苯那普利联合厄贝沙坦对早期糖尿病肾病的干预研究

目的：研究苯那普利联合厄贝沙坦对早期糖尿病肾病（diabetic nephropathy,DN）患者肾功能、血浆脂联素（adiponectin,APN）和高敏C反应蛋白（high sensitivity-C response protein,hs-CRP）的影响。方法纳入2011年1月~2012年6月北京军区总医院内分泌科早期DN患者84例,所有患者均伴有1级高血压。随机分为常规组（n=42）及联合组（n=42）,常规组予苯那普利（10～20）mg,联合组予苯那普利10mg联合厄贝沙坦（150～300）mg,疗程均为3个月。比较两组治疗前后患者内生肌酐清除率（creatinine clearance rate,Ccr）、24小时尿蛋白定量（24 h-UPE）及血浆APN和hs-CRP水平。结果两组治疗后Ccr及血浆APN水平均较治疗前明显升高,24 h-UPE和hs-CRP水平均较治疗前明显降低,差异有统计学意义（P＜0.05）。与常规组相比,联合组治疗后24 h-UPE[（124±23.1）mg/L vs.（167±38.1）mg/L]和hs-CRP[（12.8±1.1）mg/L vs.（4.1±1.3）mg/L]水平更低,而Ccr[（95±11.1）mL/min vs.（83±9.4）mL/min]和血浆APN[（6.1±1.6）mg/L vs.（4.9±1.5）mg/L]水平更高,组间比较差异有统计学意义（P＜0.05）。结论苯那普利联合厄贝沙坦治疗可更好地保护早期DN患者的肾功能,这可能与其能够较好地保护血管内皮功能和降低炎症反应有关。     

Hypertension and prognosis in established diabetic nephropathy

In the patient with diabetes mellitus the onset of intermittent and then persistent proteinuria signals the development of established nephropathy. This heralds an extremely poor prognosis and mortality in this group has been estimated to be 80 to 100 times greater than that of an age-matched normal population. The excess mortality and its associated morbidity exists for both insulin-dependent and non-insulin-dependent patients who develop proteinuria. The final cause of death is often cardiovascular, such as myocardial infarction or a cerebrovascular accident, rather than end stage renal failure with death from uraemia. Strict and aggressive control of blood pressure during this stage is the only therapy that has been shown to slow the decline in glomerular filtration. To date, there have been no studies large enough to establish if this can produce the desired effect of reducing the excess mortality in this group. The newer antihypertensive agents may have a specific role but this also remains to be shown conclusively; their major advantage may be related to their fewer side-effects especially on cardiovascular risk factors in this highly susceptible group.     

伊贝沙坦治疗早期糖尿病肾病的临床研究

63例早期糖尿病肾病患者,随机分为对照组和伊贝沙坦组。治疗12周,伊贝沙坦组HbA1c、尿白蛋白排泄率、尿β2微球蛋白、血清一氧化氮和血浆内皮素1水平均有明显下降,提示伊贝沙坦可延缓糖尿病患者肾功能损害。     

Monitoring kidney function in diabetic nephropathy

Summary Progression in diabetic nephropathy is usually determined by repeated measurements of glomerular filtration rate and expressed as rate of decline in glomerular filtration rate. Our aim was to evaluate the agreement between rate of decline in glomerular filtration rate estimated from the Cockroft-Gault formula: (140-age)^*K^*body weight^* (1/S-creatinine) and measured by the plasma clearance of ⁵¹CrEDTA. All insulin-dependent diabetic patients with diabetic nephropathy followed-up for at least 5 years with at least 5 simultaneous measurements of glomerular filtration rate, s-creatinine, and weight were included in the study. Forty-three patients (32 male/11 female), age 31 (18–61) years were enrolled. Observation period: 6.6 (5.1–9.9) years and number of investigations per patient 6 (5–16) (median(range)). Baseline glomerular filtration rate (ml/min) was 97 (30) measured and 107 (37) estimated (mean(SD))(p<0.001) and the 95% limits of agreement were –42.0 to 20.8 ml/min. Measured and estimated glomerular filtration rate correlated significantly (r = 0.91, p<0.00001). Rate of decline in kidney function ml · min^–1 · year^–1 was 4.7 (3.3) measured and 4.8 (3.5) estimated (mean(SD)) (NS), but the 95% limits of agreement showed a wide range –3.9 to 3.5 ml · min^–1 · year^–1. A significant correlation between rate of decline in measured and estimated glomerular filtration rate was present (r = 0.84, p<0.00001). In conclusion, glomerular filtration rate is overestimated by the Cockroft-Gault formula. The mean rates of decline in glomerular filtration rate are comparable, but the limits of agreement are wide, which make the Cockroft-Gault method unacceptable for clinical purposes, i.e. monitoring progression in kidney function in the individual patient. However, the estimated glomerular filtration rate may be used for comparison of groups in observational studies and in clinical trials with a long observation period.Abbreviations GFR Glomerular filtration rate - ⁵¹Cr-ED-TA ⁵¹Chromium ethylene diamine tetra-acetic acid - IDDM insulin-dependent diabetes mellitus     

