【作者】 山都斯 古龙；

【导师】 张浩；

【作者基本信息】 中南大学 ， 内科， 2010， 硕士

【摘要】 背景与目的：慢性肾脏疾病(CKD)是目前世界最为关注的公共卫生事业之一,其病因除原发肾小球疾病外还可继发于糖尿病、高血压病等,其发病率及死亡率日益增高。根据K/DOQI指南,根据GFR数值,CKD可分为5期,CKD发展至后期成为终末期肾脏疾病(ESRD)。腹膜透析是目前ESRD的首选治疗方式之一,有操作简便、有效保护残余肾功能等优势。在CKD患者中,甲状旁腺激素异常是常见的并发症之一。全段甲状旁腺激素((iPTH)是甲状旁腺主细胞合成和分泌的多肽激素。它通过骨和肾来实现升高血钙,降低血磷的作用,被认为是对慢性肾衰竭发展的标志之一,目前发表的临床研究表明,iPTH可以影响到各靶器官,主要作用于骨、肾、脑、心、肺、胰腺、肾上腺、睾丸等器官及淋巴细胞、红血细胞和平滑肌细胞功能。本文拟检测慢性肾脏病(CKD)患者及连续不卧床腹膜透析(CAPD)患者血清iPTH水平,观察其与肾小球滤过率、血清钙、血红蛋白及血压的关系,从而探讨甲状旁腺激素(iPTH)在评估慢性肾脏疾病(CKD)患者肾脏损害程度及不卧床连续性腹膜透析(CAPD)患者治疗效果评估的意义,指导诊疗。方法：选取中南大学湘雅附三医院2006年1月至2009年12月在肾内住院的病人,慢性肾脏病患者共157例,其病因分别为：慢性肾炎52.23%,良性小动脉性肾硬化症21.02%,梗阻性肾病8.28%,糖尿病肾病7.64%,其他原因7.64%,多囊肾3.18%。根据2003年设立的美国全国肾脏基金会,肾脏疾病结果质量行动(K/DOQI)治疗慢性肾脏疾病的临床实践指南,即“肾脏损害≥3个月或者GFR＜60 ml／min／1.73m2,肾脏病理,血液检查,尿液检查或影像学检查异常”,分为CKD1-5期,连续不卧床腹膜透析(CAPD)患者68例,分为透前、透后3个月和透后6个月3组,同时选取正常对照组22例,于我院体检中心排除心肾,肝,脾,肺,内分泌等主要脏器明显器质性病变。排除标准为原发性甲状旁腺功能亢进,甲状腺切除手术,肿瘤,骨质疏松症的治疗中,先天性疾病,肌肉萎缩,肥胖,急性肾功能衰竭,肾移植患者和严重的肝脏疾病。其中CKD患者按照MDRD公式计算肾小球滤过率(ml／min／1.73m2)=186.3*(血清肌酐)-1.154*(年龄)-0.203*(0.742如果女)*(1.21如果非洲美国人)。CKD 1期为,GFR≥90ml／min／1.73m2；CKD 2期为,GFR 60-89ml／min／1.73m2; CKD 3期为,GFR 30-59ml／min／1.73m2;CKD 4期为,GFR 15-29ml／min／1.73m2和CKD 5期为,GFR＜15ml／min／1.73m2(或已经透析者),其中CKD1期组11例,男性5例,女性6例,平均年龄41.54±15.44岁；CKD2期组共14例,男性11例,女性3例,平均年龄55.07±18.29岁;CKD 3期组共32例,男性19例,女性13例,平均年龄55.40±14.76岁；CKD 4期共50例,男性32例,女性18例,平均年龄53.76±14.17岁；CKD 5期共50例,男性20例,女30例,平均年龄45.32±12.68岁；腹膜透析前组共25例,男性16例,女9例,平均年龄47.64±14.89岁；腹膜透析后3个月组共17例,男性8例,女9例,平均年龄47.47±14.63岁；腹膜透析后6个月组共26例,男性12例,女14例,平均年龄53.96±15.29岁；正常对照组共22例,男性16例,女6例,平均年龄43.95±6.10岁。清晨取受检者空腹静脉血,采用仪器日立7600全自动化学分析仪(检测血尿素氮和肌酐)和瑞士生产的罗氏E601全自动电化学发光免疫分析(检测全段甲状旁腺激素;正常参考15-65 pg/ml)。数据经SPSS 16.0软件进行统计学处理,结果行ANOVA及Post hoc试验及直线性归相关分析,P＜0.05为差异,有统计学意义。结果：1)对照组iPTH33.84±9.27pg/ml,CKD 1期iPTH39.67±20.19pg/ml,CKD 2期iPTH36.08±17.12pg/ml,CKD 3期iPTH57.03±39.87pg/ml,CKD 4期iPTH104.58±72.85pg/ml,CKD5期iPTH327.75±250.95pg/ml；CKD 1期血清钙2.33±0.19mmol/l,CKD 2期血清钙2.36±0.23mmol/l,CKD 3期血清钙2.24±0.13mmol/l,CKD 4期血清钙2.22±0.24mmol/l,CKD 5期血清钙2.04±0.22mmol/l;CKD 1期血红蛋白137.45±13.49g／l,CKD 2期血红蛋白138.50±12.85 g／l,CKD 3期血红蛋白114.90±23.88 g／l,CKD 4期血红蛋白103.88±19.98g／l,CKD 5期血红蛋白70.20±19.87 g／l；CKD 1期肌酐清除率1 16.54±27.73ml/min,CKD 2期肌酐清除率67.85±18.97ml/min,CKD 3期肌酐清除率39.59±9.57ml/min,CKD 4期肌酐清除率21.44±4.65ml/min,CKD 5期肌酐清除率7.92±2.84ml/min:CKD 1期收缩压129.82±16.61mmHg,CKD 2期收缩压131.29±14.36,CKD 3期收缩压139.37±18.36mmHg,CKD 4期收缩压138.76±16.81mmHg,CKD 5期收缩压142.04±17.64mmHg。iPTH水平在对照组及CKD 1-5期各组中均呈递增趋势,经分析后CKD 1与2期无明显变化(P＞0.05),在CKD 3-5期有明显变化(P<0.05),其中以CKD 5期最显著；血红蛋白、血钙水平在对照组及CKD1-5组中呈递减趋势,经分析后CKD 1与2期无明显变化(P＞0.05),在CKD 3-5期有明显变化(P＜0.05)；肌酐清除率在对照组与CKD1-5期中递减,经分析后对照组与CKD 1期无明显变化(P>0.05),其余各组均有明显变化(P<0.05)。同时,本研究发现iPTH与肌酐清除率(r=-0.429,P＜0.01)、血红蛋白(r=-0.546,P＜0.01)、血钙浓度(r=-0.282,P＜0.01)呈负相关,有统计学意义,而与血压,性别无明显相关。并且本研究通过直线性回归分析发现发现iPTH可预计评估29%血红蛋白的变化趋势,F(1,177)=75.05,P＜0.05、及18%患者肌酐清除率的变化趋势,F(1,177)=39.88,P<0.05,但不能预计评估收缩压(SBP)水平的变化趋势,F(1,177)=1.79,P＞0.05。2)对照组iPTH33.84±9.27pg/ml,透析前组iPTH288.76±175.74pg/ml,透析后3个月iPTH259.13±186.47pg/ml,透析后6个月iPTH302.69±274.80pg/ml；透析前组血清钙2.02±0.22mmol/l,血红蛋白78.28±14.97 g／l,透析后3个月组血清钙2.05±0.17mmol/l,血红蛋白71.76±13.78 g／l,透析后6个月组透析前组血清钙2.11±0.19mmol/l,血红蛋白86.00±24.63 g／l。iPTH水平在对照组与透析前组、透析后3个月组、透析后6个月组递增,除透析后3个月与透析后6个月组之间无差异外(P>0.05),余每组之间都存在显著差异(P＜0.05)。同时,本研究发现iPTH与血红蛋白负相关(r=-0.480,P<O.01),但与收缩压(r=0.180,P=0.090)、血钙水平水平(r=0.013,P=0.917)、年龄(r=-0.020,P=0.851)无明显相关(P＞0.01)。并且本研究通过直线性回归分析发现发现iPTH可预计评估23%血红蛋白的变化趋势,F(1,88)=26.32,P<0.05。结论：1)血清全段甲状旁腺激素(iPTH)是终末期肾脏疾病(ESRD)患者肾脏严重损害的指标之一。2)慢性肾脏病(CKD)患者血清钙、血红蛋白、肌酐清除率与血清全段甲状旁腺激素(iPTH)负相关。3)腹膜透析可部分清除血清全段甲状旁腺激素(iPTH)。更多还原

