【作者】 尚攀峰；

【导师】 岳中瑾；

【作者基本信息】 兰州大学 ， 外科学， 2011， 博士

【摘要】 背景：2008年9月我国发生了因食用三聚氰胺污染奶粉致大量婴幼儿泌尿系结石事件。2个月时间内,全国累计报告三聚氰胺致泌尿系结石婴幼儿294000例,大部分为B超筛查时发现肾脏结构异常和肾结石的无症状儿童,其中51900例接受了住院治疗,至少6例婴幼儿因食用三聚氰胺污染奶粉导致死亡。目的：1.探讨婴幼儿泌尿系结石突发增多的原因,从而阻止更多婴幼儿发生泌尿系结石。2.探讨婴幼儿发生三聚氰胺泌尿系结石的危险因素。3.探讨三聚氰胺致婴幼儿泌尿系结石的临床特征及治疗功效,明确最佳治疗方式。4.评估三聚氰胺致泌尿系结石婴幼儿发生急性肾损伤的相关危险因素。5.调查三聚氰胺致泌尿系结石婴幼儿康复情况,探讨三聚氰胺对肾小球、肾小管功能的影响。6.调查三聚氰胺泌尿系结石致急性肾损伤的长期疗效。方法：1.回顾性分析2008年4月至9月兰州大学第二医院泌尿外科及儿科诊治的22例泌尿系结石婴幼儿临床资料。2.回顾性分析2008年9月14日～2009年1月6日兰州大学第二医院筛查婴幼儿病历资料,根据结石病例数按1：1的比例从筛查无泌尿系结石的健康婴幼儿中随机抽取对照组,采用Logistic回归模型对泌尿系结石的危险因素进行了单因素分析和多因素分析。3.回顾性分析甘肃省20家医院住院治疗的619例三聚氰胺致泌尿系结石婴幼儿临床资料、实验室数据、超声结果及治疗方法,对不同治疗方式的疗效进行比较；4.采用Logistic回归模型对发生急性肾损伤的危险因素进行了单因素分析和多因素分析。5.2009年9月至12月对随访患儿进行双肾B超、尿常规检查,检测血液中尿素氮(BUN)、肌酐(CR)、尿酸(UA)及尿液中α1-微球蛋白(a,-microglobulin,α1-MG)、β2-微球蛋白(β2-microglobulin,β2-MG)、微量白蛋白(Urinary microalbumin,UMA)的含量。6.回顾性分析三聚氰胺相关泌尿系结石致急性肾损伤(AKI)婴幼儿的临床资料、实验室数据、超声结果及治疗方法,2010年3月至5月对三聚氰胺泌尿系结石致急性肾损伤患儿进行了2年后随访。结果：1.最初接诊的22例婴幼儿均为人工喂养或混合喂养,正在食用三鹿牌婴幼儿配方奶粉。其中13例婴幼儿(占59.09%)出现排尿症状前有上呼吸道感染或腹泻病史。2.结石组647例,对照组647例,男678例,女616例,平均年龄19.27月。食用高三聚氰胺含量的三鹿奶粉婴幼儿发生泌尿系结石的OR为6.09(P<0.01),男性、人工喂养的OR值分别为1.39(P<0.01)和1.61(P<0.01)。随着年龄增长发生结石的风险逐渐下降,<6月、6月～、12月～婴幼儿发生结石的OR值分别是5.23(P<0.01)、2.73(P<0.01)、1.60(P<0.01)。随着服用三聚氰胺污染奶粉时间的延长,发生结石的逐渐增加越高。服用三聚氰胺污染奶粉3个月～、6个月～、12个月～婴幼儿发生结石的OR值分别是2.10(P<0.01)、2.81(P<0.01)、4.75(P<0.01)。3.回顾性分析的619例患儿中,男性408例,女性21 1例,最小1月龄,最大88月龄,平均为16.32月龄。520例(84.0%)为B超筛查时发现的无症状病例,117例(18.9%)为肾、输尿管、膀胱、尿道等尿路结石共存病例。首选保守治疗577例,454例治愈,治愈率78.7%；151例肾、输尿管结石患者,81例经1至6次的体外冲击波碎石治疗172次,治愈61例,累计成功率35.5%；70例采用膀胱镜输尿管插管置管术治疗,治愈56例,治愈率为80.0%；5例并发梗阻性急性肾损伤的患儿在缺乏微创外科条件下,采用输尿管切开取石术治愈4例,双肾造瘘术治愈1例；对于治疗3个月以上的顽固性肾、输尿管结石,经皮肾镜碎石取石术治愈9例,输尿管镜碎石取石术治愈18例；22例膀胱和/或尿道结石采用膀胱尿道镜碎石取石术治愈。4.食用三鹿奶粉婴幼儿发生AKI的OR值为19.73(P<0.01),6月～、12月～年龄段婴幼儿的0R值分别是9.59(P<0.01)和5.06(P<0.01),食用三聚氰胺污染奶粉期间出现上呼吸道感染、腹泻、脱水或发热等任何一个病史的婴幼儿发生AKI的OR值为4.29(P<0.01)。5.共81例患儿进行了1年后随访,保守组54例,3例结石残留(直径分别为0.3cm、0.3cm、0.4cm)；干预组27例,2例结石残留(直径为1.5cm、0.23cm),1.5cm残留结石经X线证实为阳性结石,行经皮肾镜碎石取石术治疗。随访患儿尿UMA水平明显高于对照组(P<0.01),其中11例超过正常值范围(说明肾小球功能受损),与正常对照组比较,差别有统计学意义(P=0.03)；血BUN、CR、UA均在正常范围,不同治疗组间差别无统计学意义。6.619例三聚氰胺致泌尿系结石患儿中47例并发了梗阻性AKI,在7家医疗机构接受了住院治疗。男性34例,女性13例,最小5月龄,最大36月龄,平均月龄为10.83±5.11,结石直径最小3 mm,最大14 mm；9例(19.15%)患儿保守治疗后成功治愈,32例(68.09%)行经膀胱镜输尿管插管置管术后结石成功排出,其中8例同期行膀胱镜和/或尿道镜碎石取石术,4例因不具备微创条件而行输尿管切开取石术后治愈,1例双肾造瘘术治愈；38例获得随访,随访时间为18.50±5.27月,血BUN、CR全部正常,无症状肾结石残留5例(13.16%),直径范围2-4 mm。结论：1.婴幼儿泌尿系结石突发增多是喂养三聚氰胺污染的三鹿牌婴幼儿配方奶粉所致,部分婴幼儿泌尿系结石的形成由上呼吸道感染、腹泻诱发,并导致结石梗阻无尿。2.食用高三聚氰胺含量奶粉(三鹿奶粉)、人工喂养和男性是婴幼儿发生泌尿系结石的危险因素,服用三聚氰胺污染奶粉时间越长、年龄越小,发生泌尿系结石的风险越高。3.大多数三聚氰胺致泌尿系结石婴幼儿采用适量输液、碱化尿液、利尿等保守治疗可成功治愈,体外冲击波碎石是保守治疗失败后安全、有效的治疗方法。4.食用三鹿奶粉,6月～、12月～年龄段婴幼儿,以及合并上呼吸道感染、腹泻、脱水或发热病史是三聚氰胺致泌尿系结石婴幼儿发生AKI的主要危险因素。5.如果1年后残留结石直径大于1.Ocm建议手术治疗。6.三聚氰胺相关泌尿系结石可导致梗阻性AKI,尽早采用外科干预措施解除梗阻,平均随访18月,疗效确切,结果满意。然而,无症状肾结石残留率为13.16%,需严密跟踪随访。更多还原

