Nephrotic Syndrome: Components,Connections, and Angiopoietin-Like 4–Related Therapeutics

Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), and lipiduria. Each component has been investigated individually over the past four decades with some success. Studies published recently have started unraveling the molecular basis of proteinuria and its relationship with other components. We now have improved understanding of the threshold for nephrotic-range proteinuria and the pathogenesis of hypertriglyceridemia. These studies reveal that modifying sialylation of the soluble glycoprotein angiopoietin-like 4 or changing key amino acids in its sequence can be used successfully to treat proteinuria. Treatment strategies on the basis of fundamental relationships among different components of nephrotic syndrome use naturally occurring pathways and have great potential for future development into clinically relevant therapeutic agents.     

血脂蛋白(a)预测儿童激素敏感型肾病综合征复发的研究

目的:探讨血脂蛋白质(a)[Lp(a)]是否可以预测儿童激素敏感型肾病综合征复发的临床参考指标.方法:50例健康儿童为对照组,22例激素敏感型肾病综合证(SSNS)为研究组,研究组又分为2组:非勤复发肾病综合征组(IRNS)为12例非勤复发者(6个月内少于2次或1年内少于3次),勤复发肾病综合征组(FRNS)为10例勤复发者(6个月内2次或1年内大于3次).测定研究对象血浆脂质代谢指标包括总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A1(Apo A1)、载脂蛋白B(Apo B)、载脂蛋白E(Apo E)和Lp(a).结果:血浆TC、TG、HDL-C、LDL-C、Apo A1、Apo B and Apo E浓度在FRNS和IRNS组无明显差异,而FRNS组血浆Lp(a)较IRNS组升高(813.7±354.6 vs 356.9±267.8 mg/L,P＜0.01).结论:Lp(a)可以作为预测儿童激素敏感型肾病综合征复发的临床参考指标.     

防己黄芪汤对阿霉素肾病大鼠蛋白尿及足细胞病变的影响

目的：探讨防己黄芪汤对蛋白尿及其发生原因——足细胞病变的影响。方法：采用阿霉素肾病大鼠造成肾病综合征模型。以防己黄芪汤、2倍剂量防已黄芪汤、防已黄芪去甘草汤灌胃。于14d、28d、42d测24h尿蛋白定量;实验42d取血、取肾,检测血生化,观察肾组织病理改变,免疫组织化学法、Western-blotting、RT-PCR检测肾组织nephrin、podoein蛋白及基因水平。结果：模型组大鼠蛋白尿明显增加,伴血Alb下降;与模型组比较,防己黄芪汤组大鼠尿蛋白定量在实验14d、28d、42d明显减少。2倍剂量防己黄芪汤组、防己黄芪去甘草汤组大鼠尿蛋白定量在42d明显减少。模型组大鼠nephrin蛋白表达上调,药物干预后表达明显下降;模型组podoein蛋白和基因表达下调,药物干预后表达明显增加。结论：防己黄芪汤明显改善阿霉素肾病大鼠蛋白尿,这可能与其对足细胞关键结构nephrin、podoein表达的调节有关。     

黄芪当归合剂配合西医治疗原发性肾病综合征

目的：观察黄芪当归合剂配合西医治疗原发性肾病综合征的疗效。方法：将黄芪当归合剂配合西医治疗组（治疗组）３６例和单纯西医治疗组（对照组）３２例对照观察。结果：治疗组完全缓解率和总有效率为５５．６％和８６．１％,显著高于对照组的２１．９％和５９．４％（Ｐ＜０．０５）;而治疗组复发率仅为５．６％,明显低于对照组１８．８％（Ｐ＜０．０５）;在肾小管功能恢复方面,３个月治疗后,同组治疗前后比,治疗组与对照组治疗后比Ｐ＞０．０５,差异无显著性,但延长治疗组治疗时间为 ６个月,与治疗前比 Ｐ＜ ０． ０５,差异有显著性。结论：在西医治疗基础上,配合黄芪当归合剂治疗原发性肾病综合征,能增加疗效,减少复发,对肾脏亦有一定的保护作用。     

