi? & Biljana O. Idiopathic hypercalciuria associated with urinary tractinfection in children[J]. Pediatr Nephrol ,2007,22:1291–1295.
[19]袁心刚,魏光辉.三聚氰胺和其衍生物与肾功能损害[J].中华小儿外科杂志,2009,30(1):48-50.
[20] Baynes RE, Smith G, Mason SE, et al. Pharmacokinetics of melamine in pigs following intravenous administration[J]. Food Chem Toxicol, 2008,46(3): 1196-1200.
[21] Hammond BG, Barbee SJ, Inoue T, et al. A review of toxicology studies on cyanurate and its chlorinated derivatives[J]. Environ Health Perspect, 1986,9: 287–292.
[22] Brown CA, Jeong KS, Poppenga RH, et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007[J]. J Vet Diagn Invest, 2007, 19(5): 525-531.
[23] Roy LM. Dobson,Safa Motlagh. Identification and Characterization of Toxicity of Contaminants in Pet Food Leading to an Outbreak of Renal Toxicity in Cats and Dogs[J] .Toxicological Sciences ,2008,106(1):251-262.
[2] Mast RW, Jeffcoat AR, Sadler BM,et al. Metabolism, disposition and excretion of [14C]melamine in male Fischer 344 rats[J]. Food Chem Toxicol. 1983, 21 (6):807-810.
[3] Baynes RE, Smith G, Mason SE,et al. Pharmacokinetics of melamine in pigs following intravenous administration[J]. Food Chem Toxicol. 2008, 46(3): 1196-1200.
[4] Gangyi Liu , Shuijun Li , Jingying Jia,et al. Pharmacokinetic study of melamine in rhesus monkey after a single oral administration of a tolerable daily intake dose[J]. Regulatory Toxicology and Pharmacology.2010,56:193-196.
[5] Na Guan, Qingfeng Fan, Jie Ding, et al. Melamine-Contaminated Powdered Formula and Urolithiasis in Young Children[J]. N Engl J Med. 2009, 360(11):1067-1074.
[6] Hammond BG, Barbee SJ, Inoue T, et al. A review of toxicology studies on cyanurate and its chlorinated derivatives[J]. Environ Health Perspect.1986, 69: 287–292.
[7] Hodge HC, Panner BJ, Downs WL, et al.Toxicity of sodium cyanurate[J]. Toxicol. Appl. Pharmacol. 1965,7:667–674.
[8] Lam CW, Lan L, Che X, Tam S, et al. Diagnosis and spectrum of melamine-related renal disease: Plausible mechanism of stone formation in humans[J].Clin Chim Acta, 2009, 402(1-2):150-155.
[9] Brown CA, Jeong KS, Poppenga RH, et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007[J]. J Vet Diagn Invest. 2007, 19(5): 525-531.
[10] SAleksandrian AV. Toxicity and sanitay standardization of melamine cyanurate (experimental data) [J]. Gig Tr Prof Zabol, 1986, (1): 44-45.
[11] Takahiro Kobayashi, Atsushi Okada, Yasuhiro Fujii, et al. The mechanism of renal stone formation and renal failure induced by administration of melamine and cyanuric acid[J]. Urol Res. 2010, 38(2):117-25.
[1]叶章群.泌尿系结石研究现况与展望[J].中华实验外科志.2005,22 (3):261-262.
[2]于晓鹏,张进,孙亚青.泌尿结石抑制物的研究进展[J].现代医药卫生. 2006, 22 (18):2814-2815.
[3]欧阳健明.枸橼酸盐抑制泌尿系结石形成的化学基础[J].无机化学学报,2004,20(12):1377-1382.
[4] Pak CYC.Citrate and renal calculi:An update[J].Miner Electrolyte Metab,1994,20:371-377.
[5]曹萍,褚小兰,范崔生.金钱草类中药的研究概况[J].江西医学院学报.2005, 45(1): 110-113.
[6]孙宁,沈颖,孙嫱,等.婴幼儿三聚氰胺相关泌尿系结石并发急性肾衰竭诊疗分析[J].中华儿科杂志. 2008, 46(11):810-815.
[7]陈兴发.三聚氰胺致婴幼儿泌尿系结石的诊断和治疗[J].现代泌尿外科杂志。2009,14(3):166-168.