【Abstract】 Background:In September 2008, China reported an epidemic of urinary stones in infants fed with melamine-contaminated milk powder. In less than two months,294,000 cases of melamine-associated kidney stones were reported, with over 51,900 babies and infants were hospitalized. Overall, at least six confirmed deaths were linked to consumption of melamine-tainted powdered milk formula. Renal disorders and renal calculi in asymptomatic children were detected by ultrasonic screening.Objective:We investigate causes of urinary stone sudden increase in infants and to prevent more occurrence of urinary stone. We also investigate the risk factors of melamine associated urolithiasis. After treatment, most children with melamine-induced urolithiasis were cured and discharged. We retrospectively analyzed the clinical features and therapeutic efficacy in chidren with urolithiasis caused by ingestion of melamine-contaminated infant formula, as well as identified the risk factors for occurrence of acute kidney injury (AKI). Also, we performed a study to investigate the rehabilitated condition, renal glomerular and tubular dysfunction of patients with melamine-induced urolithiasis at one-year follow-up. And we analyzed and evaluated long-term efficacy of treatment in young children with acute kidney injury (AKI) caused by melamine-contaminated infant formula.Methods:The clinical data of 22 infants with urinary stones visiting clinic of second hospital of Lanzhou university from April 2008 to September were analyzed retrospectively. Also the detailed data of infant and young children screened for urolithiasis from of September 14, 2008 to January 6,2009 were analysis retrospectively. According to the case:control ratios of 1:1, we selected the control group from those without urolithiasis randomly. Univariate and multivariate analysis were performed with a logistic regression model to assess for independent risk factors for urolithiasis. A total of 619 children with melamine-induced urolithiasis were admitted into 20 different hospitals in Gansu province, China. Their clinical and laboratory datas, ultrasonograms, and treatment methods were retrospective recorded and analyzed. Univariate and multivariate analysis were performed with a logistic regression model to assess for independent risk factors for occurrence of acute kidney injury (AKI). We followed up young children with melamine-induced urolithiasis from September to December 2009, which included urinalysis, renal-function tests, urinary tests for biochemical markers of renal glomerular and tubular function, and ultrasonography. Also, we retrospectively analyzed clinical and laboratory data, ultrasonograms and treatment methods in infant patients with melamine-induced urolithiasis and AKI who were hospitalized in Gansu Province, China. Patients were monitored postoperatively with data from ultrasonography, urinalysis, blood and urine biochemistry. We followed up the children suffering from melamine-induced urolithiasis and AKI from March to May 2010.Results:22 infants with urinary stones were bottle feeding or mixed feeding, and all infants were in the process of consumption of sanlu powdered infant milk formulas.13 cases have upper respiratory tract infection or diarrhea history before presenting urination symptoms, accounting for 59.09%. Of the screened children,647 included in stones group and 647 in control group. There were 678 boys and 616 girls with an average age of 19.27 months. Logistic regression analysis shows that the