老年肾病综合征临床和病理分析

目的 :了解老年肾病综合征的临床表现和病理特点。方法 :对我院住院的 34例老年肾病综合征病人进行临床表现和病理类型分析。结果 :34例老年性肾病综合征 ,原发病为原发性肾小球肾炎者 2 3例 ,占 6 7.6 %,糖尿病肾病 6例 ,占 17.6 %。临床表现以浮肿、血尿为主 ,贫血的发生率为 35 .3%,慢性肾衰竭为 17.6 %。肾活检发现 ,原发性肾病综合征中膜性肾病最常见。老年肾病综合征病人用激素或激素加免疫抑制剂治疗的缓解率为 5 2 .9%,有效率为 2 6 .5 %,未缓解率为 2 0 .6 %。合并感染者占 14.7%。结论 :在肾病综合征中老年人所占比例并不高 ,其临床表现与年轻人的肾病综合征相似 ,但合并贫血、慢性肾衰竭 (CRF)和感染的比例较高 ,最常见的病因是慢性肾小球肾炎 ,其病理类型以膜性肾病 (MN)最常见。老年肾病综合征患者对激素或激素加免疫抑制剂治疗的反应尚可。     

复方蛇芪煎剂治疗原发性肾病综合征的临床研究

目的：观察复方蛇芪煎剂治疗原发性肾病综合征的疗效。方法：将复方蛇芪煎剂配合西医治疗组（治疗组）72例和单纯西医治疗组（对照组）65例对照观察。结果：治疗组完全缓解率和总有效率为57.6%和88.1%,显著高于对照组23.8%和59.8%（P＜0.05）;而治疗组复发率仅为6.7%,明显低于对照组19.8%（P＜0.05）;在肾小管功能恢复方面,3个月治疗后,同组治疗前后对比,治疗组与对照组治疗后对比P＞0.05无显著性差异,但延长治疗组治疗时间6个月,与治疗前比P＜0.05,有显著性差异。结论：在西医治疗的基础上,配合复方蛇芪煎剂治疗原发性肾病综合征能增强疗效并能减少复发。     

肾病综合征并发血栓形成的外科治疗体会:4例报道并文献复习

目的探讨肾病综合征并发血栓形成的外科治疗特点。方法从笔者所在单位收治的肾病综合征并发血栓形成的患者中选取4例血栓形成部位罕见、治疗难度大的病例,对其临床资料进行分析。结果 1例在下肢深静脉血栓形成基础上发生下腔静脉血栓形成;1例腹主动脉急性血栓形成伴下肢动脉栓塞导致下肢坏疽行高位截肢;1例股动脉支架内反复血栓形成导致下肢坏疽行高位截肢;1例人工血管及下肢动脉支架内短时间内血栓形成,经干细胞移植后下肢缺血得到缓解。结论在血栓形成的诊治过程中提高对肾病综合征的认识,针对肾病综合征患者高凝状态在围手术期进行预防性抗凝治疗,以及充分认识肾病综合征并发血栓形成抗凝治疗的特殊性,可能会降低肾病综合征患者血栓形成的发生率,提高肾病综合征并发血栓形成的外科治疗水平。     

温阳活血方对大鼠肾病模型白细胞介素4与IgE的影响

目的：探讨肾病综合征与白细胞介素-4（IL-4）及过敏反应的关系。以推断温阳活血方治疗原发性肾病综合征的可能作用机制。方法：用阿霉素（ADR）诱导一种类似人类微小病变肾病模型。选用温阳活血方进行治疗。并设空白。病理及强的松对照组，观测尿蛋白，血清IL-4和IgE等含量的变化。结果：造模组IL-4高于正常组，温阳活血方及强的松均有降低血清IL-4的作用，且IL-4与同期尿蛋白呈直线正相关。IgE改变无统计学差异。结论：温阳活血方减轻肾病模型尿蛋白的作用可能与降低血清IL-4水平有关。     