[8]沈颖,孙宁,蒋也平,等.《与食用受污染三鹿牌婴幼儿配方奶粉相关的婴幼儿泌尿系统结石诊疗方案》解读[J].中华儿科杂志.2008,46(11):816-819.
[1] Niconletta JA and Lande MB. Medical evaluation and treatment of urolithiasis[J]. Pediatr Clin North Am, 2006,53:4-7.
[2] Coward RJ, Peters CJ, Duffy PG, et al. Epidemiology of paediatric renal stone disease in the UK[J]. Arch Dis Child, 2003;88:962–965.
[3] Alon US, Zimmerman H, Alon M. Evaluation and treatment of pediatric idiopathic urolithiasis-revisited[J]. Pediatr Nephrol, 2004,19:516–520.
[4]叶章群,邓耀良.泌尿系结石[J].北京:人民卫生出版社,2003,57-92.
[5] Hee Yeon Cho, Bum Hee Lee, Hyun Jin Choi. Renal manifestations of Dent disease and Lowe syndrome[J]. Pediatr Nephrol,2008,23:243–249.
[6] Cameron MA, Pak CYC. Approach to the patient with the first episode of nephrolithiasis[J]. Clin Rev Bone Miner Metab, 2004,2:265–278.
[7] Reddy ST, Wang CY, Sakhaee K, et al. Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism [J].Am J Kidney Dis, 2002,40:265–274.
[8] Edin-Liljegren A, Hedelin HH, Grenabo L, et al. Impact of Escherichia coli on urine citrate and urease-induced crystallization[J]. Scanning Microsc, 1995,9:901–905.
[9] Ernst Leumann,Bernd Hoppe.The Primary Hyperoxalurias[J].J Am Soc Nephrol, 2001,12:1986-1993.
[10] 1Asplin JR Hyperoxaluric calcium nephrolithiasis[J]. Endocrinol Metab Clin N Am, 2002, 31:927–949.
[11] Sorensen CM, Chandhoke PS. Hyperuricosuric calcium nephrolithiasis[J]. Endocrinol Metab Clin North Am,2002,31:915–925.
[12] Zerwekh JE, Holt K, Pak CY Natural urinary macromolecular inhibitors: Attenuation of inhibitory activity by urate salts[J]. Kidney Int,1983,23:838–841.
[13] Kraus SJ, Lebowitz RL, Royal SA. Renal calculi in children: imaging features that lead to diagnoses: a pictorial essay[J]. Pediatr Radiol ,1999,29(8):624–630.
[14] Feliubadalo L, Font M, Purroy J, et al. Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo, + AT) of rBAT[J]. Nat Genet, 1999,23(1):52-57.
[15] Thomas Knoll. Antonia Z_llner.Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up[J].Pediatr Nephrol,2005,20:19–24.
[16] Milliner DS. Urolithiasis. Pediatric nephrology.Philadelphia[J]: Lippincott Williams& Wilkins. 2004, p: 1091–1111.
[17] Gearhart JR, Herzberg GZ, Jeffs RD .Childhood urolithiasis: experiences and advances[J]. Pediatrics,1991,87:445–450.
[18] Vesna D. Stojanovi? & Biljana O. Idiopathic hypercalciuria associated with urinary tractinfection in children[J]. Pediatr Nephrol ,2007,22:1291–1295.
[19]袁心刚,魏光辉.三聚氰胺和其衍生物与肾功能损害[J].中华小儿外科杂志,2009,30(1):48-50.
[20] Baynes RE, Smith G, Mason SE, et al. Pharmacokinetics of melamine in pigs following intravenous administration[J]. Food Chem Toxicol, 2008,46(3): 1196-1200.
[21] Hammond BG, Barbee SJ, Inoue T, et al. A review of toxicology studies on cyanurate and its chlorinated derivatives[J]. Environ Health Perspect, 1986,9: 287–292.
[22] Brown CA, Jeong KS, Poppenga RH, et al. Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007[J]. J Vet Diagn Invest, 2007, 19(5): 525-531.
[23] Roy LM. Dobson,Safa Motlagh. Identification and Characterization of Toxicity of Contaminants in Pet Food Leading to an Outbreak of Renal Toxicity in Cats and Dogs[J] .Toxicological Sciences ,2008,106(1):251-262.