【Abstract】 Background and ObjectiveChronic kidney disease (CKD) is one of the world’s most concerned public health issue. In addition to its etiology due to primary glomerular disease, also can be secondary to diabetes mellitus, hypertension, etc., the incidence rate and mortality are increasing. According to K/DOQI guidelines, based on their GFR values, CKD can be divided into 5 different stages, while in the later stages CKD leads to end-stage renal disease (ESRD). Peritoneal dialysis is the preferred treatment of choice in ESRD; there are simple, effectively preserves the residual renal function and other advantages. In CKD patients, intact parathyroid hormone level abnormality is a common complication. Intact Parathyroid hormone (iPTH) is a polypeptide molecule synthesized by and secreted from the chief epithelial cells of parathyroid glands. Intact parathyroid hormone (iPTH) is a regulator of mineral homeostasis, acting mainly on bone and kidney. Intact parathyroid hormone (iPTH) is considered as one of the biomarks of the development of chronic renal failure. Previous investigations have demonstrated that intact parathyroid hormone (iPTH) can also affect the function of various target organs-brains, heart, lungs, pancreas, adrenal glands, testes and cells-lymphocytes, red blood cells and smooth muscles. This clinical study intends to investigate the intact PTH (iPTH) level in Chronic Kidney Disease and observe it is an best indicator of kidney damage, the correlation between intact parathyroid hormone (iPTH) level and creatinine clearance rate (CrCl), hemoglobin (Hb), serum calcium (Ca) and hypertension, and finally to review the strategies for the better treatment modalities in chronic kidney disease (CKD) and Continuous Ambulatory Peritoneal Dialysis (CAPD) patients.Methods and MaterialsIn a Randomized Prospective Study, medical record data of the eligible patients were collected from the Medical Record Department of 3rd Xiang-Ya Hospital, who were managed as Chronic Kidney Disease (CKD) and Continuous Ambulatory Peritoneal Dialysis (CAPD) patients, at the Nephrology Department,3rd Xiang-Ya Hospital, Central South University between January 2006 and December 2009. For the clinical analysis, patients were selected in accordance with the guidelines of the Kidney Disease Outcome Quality Initiative (K/DOQI) Clinical Practice Guidelines for Chronic Kidney Disease:Evaluation, Classification, and Stratification 2003 set out by the National Kidney Foundation (NKF). After thorough review, in accordance to the (NKF), (K/DOQI) guidelines, finally recruited 157 eligible Chronic Kidney Disease (CKD), where etiology was:Chronic Glomerulonephritis (52.23%), followed