儿童慢性肾脏病的病因及并发症的临床研究
发布时间：2018-08-27 14:30
【摘要】：目的：慢性肾脏病(chronic kidney disease, CKD)是世界范围内的严重公共健康问题,造成了严重的社会经济负担。流行病学调查显示近年来儿童CKD呈增高趋势。CKD往往起病隐匿,部分患儿可逐渐进展至终末期肾病(ESRD, end stage renal disease)。儿童CKD不仅是儿童ESRD的重要病因,这部分患儿还将成为成人CKD及ESRD的高危人群。儿童CKD的病因与成人不同,我国对儿童CKD病因的分析常局限在终末期患儿,且分析病例数有限。随着肾功能的减退与疾病的发展,高血压、贫血、营养不良、钙磷代谢异常等慢性并发症表现越来越明显,部分并发症在CKD的早期即可出现,是影响患儿预后及生活质量的重要因素之一。本研究通过对我院CKD2-5期患儿的临床分析,旨在总结十年来复旦大学附属儿科医院CKD2-5期患儿的病因构成比与起病情况,为早期发现提供依据；并通过横断面调查,观察我科住院评估的CKD2-5期患儿在生长、贫血、矿物质与骨代谢、心血管疾病等方面的并发症情况及其治疗情况,了解CKD患儿并发症的患病率状况,为临床诊断和治疗提供依据,以指导早期诊断和并发症管理；通过血成纤维细胞生长因子23 (fibroblast growth factor 23, FGF23)水平的检测,了解各期患儿FGF23的水平变化,分析FGF23与钙磷代谢相关指标的相关性,探索FGF23作为CKD并发症早期异常指标的可能。方法：1、病因的回顾性分析：收集2004年1月-2013年12月期间在我院住院的符合诊断标准的CKD2-5期患儿264例,对其病因、临床特点、起病情况进行回顾性分析。2、并发症的横断面研究：截取2012年7月-2013年12月期间在我科住院评估的CKD2-5期患儿,收集其基本资料、临床病史、生化指标、影像学检查结果、治疗情况等,分析其贫血、高血压、身材矮小、矿物质骨代谢异常、左心室肥大(left ventricular hypertrophy, LVH)等慢性并发症的患病情况。3、血FGF23水平的研究：采用酶联免疫分析法(ELISA)对CKD患儿全段及C端FGF23 (intact FGF23, iFGF23; carboxyl terminalFGF23, cFGF23)的水平进行检测,同时测定其血清肌酐、血钙、血磷、甲状旁腺激素等指标,收集临床资料,观察各期患者FGF23水平的变化与相关指标的关系。结果：1、264例CKD2-5期患儿中,先天性肾脏和尿路畸形(Congenital anomalies of the kidney and urinary tract, C AKUT)116例(43.9%),肾小球疾病61例(23.1%),遗传性肾病15例(5.7%),其他14例(5.3%),病因不明58例(22.0%)。0-5岁的患儿中,59.3%(48例)的患儿原发病为CAKUT,14.8%(12例)为肾小球疾病,10岁的患儿中,49.2%(30例)为肾小球疾病,32.0%(32例)病因未明。确诊时的分期,2期52例(19.7%),中位年龄6.9(3.7,11.0)岁,3期67例(25.4%),中位年龄8.0(4.4,10.5)岁,4期52例(19.7%),中位年龄7.3(3.4-10.8)岁,5期93例(35.2%),中位年龄10.3(7.4,12.6)岁。2011年起,我院就诊的病例数显著增加,且原发病诊断明确的比例明显升高(χ2=4.653,P=0.031),不明原因的比例由27.1%下降至16.2%。上海地区的患儿起病时为2期的占42.0%(21/52例),高于全部地区起病时为2期的比例。仅有57例(21.6%)患儿体检发现,余均为症状起病。2、在横断面研究中,共计纳入123例CKD2-5期患儿,原发病为CAKUT的56例(45.5%),肾小球疾病32例(26.0%),遗传性肾病7例(5.7%),其他6例(4.9%),病因不明22例(17.9%)。按CKD分期分,2期17例(13.8%),3期17例(13.8%),4期16例(13.0%),5期73例(59.3%)。中位年龄为9.9(6.3,13.2)岁,确诊CKD病程为1.0(0.1,2.3)年,我科随访时间为0.4(0,2.0)年,其中我科随访大于6月的有60例(48.8%)。贫血在该组病例中的患病率为80.5%,其中2期仅11.8%,3期为58.8%,至4期为87.5%,5期患儿则均患有贫血；各期患儿的血红蛋白(Hemoglobin,Hb)达标率分别为2期100%,3期30.0%,4期35.7%,5期34.2%。铁剂总体使用率达91.9%,促红细胞生成素(erythropoietin, EPO)总体使用率达79.8%,其中5期患者的铁剂和EPO使用率分别达98.6%(72/73)和95.9%(70/73),以随访时间是否大于6月分组,随访时间6月的患儿达标率明显高于≤6月的患儿(χ2=15.338,P0.05)。高血压的患病率为61.8%,从2期到5期分别为29.4%、41.2%、43.8%、78.1%；收缩压和舒张压的达标率分别为51.3%和55.3%,5期患儿的收缩压和舒张压达标率为49.1%和52.6%。65.8%(50/76)的患儿使用钙通道阻滞剂(calcium-channel blocker,CCB),64.5%(49/76)的患儿使用血管紧张素转化酶抑制剂(angiotensin-converting enzyme inhibitor, ACEI)或肾上腺素能受体结合剂(adrenergic receptor binder,ARB),另有27.6%(21/76)的患儿使用β受体阻滞剂,其中50.0%(38/76)的患儿使用≥2种降压药,；另有6.6%(5/76)未予使用降压药物。共有37.4%的患儿存在生长迟缓,2期患儿中患病率为11.8%,在3-5期中为35.30%-43.8%。CKD-MBD (mineral and bone disorder in chronic kidney disease,慢性肾脏病的矿物质和骨代谢异常)患病率达93.5%,在早期的CKD患儿中的患病率已经很高,而在CKD5期中达到了100%。116例进行心超检查的患儿中,有55例患儿诊断为左心室肥大(left ventricular hypertrophy, LVH),其中22名诊断为严重LVH。LVH患儿的CKD病程短于非LVH患儿,年龄亦较非LVH患儿小；Logistic回归分析显示,高血压,继发性甲状旁腺机能亢进(secondary hyperparathyroidism,SHPT),Hb值60-90g/L,年龄小于10岁是LVH的独立危险因素。3、针对FGF23的研究结果显示,随着估算肾小球滤过率(Estimated glomerular filtration rate, eGFR)的下降,FGF23水平有上升趋势,eGFR15ml/min·1.73m2组FGF23水平明显升高,较前两组存在显著差异,但前两组间无明显差异；血钙水平有下降趋势,但无统计学差异,血磷水平有上升趋势,eGFR≥45 ml/min·1.73m2组与eGFR15ml/min·1.73m2组相比有显著差异。Pearson相关分析显示,lniFGF23 (iFGF23的自然对数)与lncFGF23 (cFGF23的自然对数)的值存在线性正相关关系(P0.001).lniFGF23与CKD病程、血清磷、血清钙(校正)成正相关,与eGFR成负相关；lncFGF23与血清磷、血清钙(校正)、lniPTH (iPTH的自然对数；iPTH, intact parathyroid hormone,全段甲状旁腺激素)成正相关,与eGFR (r=-0.431, P0.001)成负相关。多元回归结果显示,校正钙、磷、eGFR, lniPTH是lniFGF23的影响因素,横正钙、eGFR, lniPTH是lncFGF23的影响因素。高血磷组的iPTH、iFGF23及cFGF23水平均较正常血磷组高,存在显著差异。SHPT组的血钙较低,血磷较高,但两组iFGF23及cFGF23水平无明显差异。结论：1、10年来儿童CKD2-5期的首要病因为CAKUT,占43.9%,其次为肾小球疾病,占23.1%。CAKUT起病年龄较早；对小年龄段的CKD患儿需注意完善泌尿系统影像学检查。2、CKD2-5期患儿存在贫血、高血压、生长营养、CKD-MBD等慢性并发症,影响患儿的生活和预后。贫血及CKD-MBD是该组病例中最常见的并发症,各并发症患病率随GFR的降低呈升高趋势。在CKD早期的患儿中,即有钙磷代谢异常的出现。经治疗后患儿的临床指标较前改善,但血红蛋白及血压的达标率在本组病例中的达标率不高。年龄、贫血、高血压是LVH的危险因素。需进一步重视CKD患儿相关并发症的诊断、治疗和管理。3、FGF23水平随着肾脏功能的减退明显升高,FGF23参与钙磷代谢,与血磷、血钙、PTH水平相关,其中血磷水平与FGF23水平关系密切,FGF23可能作为CKD患者血磷升高的早期预测指标。