children fed with sanlu powdered infant milk formula were 6.09 times more likely to have stones (P<0.01) than those with other melamine-contaminated formula. Boys were 1.39 times more likely to have stones (P<0.01) than girls. Children fed with formula alone were 1.61 times more likely to have stones (P<0.01) than those with formula and breast milk. Long duration of formula feeding and younger children were the risk factors for melamine associated urolithiasis (P<0.05, respectively). The children aged less than 6 months,6 to 12 months,12 to 24 months were 5.23 (P<0.01),2.73 (P<0.01),1.60 (P<0.01) times more likely to have stones than those more than 24 months. The time of formula feeding 3 to 6 months,6 to 12 months and more than or equal to 12 months were 2.10 (P<0.01),2.81 (P<0.01),4.75 (P<0.01) times more likely to have stones than those less than 3 months. Among the 619 children,408 were boys and 211 girls with age ranging from 1 month to 88 months (mean age,16.32 months).520 children (84.0%) were asymptomatic and detect by ultrasound screening program.117 (18.9%) children had co-existent renal, ureteral, bladder or/and urethral stones (stones at more than 1 site). 577 patients received conservative treatment and 454 become stone-free (78.7%). Of the 151 patients with renal and/or ureteral stones,1 to 6 session Extracorporeal Shock Wave Lithotripsy (ESWL) were performed in 81 patients (61 successes in 172 treatments, Cumulative success rate, 35.5%), retrograde ureteral catheterization (UC) in 70 patients (56 patients were successfully treated,80.0%). In centers without expertise in minimally-invasive medical technique,5 patients with bilateral obstructive renal failure were successfully treated with Ureterolithotomy (ULT,4) and percutaneous nephrostomy (PCNL,1). For the remaining 27 children with refractory renal or ureter stones,9 were successfully treated with percutaneous nephrolithotomy (PCNL) and 18 children underwent ureteroscopic lithotripsy to become stone-free. A total of 22 bladder and/or urethral stones were successfully treated with cystoscopic (Cys L) or urethroscopic lithotripsy. Logistic regression analysis reveal that the children fed with sanlu powdered infant milk formula were 19.73 times more likely to occurrence of AKI than those with other formula. A significantly higher number of patients occurrence of acute kidney injury (AKI) among children aged 6 to 11 months (OR,9.59, P<0.01) and 12 to 17 months(OR,5.06, P<0.01). The children with any one symptoms of upper respiratory tract infection, diarrhea, dehydration, and fever (OR,4.29, P<0.01) remained independent risk factor for occurrence of AKI by multivariate analysis.81 children with detailed data were enrolled and followed up one year late.51 were male and 30 female, with a mean age of 25.53±7.91 months (range 13-48 months). According to different treatment,81 children were divided into two groups. Group 1 was conservative treatment group (n=54) and group 2 was intervention treatment group (n=27). In Group 1, the outcomes of 3 (5.6%) children have stone-residual:one girl has calculus of 0.4 cm in diameter in the left kidney