by Hypertensive Nephrosclerosis (21.02%), Obstructive Nephropathy (8.28%), Diabetic Nephropathy (7.64%), other causes (7.64%) and Polycystic Kidney Disease (3.18%) respectively, and 68 eligible Continuous Ambulatory Peritoneal Dialysis (CAPD) subjects respectively. All the normal healthy patients (n=22) were recruited from the Department of Health Management,3rd Xiang-Ya Hospital of Central South University, after the patient gave their written consent to participate in the clinical research program. Every subject were thoroughly ruled out the presence of heart, liver, lungs, spleen and any other major organs damage and pathological changes, too.The definition of Chronic Kidney Disease (CKD) from the Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guideline that was published in 2003 by the National Kidney Foundation (NKF) states "chronic kidney disease is defined as either kidney damage or GFR<60 ml/min/1.73m2 for≥3 months. Kidney damage is defined as pathological abnormalities, including abnormalities in blood, urine tests or imaging studies". Most commonly and standard Continuous Ambulatory Peritoneal Dialysis (CAPD) employs 4-6 exchanges per day.The staging of the Chronic Kidney Disease (CKD) patients were done according to National Kidney Foundation (NKF), Kidney Disease Outcome Quality Initiative (K/DOQI) guideline from CKD stage 1 to CKD stage 5, and is based on an estimated glomerular filtration rate (eGFR), calculated from the serum creatinine level, using the equation abbreviated MDRD equation:GFR (ml/min/1.73m2)= 186.3* (serum creatinine)-1.154* (age)-0.203*(0.742 if female)* (1.21 if African American). Chronic Kidney Disease (CKD) stage 1 is defined by an eGFR of≥90 ml/min/1.73 m2 or other evidence of structural damage to the kidney; Chronic Kidney Disease (CKD) stage 2 has a similar definition, but an eGFR of 60-89 ml/min/1.73 m2. And, Chronic Kidney Disease (CKD) stages 3,4, and 5 are defined solely by an estimated glomerular filtration rate (eGFR) of 30-59,15-29, and less than 15 ml/min/1.73 m2 respectively. Continuous Ambulatory Peritoneal Dialysis (CAPD) group was categorized into 3 groups depending upon the duration of dialysis, as before continuous ambulatory peritoneal dialysis, after 3 months on continuous ambulatory peritoneal dialysis and after 6 months on continuous ambulatory peritoneal dialysis respectively. Finally, had CKD 1 (n=11, Male=5, Female=6, mean age=41.54±15.44 years); CKD 2 (n=14, Male=11, Female=3, mean age=55.07±18.29 years); CKD 3 (n=32, Male=19, Female=13, mean age=55.40±14.76 years); CKD 4 (n=50, Male=32, Female=18, mean age=53.7614.17 years); CKD 5 (n=50, Male=20, Female=30, mean age=45.32±12.68 years); before continuous ambulatory peritoneal dialysis group (n=25, Male=16, Female=9, mean age=47.64±14.89 years); after 3 months on CAPD group (n=17, Male=8, Female=9, mean age=47.47.40±14.63 years), after 6 months on CAPD group (n=26, Male=12, Female=14, mean age=53.96±15.29 years) and Control group (n=22, Male=16, Female=6, mean age=43.95±6.10 years).Inclusion characteristics consisted of patients with the diagnosis of