Monitoring kidney function in diabetic nephropathy

We investigated the validity of a one plasma sample method (I) compared with a multiple plasma sample method (II) for routine clinical determination of glomerular filtration rate (GFR) in 35 insulin-dependent diabetic patients suffering from nephropathy. GFR was measured after an intravenous bolus injection of 100 microCi 51Cr-EDTA by determination of plasma radioactivity in venous blood samples taken from the other arm 180, 200, 220 and 240 min after the injection (II). The plasma radioactivity in the sample drawn 240 min after injection was used in method I. During the mean investigation period of 32 months (12-62 months) a total of 184 GFR determinations were performed. The average interval between the GFR measurements was 6 months (1-21 months). In 127/184 of the study intervals method I indicated a decrease in GFR. The corresponding figure for method II was almost identical, 130/184. The mean decline in GFR was 8.1 +/- 7.2 and 7.8 +/- 6.9 ml year-1 1.73 m-2 using methods I and II, respectively (NS). The methods essentially provided the same GFR values in absolute terms (r = 0.98, P less than 0.001). We conclude that the one plasma sample method can be used as a valid routine technique in non-uraemic patients with nephropathy.     

厄贝沙坦联合阿魏酸钠治疗糖尿病肾病的临床观察

目的观察厄贝沙坦联合阿魏酸钠治疗糖尿病。肾病Ⅲ～Ⅳ期的临床疗效。方法将60例糖尿病肾病患者随机分为对照组和治疗组,每组各30例。对照组给予糖尿病饮食、口服降糖药物或胰岛素控制血糖治疗,并口服厄贝沙坦150～300mg,1次/d;治疗组在以上治疗的基础上加用阿魏酸钠300mg/d静脉滴注,2周为1个疗程,休息2d继续第2个疗程,共2个疗程后测定治疗前后尿微量白蛋白(24h U-mAlb)、24h尿蛋白定量(U-Pro)、血清尿素氮(BUN)、血清肌酐(SCr)、甘油三酯(TG)、总胆固醇(TC)。结果治疗后两组患者24h U-mAlb、U-Pro、BUN、SCr、TG、TC均下降,但治疗组下降更为明显。结论厄贝沙坦联合阿魏酸钠对糖尿病肾病Ⅲ～Ⅳ期患者有较好的疗效,是一种临床较为实用的治疗方法,两药联用可增强对肾脏的保护作用。     

厄贝沙坦联合前列地尔治疗糖尿病肾病的Meta分析

目的 对公开发表的厄贝沙坦联合前列地尔治疗糖尿病肾病的文献进行Meta分析,评价厄贝沙坦联合前列地尔对糖尿病肾病的治疗效果.方法 检索Pubmed、Medline、中国期刊全文数据库、中文科技期刊全文数据库及万方全文数据库公开发表的厄贝沙坦联合前列地尔治疗糖尿病肾病的随机对照临床试验资料.采用RevMan 5.1软件对纳入资料进行统计分析.结果 纳入Meta分析的文献共7篇,随机对照研究总人数442例,其中试验组224例,对照组218例.厄贝沙坦联合前列地尔对糖尿病肾病的治疗在降低尿白蛋白排泄率[WMD=-42.28,95％ CI(-66.81,- 18.15),P=0.0006]、血肌酐[WMD=- 11.64,95％ CI(- 18.15,-5.14),P=0.0005]、24小时尿蛋白[WMD=-0.16,95％ CI(-0.31,-0.01),P=0.03]方面均优于对照组,对尿素氮的影响[WMD=-0.01,95％ CI( -0.31,0.30),P=0.97]与对照组比较差异无统计学意义.结论 厄贝沙坦联合前列地尔治疗糖尿病肾病优于单用厄贝沙坦治疗.     