Cyclosporin in the Treatment of Steroid-responsive and Steroid-resistant Nephrotic Syndrome in Adults

The effect of cyclosporin on proteinuria was studied in 11 patientswith steroid-responsive nephrotic syndrome (10 minimal changenephropathy, one IgM nephropathy) and in four patients withsteroid-resistant nephrotic syndrome from focal segmental glomerulosclerosis.Cyclosporin (mean initial dose 7.7mg/kg per day) produced acomplete remission of proteinuria in 15 nephrotic episodes inthe ten patients with minimal-change nephropathy after a mean14.3 days (range 7–23 days) of therapy. All patients remainedin remission while receiving cyclosporin (mean duration of follow-up147 days; range 40–230 days). However, when cyclosporinwas discontinued on nine occasions in five patients, all relapsedafter a mean 47.8 days (range 7–180 days). Four of thefive patients were subsequently rechallenged with cyclosporinand all responded. Maintenance cyclosporin therapy to prevent relapse was not associatedwith any adverse effects, and there was no significant differencebetween the creatinine clearance before and after 30 days oftherapy (86.9±19.3 and 81.7±23.5 ml/min respectively,P>0.1). The patient with steroid-responsive IgM nephroticsyndrome did not respond to cyclosporin, and there was no significanteffect of cyclosporin on proteinuria in the four patients withFSGS. Cyclosporin is an effective agent for the treatment of patientswith frequently relapsing minimal-change nephropathy who becamesteroid dependent when cyclophosphamide is contraindicated.However, unlike cyclophosphamide, long-term remissions whichpersist after treatment is withdrawn are not obtained, and patientsmay be said to be cyclosporin dependent.     

成人常复发性原发性肾病综合征的中西医结合治疗疗效观察

目的 :比较中西医结合疗法和单纯西医药疗法治疗成人常复发性原发性肾病综合征 (FRNS)的疗效。方法 :6 0例FRNS病人随机分为治疗组 (30例 ,采用中西医结合治疗 )和对照组 (30例 ,采用单纯西药治疗 ) ,比较二组患者临床疗效。结果 :治疗组完全缓解率为 76 .7% ,缓解后 6个月、1年、4年复发率分别为 0、4 .3%、17.4 % ,平均缓解期为 (33.7± 3.6 )月 ,激素不良反应发生率 2 6 .7% ;对照组缓解率为 4 0 % ,6个月、1年、4年复发率分别为 16 .7%、4 1.7%、5 8.3% ,平均缓解期为 (12 .5± 3.6 )月 ,激素不良反应发生率为 6 3.3%。治疗组均明显优于对照组 ,P <0 .0 1。结论 :中西医结合治疗FRNS疗效较为满意。     

高效液相色谱法检测肾病综合征患者泼尼松血药浓度及其临床意义

目的：建立一种高效液相色谱（HPLC）法测定泼尼松（PS）血药浓度的方法,并探讨肾病综合征PS血药浓度与蛋白尿消减关系。方法：以乙酰苯胺为内标,采用HP1100系列高效液相色谱仪,分析柱HPLichrosphere Ca柱（250mm×4mm,5μm）;流动相为：甲醇∶四氢呋喃∶水=25∶25∶50（V/V）,流速为1.0ml/min;检测波长为240nm;室温25℃。血清标本以甲醇沉淀蛋白。结果：泼尼松浓度与峰面积比值之间的线性关系良好,回归方程为Y=6.84×10-4×-39.4×10-4,相关系数为0.99993,回收率为98.70%,批间CV3.76%,批内CV2.25%。线性范围：10～500μg/ml;检测限：5μg/ml。NS组与对照组比较血液平均SP浓度,差异有统计学意义（P〈0.05）;男女组别比较,差异无统计学意义（P〉0.05）;激素抵抗组与激素敏感组血药浓度比较,抵抗组患者SP血药低于敏感组血药浓度,浓度差异有统计学意义（P〈0.05）。结论：高效液相色谱法检测SP血药浓度,色谱峰分离良好,无干扰,是一种可靠、便捷的检测血清PS浓度的方法,对监测长期应用泼尼松治疗类疾病和肾病综合征的血药浓度监测（TDM）,了解用药个体化差异,规范用药方法,为临床治疗提供科学、合理用药理论依据和重要参考,对药效学研究具有重要临床意义。     