[Abstract]:Objective: Chronic kidney disease (CKD) is a serious public health problem worldwide, causing a serious social and economic burden. Epidemiological investigation shows that CKD in children is increasing in recent years. CKD is not only an important cause of ESRD in children, but also a high-risk group for CKD and ESRD in adults. The causes of CKD in children are different from those in adults. The analysis of the causes of CKD in children in China is often limited to the end-stage children, and the number of cases is limited. Chronic complications such as abnormal metabolism are becoming more and more obvious. Some complications occur early in CKD, which is one of the important factors affecting the prognosis and quality of life of children. To provide evidence for early detection, and to observe the complications and their treatment in growth, anemia, mineral and bone metabolism, cardiovascular diseases and other aspects of children with CKD 2-5 hospitalized in our department by cross-sectional survey, to understand the prevalence of complications in children with CKD, to provide basis for clinical diagnosis and treatment, to guide the early stage of treatment. Methods: 1. Retrospective analysis of the etiology of CKD complications. Methods: 1. Analysis: 264 cases of CKD2-5 hospitalized in our hospital from January 2004 to December 2013 were analyzed retrospectively. 2. Cross-sectional study of complications: The basic data of 264 cases of CKD2-5 hospitalized in our department from July 2012 to December 2013 were collected. History, biochemical indicators, imaging findings, treatment, analysis of anemia, hypertension, short stature, mineral bone metabolism abnormalities, left ventricular hypertrophy (LVH) and other chronic complications of the prevalence. 3, serum levels of fibroblast growth factor 23 in children with C KD: enzyme-linked immunoassay (ELISA) of the whole and C-terminal fibroblast growth factor 23 (intact fibroblast growth factor 23, iFGF23; carboxyl terminal fibroblast growth factor 23, cFGF23) levels were detected, and serum creatinine, serum calcium, serum phosphorus, parathyroid hormone and other indicators were measured. Clinical data were collected to observe the relationship between the levels of fibroblast growth factor 23 and related indicators. Results: Congenital kidney and urinary tract malformations (Cong) were found in 1,264 children with CKD2-5. Of the kidney and urinary tract, 116 (43.9%) had CAKUT, 61 (23.1%) had glomerular disease, 15 (5.7%) had inherited nephropathy, and 14 (5.3%) had nephropathy. Of the 58 (22.0%) with unknown etiology, 59.3% (48) had CAKUT, 14.8% (12) had glomerular disease, and 49.2% (30) had small kidney in 10-year-old children. There were 52 cases (19.7%) in stage 2, 67 cases (25.4%) in stage 3, 67 cases (8.0 (4.4, 10.5) in stage 3, 52 cases (19.7%) in stage 4, and the median age was 7.3 (3.4-10.8) years, 93 cases (35.2%) in stage 5, and the median age was 10.3 (7.4, 12.6) years. The proportion of children with definite diagnosis increased significantly (_2 = 4.653, P = 0.031), and the proportion of unknown causes decreased from 27.1% to 16.2%. 