舒洛地特联合厄贝沙坦治疗老年糖尿病肾病疗效观察

目的 观察舒洛地特联合厄贝沙坦治疗老年糖尿病肾病的临床疗效.方法 选择糖尿病肾病患者65例,随机分为对照组和治疗组.对照组在常规治疗的基础上加用厄贝沙坦,治疗组在对照组的基础上加用舒洛地特,8周后测定2组病人空腹血糖(FBG)、24h尿蛋白定量、血清光抑素C、三酰甘油(TG)、纤维蛋白原(FIB)的变化.结果 治疗组与对照组光抑素C、24h尿蛋白定量都有所下降,治疗组比对照组下降更为明显(P＜0.05);而TG、FIB只有在治疗组有所下降,明显低于对照组(P＜0.01).结论 舒洛地特联合厄贝沙坦可以更有效地改善老年糖尿病肾病患者的肾功能.     

伊贝沙坦对糖尿病大鼠一氧化氮系统及肾脏的影响

目的　研究伊贝沙坦对糖尿病大鼠一氧化氮 (NO)系统及肾脏的影响。　方法　随机将 4 0只Wistar大鼠分为 4组 ,每组 10只 ,分别为正常对照组、糖尿病组、伊贝沙坦组和开搏通组。病程 12周时处死大鼠 ,取血、尿和肾脏标本 ,测定尿量、体重、肾重 /体重比值、血糖、糖化血红蛋白(HbA1c) ;测定血清、尿液和肾组织的NO水平 ,通过免疫组化方法 ,检测肾脏组织诱导型一氧化氮合酶 (iNOS)蛋白的合成 ,并通过光镜和电镜观察肾脏的病理结构变化。　结果　治疗 12周后 ,糖尿病各组大鼠的尿量、肾重 /体重比值、血糖、HbA1c、血清、尿液和肾脏组织的NO水平、肾脏组织iNOS蛋白的合成、肾小球体积和肾小球基底膜厚度明显高于或大于正常组 ,体重明显低于正常组 (P <0 .0 1) ;伊贝沙坦组大鼠的血清、尿液和肾脏组织的NO水平、肾脏组织iNOS蛋白的合成、肾小球体积和肾小球基底膜厚度比糖尿病组明显减少 (P <0 .0 5 ) ;血清、尿液和肾组织NO水平与肾小球体积和肾小球基底膜厚度呈正相关。　结论　伊贝沙坦能延缓糖尿病大鼠肾脏功能损害的进展 ,其机制可能与伊贝沙坦不同程度地抑制糖尿病大鼠NO的产生有关。     

Reported parental age of death in type 2 diabetic patients with and without established diabetic nephropathy

BACKGROUND: Diabetic patients with renal disease have increased mortality, largely from cardiovascular disease. This could be related to insulin resistance or to other inherited factors. The aim of the present study was to investigate whether there is evidence of the familial aggregation of increased mortality, even in the absence of diabetes, by studying the reported parental age of death in type 2 diabetes. METHODS: Patients with type 2 diabetes and nephropathy (group A), patients with type 2 diabetes but without nephropathy (group B) and normal controls (group C) were interviewed and asked to report the age of death of their parents. RESULTS: The mean (+/-standard deviation) parental age of death was 68.2 (+/-13.8) years in group A, 67.3 (+/-16.0) years in group B and 68.1 (+/-14.9) years in group C. There was no statistical difference between any of the groups. CONCLUSION: Our preliminary study has failed to show evidence of reduced life expectancy of parents of patients with type 2 diabetes and nephropathy.     

Natural course of kidney function in Type 2 diabetic patients with diabetic nephropathy.