Chronic Kidney Disease in accordance with National Kidney Foundation (NKF), Kidney Disease Outcome Quality Initiative (K/DQOI) guidelines 2003; either sex of age 18 years and above; patients on continuous ambulatory peritoneal dialysis (CAPD) and chronic kidney disease (CKD) patients not yet on any form of dialysis; while exclusion characteristics consisted of primary hyperparathyroidism; previous parathyroidectomy; neoplasia; osteoporosis under treatment; congenital conditions; wasting; obese; acute kidney failure (ARF); kidney transplantation patients and severe liver disease.Early morning fasting venous blood was collected and analyzed with Instrument HITACHI 7600 automatic chemical analyzer (detection of BUN and Cr), and Roche E601 fully-automatic electrochemiluminescence assay (detection of iPTH; normal range 15-65 pg/ml),at the clinical laboratory and the Nuclear medicine laboratory of the 3rd Xiang-Ya hospital, Central South University respectively.After staging, significant differences among Chronic Kidney Disease (CKD) stages and Continuous Ambulatory Peritoneal Dialysis (CAPD) groups were obtained in gender, age, serum creatinine (Scr), creatinine clearance rate (CrCl), serum calcium (Ca), systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin (Hb), Blood Urea Nitrogen (BUN) and intact parathyroid hormone (iPTH) level, using ANOVA and later determined by Post Hoc test, respectively. All the data were compared between groups and later with Control group. To analyze the correlation between intact parathyroid hormone (iPTH) and other related variables we used Pearson correlation and by linear regression analysis the cause and effect was observed.Clinical data were presented as mean±SD or percentage. Data were analyzed using the statistical Package for the Social Sciences (SPSS) software package (16.0) for Windows (SPSS Inc., Chicago, IL, USA). Numeration data were analyzed by Chi-Square test (x2).Results were considered significant at P＜0.05.Result:1. Control group mean iPTH 33.84±9.27 pg/ml, CKD 1 mean iPTH 39.67±20.19 pg/ml, CKD 2 mean iPTH 36.08±17.12 pg/ml, CKD 3 mean iPTH 57.03±39.87 pg/ml, CKD 4 mean iPTH 104.58±72.85 pg/ml, CKD 5 mean iPTH 327.74±250.95 pg/ml; CKD 1 mean serum calcium 2.33±0.19 mmol/l, CKD 2 mean serum calcium 2.36±0.23 mmol/l, CKD 3 mean serum calcium 2.24±0.13 mmol/1, CKD 4 mean serum calcium 2.22±0.24 mmol/1, CKD 5 mean serum calcium 2.04±0.22 mmol/l; CKD 1 mean Hb 137.45±13.49 g/l, CKD 2 mean Hb 138.50±12.85 g/l, CKD 3 mean Hb 114.90±223.88 g/l, CKD 4 mean Hb 103.88±19.98 g/l, CKD 5 mean Hb 70.20±19.87 g/l; CKD 1 mean CrCl 116.54±27.73 ml/min, CKD 2 mean CrCl 67.85±18.97 ml/min, CKD 3 mean CrCl 39.59±9.57 ml/min, CKD 4 mean CrCl 21.44±4.65 ml/min, CKD 5 mean CrCl 7.92±2.84 ml/min; CKD 1 mean SBP 129.82±16.61 mmHg, CKD 2 mean SBP 131.29±14.36 mmHg, CKD 3 mean SBP 139.37±18.36 mmHg, CKD 4 mean SBP 138.76±16.81 mmHg, CKD 5 mean SBP 142.04±17.64 mmHg. The iPTH level was in increasing order, from control group, stage CKD 1 to CKD 5, was statistically significant (P<0.05). iPTH level was more prominently elevated at CKD 5 (P<0.05), which