42.0% (21/52) of the children with stage 2 onset in Shanghai area was higher than that of the children with stage 2 onset in all areas. Only 57 (21.6%) of the children were found to have symptomatic onset. 2. A total of 123 children were included in the cross-sectional study. There were 56 cases (45.5%) with CAKUT, 32 cases (26.0%) with glomerular disease, 7 cases (5.7%) with hereditary nephropathy, 6 cases (4.9%) with unknown etiology and 22 cases (17.9%) with CKD stage 2, 17 cases (13.8%) with stage 3, 16 cases (13.0%) with stage 4, and 73 cases (59.3%) with stage 5. The follow-up time was 0.4 (0,2.0) years, of which 60 cases (48.8%) were followed up for more than 6 months. The prevalence rate of anemia in this group was 80.5%. The prevalence rate of anemia was only 11.8% in stage 2, 58.8% in stage 3 and 87.5% in stage 4 and 87.5% in stage 5, respectively. The overall usage rate of iron was 91.9%, and that of erythropoietin (EPO) was 79.8%. The usage rates of iron and EPO were 98.6% (72/73) and 95.9% (70/73) in stage 5 patients, respectively. Whether the follow-up time was longer than 6 months or not, the compliance rate in 6 months was significantly higher than that in < 6 months (2 = 15.338, P 0.05). The prevalence of hypertension was 61.8%, 29.4%, 41.2%, 43.8%, 78.1% from stage 2 to stage 5, 51.3% for systolic blood pressure and 55.3% for diastolic blood pressure, 49.1% for systolic blood pressure and 52.6% for diastolic blood pressure in stage 5, and 65.8% (50/76) for calcium channel blocker (CCB) and 64.5% (49/76) for calcium channel blocker (CCB). Angiotensin-converting enzyme inhibitor (ACEI) or adrenergic receptor binder (ARB) were used in 27.6% (21/76) of the patients, 50.0% (38/76) of whom used more than two kinds of antihypertensive drugs, and 6.6% (5/76) of whom did not use antihypertensive drugs. The prevalence of CKD-MBD (mineral and bone disorder in chronic kidney disease) was 93.5%. The prevalence of CKD in early stage was very high, but reached 100% in CKD 5. Among the children who underwent echocardiography, 55 were diagnosed as left ventricular hypertrophy (LVH), of whom 22 were diagnosed as severe LVH. LVH. The duration of CKD was shorter and the age was younger than that of non-LVH. Logistic regression analysis showed hypertension and secondary hyperparathyroidism. Hyroidism, SHPT, Hb value 60-90 g/L, age less than 10 years old is an independent risk factor for LVH. 3 The results of the study of FGF23 showed that with the decrease of Estimated glomerular filtration rate (eGFR), the level of FGF23 increased significantly in eGFR15 ml/min. However, there was no significant difference between the two groups; serum calcium level had a downward trend, but there was no statistical difference; serum phosphorus level had an upward trend. There was a significant difference between eGFR (> 45 ml / min < 1.73 m2) and eGFR (> 15 ml / min < 1.73 m2). Pearson correlation analysis showed that the values of lniFGF23 (the natural logarithm of iFGF23) and lncFGF23 (the natural logarithm of cFGF23) were linear. There