AIMS: To determine the natural course of kidney function and to evaluate the impact of putative progression promoters in Caucasian Type 2 diabetes mellitus (DM) patients with diabetic nephropathy who had never received any antihypertensive treatment. METHODS: A long-term observational study of 13 normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy. Glomerular filtration rate (GFR) was measured approximately every year (51Cr-EDTA plasma clearance technique). Albuminuria, blood pressure (BP) and haemoglobin A1c (HbA1c) was determined 2-4 times per year and serum cholesterol every second year. RESULTS: The patients (12 males/one female), age 56+/-9 (mean +/- SD) years, with a known duration of diabetes of 10+/-6 years, were followed for 55 (24-105) (median (range)) months. GFR decreased from 104 (50-126) to 80 (39-112) ml x min(-1) x 1.73 m(-2) (P = 0.002) with a median rate of decline of 4.5 (-0.4 to 12) ml x min(-1) x year(-1). During follow-up, albuminuria rose from 494 (301-1868) to 908 (108-2169) mg/24 h (P = 0.25), while BP, HbA1c and serum cholesterol remained essentially unchanged. In univariate analysis the rate of decline in GFR did not correlate significantly with neither baseline nor mean values during follow-up of BP, albuminuria, HbA1c and serum cholesterol. CONCLUSIONS: Our study suggests that normotensive to borderline hypertensive Type 2 DM patients with diabetic nephropathy have a rather slow decline in kidney function, but we did not unravel the putative progression promoters responsible for the variation in rate of decline in GFR.     

Effect of long-term near-normoglycemia on the progression of diabetic nephropathy

The effect of prolonged restoration of near-normoglycemia on the progression of diabetic nephropathy was evaluated in a controlled study in which 10 insulin-dependent (type 1) diabetic patients with clinical proteinuria were randomized to continue with conventional insulin treatment (CIT) or to undertake more intensive diabetic therapy using continuous subcutaneous insulin infusion (CSII). The patients, mean age 33 +/- 8 yr, mean duration of diabetes 15 +/- 4 yr, were studied before and during 12 months of either CIT or CSII therapy. Glycemic control was assessed by means of mean blood glucose (MBG) +/- Standard deviation (SD), urinary glucose excretion and glycosylated hemoglobin, while renal function was assessed by albumin, IgG and beta-2-microglobulin urinary excretion rates, serum creatinine and creatinine clearance. Blood glucose level, urinary glucose excretion and glycosylated hemoglobin fell significantly in the CSII group, while no differences were found in the CIT group after the 12 months observation period. Both groups showed a deterioration in all indices of renal function, as illustrated by an increase of protein excretion rates and of serum creatinine, and by a decline in creatinine clearance. Comparison of the rate of increase of urinary albumin and IgG excretion and of serum creatinine and of the rate of fall in creatinine clearance between CIT and CSII groups demonstrated that the rate of progression of diabetic nephropathy may be slowed by correction of hyperglycemia. Our study, with due reservations because of the small number of examined patients and differences in kidney function at the beginning of the trial shows that intensive diabetic care may play a role in the proteinuric stage of diabetes in slowing further destruction of residual glomerular structure and in delaying end stage renal failure.     

雷公藤多甙联合厄贝沙坦对糖尿病肾病大鼠足细胞nephrin和podocin表达的影响

目的 观察雷公藤多甙联合厄贝沙坦对糖尿病肾病大鼠足细胞nephrin和podocinmRNA和蛋白表达的影响.方法 将体重200 ～ 260 g的50只SD大鼠按随机数字表法分为正常对照组和4个模型组（n=10）,后者分别应用链脲佐菌素造模成功后分为糖尿病肾病组（DN组）、厄贝沙坦组、雷公藤多甙组和雷公藤多甙联合厄贝沙坦组.给予相应干预8周后,检测血尿指标,HE染色观察肾组织病理变化,逆转录-多聚酶链反应（RT-PCR）法检测各组大鼠肾皮质中nephrin和podocinmRNA和蛋白表达.结果 （1）与DN组大鼠比较,雷公藤多甙联合厄贝沙坦组大鼠肾皮质nephrin mRNA （0.507±0.024比0.276 ±0.015,P ＜0.01）和podocin mRNA （0.533±0.024比0.463±0.022,P＜0.01）表达上调.（2）与DN组大鼠比较,雷公藤多甙联合厄贝沙坦组大鼠肾皮质nephrin蛋白（0.738±0.029比0.199±0.012,P＜0.01）和podocin蛋白（0.811 ±0.032比0.227±0.014,P＜0.01）表达上调.（3） HE染色和Masson染色显示,糖尿病组大鼠肾脏肾小球体积增大,系膜基质弥漫增多,系膜细胞明显增多,基底膜弥漫增厚,间质可见灶性淋巴细胞及单核细胞浸润,厄贝沙坦组和雷公藤多甙组病变较糖尿病组减轻,雷公藤多甙联合厄贝沙坦组大鼠肾脏组织病变较厄贝沙坦组和雷公藤多甙组进一步减轻.结论 雷公藤多甙联合厄贝沙坦对糖尿病大鼠的肾脏足细胞具有保护作用,这种保护作用可能是通过上调足细胞nephrin和podocin mRNA和蛋白表达有关.     