Prandial Hypertriglyceridemia in Metabolic Syndrome Is Due to an Overproduction of Both Chylomicron and VLDL Triacylglycerol

The aim was to determine whether fed VLDL and chylomicron (CM) triacylglycerol (TAG) production rates are elevated in metabolic syndrome (MetS). Eight men with MetS (BMI 29.7 ± 1.1) and eight lean age-matched healthy men (BMI 23.1 ± 0.4) were studied using a frequent feeding protocol. After 4 h of feeding, an intravenous bolus of ²H₅-glycerol was administered to label VLDL1, VLDL2, and TAG. ¹³C-glycerol tripalmitin was administered orally as an independent measure of CM TAG metabolism. Hepatic and intestinal lipoproteins were separated by an immunoaffinity method. In MetS, fed TAG and the increment in TAG from fasting to feeding were higher (P = 0.03 and P = 0.04, respectively) than in lean men. Fed CM, VLDL1, and VLDL2 TAG pool sizes were higher (P = 0.006, P = 0.03, and P < 0.02, respectively), and CM, VLDL1, and VLDL2 TAG production rates were higher (P < 0.002, P < 0.05, and P = 0.06, respectively) than in lean men. VLDL1, VLDL2, and CM TAG clearance rates were not different between groups. In conclusion, prandial hypertriglyceridemia in men with MetS was due to an increased production rate of both VLDL and CM TAG. Since both groups received identical meals, this suggests that in MetS the intestine is synthesizing more TAG de novo for export in CMs.Abnormally elevated blood triacylglycerol (TAG) level in the postprandial period is a feature of metabolic syndrome (MetS) and is predictive of an increased risk of cardiovascular disease (1–3). Hypertriglyceridemia is due to excess triglyceride-rich lipoproteins (TRLs): VLDLs synthesized by the liver, containing the higher–molecular weight form of apolipoprotein (apo)B, apoB100, and chylomicrons (CMs), which are synthesized in the intestine in response to an intake of dietary fat and contain the lower–molecular weight form of apoB, apoB48. Both VLDL and CMs share a common lipolytic pathway and are hydrolyzed by lipoprotein lipase, an enzyme predominantly found on the endothelial surfaces of the capillaries of adipose tissue and heart and skeletal muscle (4).Postprandial hypertriglyceridemia in MetS may be due to the overproduction of intestinal or hepatic TRLs, impaired clearance, or a combination of both. Insulin resistance is associated with a postprandial increase in apoB48 particles (5), and some studies suggested that this is due to impaired catabolism of intestinally derived TRL and remnant lipoprotein TAG (6,7). However, the small intestine is capable of utilizing endogenous substrates for TAG synthesis. Duez et al. (8) have used a constant feeding protocol combined with an infusion of labeled leucine to measure apoB48 kinetics, a surrogate measure of intestinal TRL kinetics, in men with a range of insulin sensitivity. The study showed that insulin resistance was associated with increased intestinal apoB48 production rate. In addition, diet-induced insulin resistance in the Syrian golden hamster has been shown to be associated with a marked increase in intestinal lipoprotein production rate in both the fasting and the fed states (9), which could be reduced by treatment with rosiglitazone (10). Since insulin resistance is associated with elevated nonesterified fatty acid (NEFA) flux from adipose tissue, the mechanism that leads to apoB48 overproduction may be increased delivery of NEFAs to the enterocyte, since an acute elevation of NEFAs in hamsters has been shown to increase basal intestinal apoB48 production (11).A number of studies have shown that VLDL apoB100 and VLDL TAG production rate is increased by insulin resistance (12,13) in the fasted state, but no studies have measured VLDL TAG production rate quantitatively, in the fed state, in MetS. We have recently demonstrated that intravenously administered ²H₅-glycerol is incorporated into CM TAG and can be used to measure both CM and VLDL TAG kinetics in a frequent feeding study (14). In the current study, we have used this methodology to investigate whether the greater increase in postprandial TAG in MetS compared with lean healthy subjects is due to an increase in CM and/or VLDL TAG production rate or a decrease in clearance rate. We hypothesized that an increased synthesis of both CM and VLDL TAG in MetS would be the major cause of the increased postprandial TAG.     