was statistically significant. iPTH level between the control group, stage CKD 1 and stage CKD 2 had no significant difference. Hemoglobin (Hb) level was significantly decreased as it progresses from control group and stage CKD 1 to CKD 5 (P<0.05), consistent with the advancing degree of renal failure, but no significant difference between stage CKD 1 and CKD 2. Serum calcium (Ca) level increases from stage CKD 1 to CKD 2 and decreases afterwards, with progression from stage CKD 1 to CKD 5, which reaches a statistically significant difference (P＜0.05) at stage CKD 4 and CKD 5, and CrCl was declining as it progresses from control group, stage CKD 1 to CKD 5, which was statistically significant (P<0.05), but no significant difference between stage CKD 1 and Control group (P<0.05).iPTH was negatively correlated with CrCl (r=-0.429, P＜0.01), Serum Calcium (Ca) (r=-0.282, P＜0.01) and Hemoglobin (Hb) (r=-0.546, P＜0.01), which was statistically significant (P<0.01). But, the SBP (r=0.100, P=0.183), age (r=-0.019, P=0.805) and sex (r= 0.060, P =0.427) was not correlated significantly (P>0.01). In linear regression analysis, found that 29% variability of Hemoglobin (Hb), F (1,177)= 75.05, P＜0.05; 18% variability of Creatinine Clearance Rate (CrCl), F (1,177)= 39.88, P<0.05, predicted significantly but, cannot predict the variability of Systolic blood pressure (SBP), F (1,177)= 1.79, P>0.05 by the iPTH level.2. Control group mean iPTH 33.84±9.27 pg/ml, pre-dialysis group mean iPTH 288.76±175.74 pg/ml, after 3 months of dialysis mean iPTH 259.13±186.47 pg/ml, after 6 months of dialysis mean iPTH 302.69±274.80 pg/ml, pre-dialysis group mean serum calcium 2.02±0.22 mmol/l, mean Hb 78.28±14.97 g/l, after 3 months of dialysis mean serum calcium 2.05±0.17 mmol/1, mean Hb 71.76±13.78 g/l, after 6 months of dialysis mean serum calcium 2.11±0.19 mmol/l, mean Hb 86.00±24.63 g/l. iPTH level was a statistically significant between Control group and other CAPD groups (P＜0.05). But, between before PD group, after 3 months and 6 months CAPD groups, there was no statistical significant (P>0.05). iPTH level in control group, pre-dialysis, after 3 and 6 months of CAPD groups was in increasing order, respectively. iPTH was negatively correlated with Hemoglobin (Hb) (r= -0.480, P= 0.000), which was statistically significant (P<0.01). But, other variables SBP (r= 0.180, P= 0.090), Serum calcium (Ca) (r= 0.013, P= 0.917), and age (r=-0.020, P= 0.851) was not significantly correlated (P>0.01). In linear regression analysis, found that 23% variability of Hemoglobin (Hb), F (1,88)= 26.32, P<0.05; can be predicted significantly by the iPTH level.Conclusion:1) Serum intact parathyroid hormone (iPTH) is one of the important indicators of kidney damage in patient with End-Stage Renal Disease (ESRD).2) Serum calcium (Ca), Creatinine Clearance Rate (CrCl) and Hemoglobin (Hb) are negatively correlated with intact parathyroid hormone (iPTH) in patients with Chronic Kidney Disease (CKD), which was statistically significant.3) Peritoneal Dialysis can partially eliminate intact parathyroid hormone (iPTH).更多还原