The course of kidney function in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy

Summary We evaluated the impact of some putative progression promoters on kidney function in albuminuric Type 2 (non-insulin-dependent) diabetic patients with biopsyproven diabetic glomerulosclerosis. Twenty-six patients (1 female) with a mean age of 52 (standard error 2) years and a known mean duration of diabetes of 9 (1) years were followed-up prospectively for a mean of 5.2 (range 1.0–7.0) years. Twenty-one patients received antihypertensive treatment. During the observation period the glomerular filtration rate decreased from 83 (24–146) to 58 (2–145) ml·min⁻¹·1.73 m⁻² (mean (range)) (p<0.001). The mean rate of decline in glomerular filtration rate was 5.7 (−3.5 to 22.0) ml/min per year. Albuminuria increased from 1.2 (0.3–7.2) to 2.3 (0.4–8.0) g/24 h (geometric mean (range)) (p<0.001). Arterial blood pressure remained unchanged: 162/93 (SE 4/3) and 161/89 (4/2) mm Hg. Univariate analysis showed the rate of decline in glomerular filtration rate to correlate with systolic blood pressure (r=0.71,p<0.001), mean blood pressure (r=0.56,p<0.005), albuminuria (r=0.58,p<0.005) and the initial glomerular filtration rate (r=−0.49,p<0.02). The rate of decline in glomerular filtration rate did not correlate significantly with dietary protein intake, total cholesterol, high-density lipoprotein cholesterol or HbA_1c. Three patients died from uraemia and four patients died from cardiovascular disease. Two patients required renal replacement therapy at the end of the observation period. Our prospective observational study revealed that one-fifth of the patients developed end-stage renal failure during the 5-year observation period. The decline in glomerular filtration rate varied considerably between patients. Increase in arterial blood pressure to a hypertensive level is an early feature of diabetic nephropathy. Elevated systolic blood pressure accelerates the progression of diabetic nephropathy in Type 2 diabetic patients.     

Effects of acetazolamide on kidney function in Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy

Summary We investigated the effects of 3 days treatment with acetazolamide 250 mg three times daily on kidney function in 8 Type 1 (insulin-dependent) diabetic patients with nephropathy, and in 7 healthy subjects in a double-blind placebo controlled cross-over study. Glomerular filtration rate and extracellular fluid volume were measured with the single injection ⁵¹Cr-EDTA technique and fluid flow rate from the proximal tubules was determined by measurement of the renal lithium clearance. A 24% decline in glomerular filtration rate was observed in both groups during acetazolamide treatment (control subjects: 108±11 vs 82±9 ml/min, p<0.02, diabetic patients: 71±19 vs 54±14 ml/min, p<0.01). The renal lithium clearance (ml/min) remained about the same (control subjects: 22±6 vs 27±8, NS, diabetic patients: 14±5 vs 15±4, NS). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one-third (control subjects: 85±11 vs 56±7, p<0.02, diabetic patients: 55±17 vs 37±6, p<0.02), and fractional proximal reabsorption of water and sodium (%) declined (control subjects: 79±5 vs 67±8, p<0.02, diabetic patients: 79±5 vs 72±6, p<0.02). Renal sodium clearance and distal fractional reabsorption of sodium was unchanged. Extracellular fluid volume declined by 10% in both groups (p<0.02). Albuminuria and fractional albumin clearance decreased significantly in the nephropathic patients (p<0.02). Our study suggests that the effects of acetazolamide on kidney function are similar in healthy subjects and patients with diabetic nephropathy.     