and two girls have calculus of 0.3 cm in diameter in the right kidney. In Group 2, the outcomes of 2 (7.4%) children have stone-residual, one boy has crystallization of 0.23 cm in diameter in the right kidney, one boy has calculus of 1.5 cm in diameter in the left kidney, positive stone was confirmed by X-ray and accepted percutaneous nephrolithotomy. Urinary microalbumin levels were significantly increased in children with melamine-induced urolithiasis compared with the normal control group (P<0.01). And the incidence of glomerular dysfunction (UMA more than 19μg/ml) among children with melamine-induced urolithiasis, was significantly increased compared with control group (P=0.03). Blood urea nitrogen and serum creatinine were within the normal range and these is not any significant difference between two groups. A total of 47 children with melamine-induced urolithiasis and AKI was hospitalized in 7 institutions. The mean age was 10 months (mean±SD,10.83±5.11 months). Thirty-four (72.34%) were male. Calculi size ranged from 3 to 14 mm in diameter. Nine patients (19.15%) were successfully treated with conservative treatment; 32 (68.09%) underwent retrograde ureteral catheterization and 8 had simultaneous cystoscopic or urethroscopic lithotripsy; Four were successfully treated with ureterolithotomy, and 1 underwent percutaneous nephrostomy. Thirty-eight patients were followed up for a mean±SD of 18.50±5.27 months and their renal functions were found to have completely recovered. Five (13.16%) cases had residual renal stones with diameter ranged from 2 to 4 mm.Conclusion:The epidemic of urinary stones in infants were related to exposure to melamine-tainted sanlu powdered infant milk formulas. Upper respiratory tract infection or diarrhea most likely induce urinary stones formation and obstructive anuria in infants. We confirmed that the children fed with high melamine infant formula (sanlu powdered infant milk formula), boy, children fed with formula alone were risk factors of melamine associated urolithiasis. We also found the risk for melamine associated urolithiasis decreased with age, and increased with time of formula feeding. Most children with melamine-induced urolithiasis were treated successfully with infusion of fluids, urine basification and diuresis. ESWL is a safe and effective technique for cases where conservative treatment fails. Fed with sanlu powdered infant milk formula and children with any one symptoms of upper respiratory tract infection, diarrhea, dehydration, and fever were risk factors for occurrence of acute kidney injury (AKI) in children with melamine-induced urolithiasis. We also found that children aged 6 to 11 monthsn and 12 to 17 months more prone to developed AKI. By now (1 year follow-up) the patients with stone-residual>10 mm, surgery been recommend. Melamine-induced urolithiasis could lead to AKI. Removing obstruction promptly by surgical intervention has been found to be effective with satisfactory outcomes observed at mean follow-up period of 18-month. However, residual renal stone remained in 13.16% of the cases which required continued close observation.更多还原