was a positive correlation (P 0.001). lniFGF23 was positively correlated with the course of CKD, serum phosphorus, serum calcium (correction) and negatively correlated with eGFR; lncFGF23 was positively correlated with serum phosphorus, serum calcium (correction), and lniPTH (natural logarithm of iPTH; iPTH, intact parathyroid hormone, whole parathyroid hormone) and negatively correlated with eGFR (r = - 0.431, P 0.001). The results showed that calibrated calcium, phosphorus, eGFR, and lniPTH were the influencing factors of lniFGF23. Transverse positive calcium, eGFR and lniPTH were the influencing factors of lncFGF23. The levels of iPTH, iFGF23 and cFGF23 in the hyperphosphorus group were higher than those in the normal group, and there were significant differences. The primary cause of CKD 2-5 in children was CAKUT, accounting for 43.9%, followed by glomerular disease, accounting for 23.1%. The onset age of CAKUT was earlier; the imaging examination of urinary system should be improved in young children with CKD. 2. Children with CKD 2-5 had chronic complications such as anemia, hypertension, growth nutrition, CKD-MBD, which affected the life and prognosis of children. CKD-MBD and CKD-MBD were the most common complications in this group. The prevalence of complications increased with the decrease of GFR. In the early stage of CKD, there was abnormal metabolism of calcium and phosphorus. Blood pressure is a risk factor for LVH. More attention should be paid to the diagnosis, treatment and management of complications associated with CKD. 3. Fibroblast growth factor 23 (FGF23) levels are significantly elevated with the decline of renal function. Fibroblast growth factor 23 (FGF23) is involved in calcium and phosphorus metabolism, and is closely related to serum phosphorus, calcium and PTH levels. Predictors.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R726.9
本文编号：2207563
[Abstract]:Objective: Chronic kidney disease (CKD) is a serious public health problem worldwide, causing a serious social and economic burden. Epidemiological investigation shows that CKD in children is increasing in recent years. CKD is not only an important cause of ESRD in children, but also a high-risk group for CKD and ESRD in adults. The causes of CKD in children are different from those in adults. The analysis of the causes of CKD in children in China is often limited to the end-stage children, and the number of cases is limited. Chronic complications such as abnormal metabolism are becoming more and more obvious. Some complications occur early in CKD, which is one of the important factors affecting the prognosis and quality of life of children. To provide evidence for early detection, and to observe the complications and their treatment in growth, anemia, mineral and bone metabolism, cardiovascular diseases and other aspects of children with CKD 2-5 hospitalized in our department by cross-sectional survey, to understand the prevalence of complications in children with CKD, to provide basis for clinical diagnosis and treatment, to guide the early stage of treatment. Methods: 1. Retrospective analysis of the etiology of CKD complications. Methods: 1. Analysis: 264 cases of CKD2-5 hospitalized in our hospital from January 2004 to December 2013 were analyzed retrospectively. 