【摘要】：目的：慢性腎臟病(chronic kidney disease, CKD)是世界范圍內(nèi)的嚴(yán)重公共健康問(wèn)題,造成了嚴(yán)重的社會(huì)經(jīng)濟(jì)負(fù)擔(dān)。流行病學(xué)調(diào)查顯示近年來(lái)兒童CKD呈增高趨勢(shì)。CKD往往起病隱匿,部分患兒可逐漸進(jìn)展至終末期腎病(ESRD, end stage renal disease)。兒童CKD不僅是兒童ESRD的重要病因,這部分患兒還將成為成人CKD及ESRD的高危人群。兒童CKD的病因與成人不同,我國(guó)對(duì)兒童CKD病因的分析常局限在終末期患兒,且分析病例數(shù)有限。隨著腎功能的減退與疾病的發(fā)展,高血壓、貧血、營(yíng)養(yǎng)不良、鈣磷代謝異常等慢性并發(fā)癥表現(xiàn)越來(lái)越明顯,部分并發(fā)癥在CKD的早期即可出現(xiàn),是影響患兒預(yù)后及生活質(zhì)量的重要因素之一。本研究通過(guò)對(duì)我院CKD2-5期患兒的臨床分析,旨在總結(jié)十年來(lái)復(fù)旦大學(xué)附屬兒科醫(yī)院CKD2-5期患兒的病因構(gòu)成比與起病情況,為早期發(fā)現(xiàn)提供依據(jù)；并通過(guò)橫斷面調(diào)查,觀(guān)察我科住院評(píng)估的CKD2-5期患兒在生長(zhǎng)、貧血、礦物質(zhì)與骨代謝、心血管疾病等方面的并發(fā)癥情況及其治療情況,了解CKD患兒并發(fā)癥的患病率狀況,為臨床診斷和治療提供依據(jù),以指導(dǎo)早期診斷和并發(fā)癥管理；通過(guò)血成纖維細(xì)胞生長(zhǎng)因子23 (fibroblast growth factor 23, FGF23)水平的檢測(cè),了解各期患兒FGF23的水平變化,分析FGF23與鈣磷代謝相關(guān)指標(biāo)的相關(guān)性,探索FGF23作為CKD并發(fā)癥早期異常指標(biāo)的可能。方法：1、病因的回顧性分析：收集2004年1月-2013年12月期間在我院住院的符合診斷標(biāo)準(zhǔn)的CKD2-5期患兒264例,對(duì)其病因、臨床特點(diǎn)、起病情況進(jìn)行回顧性分析。2、并發(fā)癥的橫斷面研究：截取2012年7月-2013年12月期間在我科住院評(píng)估的CKD2-5期患兒,收集其基本資料、臨床病史、生化指標(biāo)、影像學(xué)檢查結(jié)果、治療情況等,分析其貧血、高血壓、身材矮小、礦物質(zhì)骨代謝異常、左心室肥大(left ventricular hypertrophy, LVH)等慢性并發(fā)癥的患病情況。3、血FGF23水平的研究：采用酶聯(lián)免疫分析法(ELISA)對(duì)CKD患兒全段及C端FGF23 (intact FGF23, iFGF23; carboxyl terminalFGF23, cFGF23)的水平進(jìn)行檢測(cè),同時(shí)測(cè)定其血清肌酐、血鈣、血磷、甲狀旁腺激素等指標(biāo),收集臨床資料,觀(guān)察各期患者FGF23水平的變化與相關(guān)指標(biāo)的關(guān)系。結(jié)果：1、264例CKD2-5期患兒中,先天性腎臟和尿路畸形(Congenital anomalies of the kidney and urinary tract, C AKUT)116例(43.9%),腎小球疾病61例(23.1%),遺傳性腎病15例(5.7%),其他14例(5.3%),病因不明58例(22.0%)。0-5歲的患兒中,59.3%(48例)的患兒原發(fā)病為CAKUT,14.8%(12例)為腎小球疾病,10歲的患兒中,49.2%(30例)為腎小球疾病,32.0%(32例)病因未明。確診時(shí)的分期,2期52例(19.7%),中位年齡6.9(3.7,11.0)歲,3期67例(25.4%),中位年齡8.0(4.4,10.5)歲,4期52例(19.7%),中位年齡7.3(3.4-10.8)歲,5期93例(35.2%),中位年齡10.3(7.4,12.6)歲。2011年起,我院就診的病例數(shù)顯著增加,且原發(fā)病診斷明確的比例明顯升高(χ2=4.653,P=0.031),不明原因的比例由27.1%下降至16.2%。上海地區(qū)的患兒起病時(shí)為2期的占42.0%(21/52例),高于全部地區(qū)起病時(shí)為2期的比例。僅有57例(21.6%)患兒體檢發(fā)現(xiàn),余均為癥狀起病。2、在橫斷面研究中,共計(jì)納入123例CKD2-5期患兒,原發(fā)病為CAKUT的56例(45.5%),腎小球疾病32例(26.0%),遺傳性腎病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%)。中位年齡為9.9(6.3,13.2)歲,確診CKD病程為1.0(0.1,2.3)年,我科隨訪(fǎng)時(shí)間為0.4(0,2.0)年,其中我科隨訪(fǎng)大于6月的有60例(48.8%)。貧血在該組病例中的患病率為80.5%,其中2期僅11.8%,3期為58.8%,至4期為87.5%,5期患兒則均患有貧血；各期患兒的血紅蛋白(Hemoglobin,Hb)達(dá)標(biāo)率分別為2期100%,3期30.0%,4期35.7%,5期34.2%。