Economic evaluation of the use of irbesartan and amlodipine in the treatment of diabetic nephropathy in patients with hypertension in Canada

BACKGROUND: Irbesartan has been shown to reduce the doubling of serum creatinine (a strong predictor of progression to end-stage renal disease), the onset of end-stage renal disease and all-cause mortality in patients with type 2 diabetes when compared with standard care and amlodipine. OBJECTIVE: The present study assessed the cost effectiveness of irbesartan, an angiotensin II receptor antagonist, and amlodipine, a calcium channel blocker, in the treatment of Canadian patients with diabetic nephropathy and hypertension. METHODS: The analysis was conducted based on a Markov model using Monte Carlo simulation analysis to estimate the expected values for outcomes of interest. Transition probabilities were obtained from a comparative trial of amlodipine, irbesartan and standard care (antihypertensive treatment excluding other angiotensin II receptor antagonists or calcium channel blockers) in patients with overt diabetic nephropathy and hypertension. Canadian costs for the health states studied were obtained from published data. RESULTS: Based on the results of the Monte Carlo simulation, irbesartan was dominant over standard care and amlodipine because it both reduces costs and leads to greater life expectancy. The incremental cost-effectiveness ratio for amlodipine in comparison with standard care was 102,000 dollars. Estimates of net benefit were correlated with transition probabilities relating to progression from the initial health state. The results were insensitive to univariate sensitivity analysis. CONCLUSIONS: Irbesartan use would lead to a reduction in medical costs and an increase in life expectancy when compared with amlodipine or standard care.     

Pregnancies in women with diabetic nephropathy: long-term outcome for mother and child

Summary In order to improve the basis upon which to advise women with diabetic nephropathy about pregnancy, we studied the effect of diabetic nephropathy on the course of pregnancy, perinatal out-come, infant development and long-term outcome of the mothers. All pregnancies of women with diabetic nephropathy (defined as proteinuria >400 mg/day (n=26), creatinine clearance <80 ml/min and hypertension in the first trimester (n=10)) followed at our centre from 1982 to 1992 were identified (34 White class F and 2 White class T) and the women and their children re-examined in the spring 1993. From the first to the third trimester the percentage of women with proteinuria over 3 g/day increased from 14 to 53% and those treated with anti-hypertensive medication from 53 to 97%. There were no intrauterine or perinatal deaths, but one child died suddenly 4 weeks postpartum. Of 36 new-borns (gestational week at birth 36(3), birth weight 2384(834) g)), 11 were born before week 34 and 8 had respiratory distress syndrome. Renal function in the first trimester, diastolic blood pressure in the third trimester and an HbA_1c above normal were predictive of gestational age at delivery and low birth weight (stepwise regression analysis). At follow-up of the children (n=35, age 4.5 (0.4–10) years) the majority (n=27) were normally developed but seven had psychomotor retardation (four of them major). One child had a severe motor retardation due to a congenital anomaly. At follow up, 21 of the 29 mothers had preserved renal function (creatinine 1.3 (0.8–4.3) mg/dl and 8 had developed end stage renal disease and required dialysis (2 of whom were White class T) within 3 (1–9) years postpartum. Of those, 4 women (3 White F and 1 White T) had died. Pregnancy did not seem to specifically accelerate the rate of decline of renal function. In women with diabetic nephropathy perinatal mortality can be prevented but perinatal and long-term infant morbidity remains elevated. Women with severely impaired renal function before pregnancy are at risk for serious morbidity when their children are still young. Improvement might be made if all women were to receive specialized care and counselling before, throughout and after pregnancy.Abbreviations ESRD end-stage renal disease - DSST Denver developmental test     

Different long non-coding RNA expression profiles in diabetes and diabetic nephropathy mice kidney

<正>Objective To find the differentially expressed long non-coding RNA (lncRNA) between db/db mice that with nephropathy (DN) or not (DM). Methods In this study,3 DM db/db mice and 2 DN db/db mice proven