Unspecific Increase of Tumor Markers in a Girl with Nephrotic Syndrome and Ovarian Teratoma

Coexistence of nephrotic syndrome and neoplasm is rarely observed in children. We report the diagnostic and therapeutic problems of a 16-year-old female with nephrotic syndrome, ovarian tumor, and increased levels of tumor markers. She was suspected to have paraneoplastic nephrotic syndrome. After ovarian tumor resection, the nephrotic syndrome remission was not observed, while increased tumor marker levels were noted. The patient’s final diagnosis was nephrotic syndrome in the course of primary mesangial proliferative glomerulonephritis. In conclusion, nephrotic syndrome in a patient with neoplasia might occur in the course of the primary and nonparaneoplastic glomerulopathy. Elevated serum tumor markers in patients with nephrotic syndrome might be nonspecific because of the stimulation of their production by peritoneal mesothelium, due to transudation to body cavities, that is, ascites.     

Divergent Effects of Glucocorticoids on Cortical and Trabecular Compartment BMD in Childhood Nephrotic Syndrome

Glucocorticoid (GC) effects on skeletal development have not been established. The objective of this pQCT study was to assess volumetric BMD (vBMD) and cortical dimensions in childhood steroid‐sensitive nephrotic syndrome (SSNS), a disorder with minimal independent deleterious skeletal effects. Tibia pQCT was used to assess trabecular and cortical vBMD, cortical dimensions, and muscle area in 55 SSNS (age, 5–19 yr) and >650 control participants. Race‐, sex‐, and age‐, or tibia length‐specific Z‐scores were generated for pQCT outcomes. Bone biomarkers included bone‐specific alkaline phosphatase and urinary deoxypyridinoline. SSNS participants had lower height Z‐scores (p < 0.0001) compared with controls. In SSNS, Z‐scores for cortical area were greater (+0.37; 95% CI = 0.09, 0.66; p = 0.01), for cortical vBMD were greater (+1.17; 95% CI = 0.89, 1.45; p < 0.0001), and for trabecular vBMD were lower (?0.60; 95% CI, = ?0.89, ?0.31; p < 0.0001) compared with controls. Muscle area (+0.34; 95% CI = 0.08, 0.61; p = 0.01) and fat area (+0.56; 95% CI = 0.27, 0.84; p < 0.001) Z‐scores were greater in SSNS, and adjustment for muscle area eliminated the greater cortical area in SSNS. Bone formation and resorption biomarkers were significantly and inversely associated with cortical vBMD in SSNS and controls and were significantly lower in the 34 SSNS participants taking GCs at the time of the study compared with controls. In conclusion, GCs in SSNS were associated with significantly greater cortical vBMD and cortical area and lower trabecular vBMD, with evidence of low bone turnover. Lower bone biomarkers were associated with greater cortical vBMD. Studies are needed to determine the fracture implications of these varied effects.