鐵劑總體使用率達(dá)91.9%,促紅細(xì)胞生成素(erythropoietin, EPO)總體使用率達(dá)79.8%,其中5期患者的鐵劑和EPO使用率分別達(dá)98.6%(72/73)和95.9%(70/73),以隨訪(fǎng)時(shí)間是否大于6月分組,隨訪(fǎng)時(shí)間6月的患兒達(dá)標(biāo)率明顯高于≤6月的患兒(χ2=15.338,P0.05)。高血壓的患病率為61.8%,從2期到5期分別為29.4%、41.2%、43.8%、78.1%；收縮壓和舒張壓的達(dá)標(biāo)率分別為51.3%和55.3%,5期患兒的收縮壓和舒張壓達(dá)標(biāo)率為49.1%和52.6%。65.8%(50/76)的患兒使用鈣通道阻滯劑(calcium-channel blocker,CCB),64.5%(49/76)的患兒使用血管緊張素轉(zhuǎn)化酶抑制劑(angiotensin-converting enzyme inhibitor, ACEI)或腎上腺素能受體結(jié)合劑(adrenergic receptor binder,ARB),另有27.6%(21/76)的患兒使用β受體阻滯劑,其中50.0%(38/76)的患兒使用≥2種降壓藥,；另有6.6%(5/76)未予使用降壓藥物。共有37.4%的患兒存在生長(zhǎng)遲緩,2期患兒中患病率為11.8%,在3-5期中為35.30%-43.8%。CKD-MBD (mineral and bone disorder in chronic kidney disease,慢性腎臟病的礦物質(zhì)和骨代謝異常)患病率達(dá)93.5%,在早期的CKD患兒中的患病率已經(jīng)很高,而在CKD5期中達(dá)到了100%。116例進(jìn)行心超檢查的患兒中,有55例患兒診斷為左心室肥大(left ventricular hypertrophy, LVH),其中22名診斷為嚴(yán)重LVH。LVH患兒的CKD病程短于非LVH患兒,年齡亦較非LVH患兒�。籐ogistic回歸分析顯示,高血壓,繼發(fā)性甲狀旁腺機(jī)能亢進(jìn)(secondary hyperparathyroidism,SHPT),Hb值60-90g/L,年齡小于10歲是LVH的獨(dú)立危險(xiǎn)因素。3、針對(duì)FGF23的研究結(jié)果顯示,隨著估算腎小球?yàn)V過(guò)率(Estimated glomerular filtration rate, eGFR)的下降,FGF23水平有上升趨勢(shì),eGFR15ml/min·1.73m2組FGF23水平明顯升高,較前兩組存在顯著差異,但前兩組間無(wú)明顯差異；血鈣水平有下降趨勢(shì),但無(wú)統(tǒng)計(jì)學(xué)差異,血磷水平有上升趨勢(shì),eGFR≥45 ml/min·1.73m2組與eGFR15ml/min·1.73m2組相比有顯著差異。Pearson相關(guān)分析顯示,lniFGF23 (iFGF23的自然對(duì)數(shù))與lncFGF23 (cFGF23的自然對(duì)數(shù))的值存在線(xiàn)性正相關(guān)關(guān)系(P0.001).lniFGF23與CKD病程、血清磷、血清鈣(校正)成正相關(guān),與eGFR成負(fù)相關(guān)；lncFGF23與血清磷、血清鈣(校正)、lniPTH (iPTH的自然對(duì)數(shù)；iPTH, intact parathyroid hormone,全段甲狀旁腺激素)成正相關(guān),與eGFR (r=-0.431, P0.001)成負(fù)相關(guān)。多元回歸結(jié)果顯示,校正鈣、磷、eGFR, lniPTH是lniFGF23的影響因素,橫正鈣、eGFR, lniPTH是lncFGF23的影響因素。高血磷組的iPTH、iFGF23及cFGF23水平均較正常血磷組高,存在顯著差異。SHPT組的血鈣較低,血磷較高,但兩組iFGF23及cFGF23水平無(wú)明顯差異。結(jié)論：1、10年來(lái)兒童CKD2-5期的首要病因?yàn)镃AKUT,占43.9%,其次為腎小球疾病,占23.1%。CAKUT起病年齡較早；對(duì)小年齡段的CKD患兒需注意完善泌尿系統(tǒng)影像學(xué)檢查。2、CKD2-5期患兒存在貧血、高血壓、生長(zhǎng)營(yíng)養(yǎng)、CKD-MBD等慢性并發(fā)癥,影響患兒的生活和預(yù)后。貧血及CKD-MBD是該組病例中最常見(jiàn)的并發(fā)癥,各并發(fā)癥患病率隨GFR的降低呈升高趨勢(shì)。在CKD早期的患兒中,即有鈣磷代謝異常的出現(xiàn)。經(jīng)治療后患兒的臨床指標(biāo)較前改善,但血紅蛋白及血壓的達(dá)標(biāo)率在本組病例中的達(dá)標(biāo)率不高。年齡、貧血、高血壓是LVH的危險(xiǎn)因素。需進(jìn)一步重視CKD患兒相關(guān)并發(fā)癥的診斷、治療和管理。3、FGF23水平隨著腎臟功能的減退明顯升高,FGF23參與鈣磷代謝,與血磷、血鈣、PTH水平相關(guān),其中血磷水平與FGF23水平關(guān)系密切,FGF23可能作為CKD患者血磷升高的早期預(yù)測(cè)指標(biāo)。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R726.9

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