2. Cross-sectional study of complications: The basic data of 264 cases of CKD2-5 hospitalized in our department from July 2012 to December 2013 were collected. History, biochemical indicators, imaging findings, treatment, analysis of anemia, hypertension, short stature, mineral bone metabolism abnormalities, left ventricular hypertrophy (LVH) and other chronic complications of the prevalence. 3, serum levels of fibroblast growth factor 23 in children with C KD: enzyme-linked immunoassay (ELISA) of the whole and C-terminal fibroblast growth factor 23 (intact fibroblast growth factor 23, iFGF23; carboxyl terminal fibroblast growth factor 23, cFGF23) levels were detected, and serum creatinine, serum calcium, serum phosphorus, parathyroid hormone and other indicators were measured. Clinical data were collected to observe the relationship between the levels of fibroblast growth factor 23 and related indicators. Results: Congenital kidney and urinary tract malformations (Cong) were found in 1,264 children with CKD2-5. Of the kidney and urinary tract, 116 (43.9%) had CAKUT, 61 (23.1%) had glomerular disease, 15 (5.7%) had inherited nephropathy, and 14 (5.3%) had nephropathy. Of the 58 (22.0%) with unknown etiology, 59.3% (48) had CAKUT, 14.8% (12) had glomerular disease, and 49.2% (30) had small kidney in 10-year-old children. There were 52 cases (19.7%) in stage 2, 67 cases (25.4%) in stage 3, 67 cases (8.0 (4.4, 10.5) in stage 3, 52 cases (19.7%) in stage 4, and the median age was 7.3 (3.4-10.8) years, 93 cases (35.2%) in stage 5, and the median age was 10.3 (7.4, 12.6) years. The proportion of children with definite diagnosis increased significantly (_2 = 4.653, P = 0.031), and the proportion of unknown causes decreased from 27.1% to 16.2%. 42.0% (21/52) of the children with stage 2 onset in Shanghai area was higher than that of the children with stage 2 onset in all areas. Only 57 (21.6%) of the children were found to have symptomatic onset. 2. A total of 123 children were included in the cross-sectional study. There were 56 cases (45.5%) with CAKUT, 32 cases (26.0%) with glomerular disease, 7 cases (5.7%) with hereditary nephropathy, 6 cases (4.9%) with unknown etiology and 22 cases (17.9%) with CKD stage 2, 17 cases (13.8%) with stage 3, 16 cases (13.0%) with stage 4, and 73 cases (59.3%) with stage 5. The follow-up time was 0.4 (0,2.0) years, of which 60 cases (48.8%) were followed up for more than 6 months. The prevalence rate of anemia in this group was 80.5%. The prevalence rate of anemia was only 11.8% in stage 2, 58.8% in stage 3 and 87.5% in stage 4 and 87.5% in stage 5, respectively. The overall usage rate of iron was 91.9%, and that of erythropoietin (EPO) was 79.8%. The usage rates of iron and EPO were 98.6% (72/73) and 95.9% (70/73) in stage 5 patients, respectively. Whether the follow-up time was longer than 6 months or not, the compliance rate in 6 months was significantly higher than that in < 6 months (2 = 15.338, P 0.05). The prevalence of hypertension was 61.8%, 29.4%, 41.2%, 43.8%, 78.1% from stage 2 to stage 5, 51.3% for systolic blood pressure and 55.3% for diastolic blood pressure, 49.1% for systolic blood pressure and 52.6% for diastolic blood pressure in stage 5, and 65.8% (50/76) for calcium channel blocker (CCB) and 64.5% (49/76) for calcium channel blocker (CCB). Angiotensin-converting enzyme inhibitor (ACEI) or adrenergic receptor binder (ARB) were used in 27.6% (21/76) of the patients, 50.0% (38/76) of whom used more than two kinds of antihypertensive drugs, and 6.6% (5/76) of whom did not use antihypertensive drugs. The prevalence of CKD-MBD (mineral and bone disorder in chronic kidney disease) was 93.5%. The prevalence of CKD in early stage was very high, but reached 100% in CKD 5. Among the children who underwent echocardiography, 55 were diagnosed as left ventricular hypertrophy (LVH), of whom 22 were diagnosed as severe LVH. LVH. The duration of CKD was shorter and the age was younger than that of non-LVH. Logistic regression analysis showed hypertension and secondary hyperparathyroidism. Hyroidism, SHPT, Hb value 60-90 g/L, age less than 10 years old is an independent risk factor for LVH. 3 The results of the study of FGF23 showed that with the decrease of Estimated glomerular filtration rate (eGFR), the level of FGF23 increased significantly in eGFR15 ml/min. However, there was no significant difference between the two groups; serum calcium level had a downward trend, but there was no statistical difference; serum phosphorus level had an upward trend. There was a significant difference between eGFR (> 45 ml / min < 1.73 m2) and eGFR (> 15 ml / min < 1.73 m2). Pearson correlation analysis showed that the values of lniFGF23 (the natural logarithm of iFGF23) and lncFGF23 (the natural logarithm of cFGF23) were linear. There was a positive correlation (P 0.001). lniFGF23 was positively correlated with the course of CKD, serum phosphorus, serum calcium (correction) and negatively correlated with eGFR; lncFGF23 was positively correlated with serum phosphorus, serum calcium (correction), and lniPTH (natural logarithm of iPTH; iPTH, intact parathyroid hormone, whole parathyroid hormone) and negatively correlated with eGFR (r = - 0.431, P 0.001). The results showed that calibrated calcium, phosphorus, eGFR, and lniPTH were the influencing factors of lniFGF23. Transverse positive calcium, eGFR and lniPTH were the influencing factors of lncFGF23. The levels of iPTH, iFGF23 and cFGF23 in the hyperphosphorus group were higher than those in the normal group, and there were significant differences. The primary cause of CKD 2-5 in children was CAKUT, accounting for 43.9%, followed by glomerular disease, accounting for 23.1%. The onset age of CAKUT was earlier; the imaging examination of urinary system should be improved in young children with CKD. 2. Children with CKD 2-5 had chronic complications such as anemia, hypertension, growth nutrition, CKD-MBD, which affected the life and prognosis of children. CKD-MBD and CKD-MBD were the most common complications in this group. The prevalence of complications increased with the decrease of GFR. In the early stage of CKD, there was abnormal metabolism of calcium and phosphorus. Blood pressure is a risk factor for LVH. More attention should be paid to the diagnosis, treatment and management of complications associated with CKD. 3. Fibroblast growth factor 23 (FGF23) levels are significantly elevated with the decline of renal function. Fibroblast growth factor 23 (FGF23) is involved in calcium and phosphorus metabolism, and is closely related to serum phosphorus, calcium and PTH levels. Predictors.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R726.9
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