高通量血液透析治疗慢性肾衰竭尿毒症的疗效及对尿毒症毒素、免疫球蛋白及肺功能指标的影响

目的:探讨高通量血液透析(HFHD)治疗慢性肾衰竭尿毒症的疗效及对尿毒症毒素、免疫球蛋白及肺功能指标的影响。方法:选取90例于2012年1月-2017年3月期间在喀什地区第一人民医院治疗的慢性肾衰竭尿毒症患者,依据随机数字表法将其分为对照组(n=45)和观察组(n=45),对照组给予血液透析滤过(HDF)治疗,观察组给予HFHD治疗,两组均透析治疗1个月。对比两组患者透析前后症状缓解情况及尿毒症毒素、免疫球蛋白及肺功能指标水平,记录两组相关并发症的发生情况。结果:透析治疗结束后观察组患者缓解率为91.11%(41/45),高于对照组的73.33%(33/45)(P0.05)。两组患者透析后血磷(P~-)、血钾(K~+)、甲状旁腺激素(PTH)、β2-微球蛋白(β2-MG)水平明显低于透析前,血钙(Ca~(2+))水平明显高于透析前(P0.05);观察组透析后K~+、Ca~(2+)、P~-等尿毒症毒素水平与对照组比较差异无统计学意义(P0.05),观察组透析后PTH、β2-MG水平明显低于对照组(P0.05)。透析后,两组患者的免疫球蛋白Ig M、Ig A、Ig G水平均较透析前上升,且观察组高于对照组(P0.05)。透析后,两组患者残气量(RV)均低于治疗前,最大肺活量(FVC)、肺活量(VC)、肺总量(TLC)均高于治疗前,且观察组RV低于对照组,FVC、VC、TLC均高于对照组(P0.05)。观察组并发症发生率为8.89%(4/45),低于对照组的24.44%(11/45)(P0.05)。结论:HFHD治疗慢性肾衰竭尿毒症能够安全有效地清除尿毒症毒素,缓解患者的临床症状,且能够提高患者的免疫功能和肺功能。     

蛋白结合尿毒症毒素及其清除技术的研究进展

尿毒症毒素是一大组体内代谢的产物,在肾功能衰竭患者体液中水平明显升高,并与尿毒症毒素代谢紊乱或临床表现密切相关。部分毒素可与蛋白结合,形成大分子复合物,称为蛋白结合毒素。它们具有多种生物学作用,产生一系列尿毒症并发症,如心血管疾病、免疫功能紊乱、脏器纤维化等。研究发现:血浆分离吸附、高通量血液透析、服用肠道吸附剂等方法可增加蛋白结合毒素的清除。评价尿毒症患者的透析充分性时,也应考虑到蛋白结合毒素。     

高频短时无肝素血液透析治疗尿毒症合并脑出血疗效观察

目的探讨高频短时无肝素血液透析治疗尿毒症合并脑出血的临床效果及安全性。方法对我院2012年1月~2013年12月收治的尿毒症合并脑出血患者18例,在常规治疗的基础上给予高频短时无肝素血液透析治疗,第1周每日1次,每次2h;第2~4周每周3次,每次3h,并观察患者病情变化及预后。结果 18例患者均安全度过脑出血危险期,4周后转低分子肝素规律血液透析。结论高频短时无肝素透析治疗尿毒症合并脑出血是一种安全有效的方法。     

硫酸吲哚酚在终末期肾病心血管并发症中的研究进展

心血管疾病是慢性肾脏病患者最常见的并发症之一,也是慢性肾脏病患者死亡的主要原因。尿毒症毒素是肾功能不全时导致心血管疾病发生的重要因素。在慢性肾脏病患者中,以硫酸吲哚酚为代表的蛋白结合性尿毒症毒素,是一类很难通过常规透析方式清除的物质,且毒性极大。近年来,已有研究证实慢性肾脏病诱导心血管疾病的发生与硫酸吲哚酚的蓄积密切相关。硫酸吲哚酚可通过诱导氧化应激导致内皮损伤,平滑肌细胞增殖和迁移,促进动脉粥样硬化发生,从而影响全身多个系统。本文就尿毒症毒素硫酸吲哚酚在终末期肾病心血管并发症中的研究进展作一综述。     

血液透析滤过和血液透析联合血液灌流治疗尿毒症伴皮肤瘙痒的疗效

目的：探讨不同透析模式对长期行血液透析（hemodialysis,HD）尿毒症伴皮肤瘙痒患者的治疗效果。方法：采用回顾性方法,选择规律性行HD尿毒症伴皮肤瘙瘁患者46例,根据患者接受治疗的模式分为血液透析滤过组（HDF组）和血液透析联合血液灌流组（HP／HD组）,收集患者皮肤瘙痒、血清甲状旁腺素（PTH）、B2．微球蛋白（p2一MG）等指标资料进行分析。结果：HDF和HP／HD治疗后。患者皮肤瘙痒症状得到有效缓解（P〈0．05）,且HP／HD组缓解率（91-3％）显著高于HDF组（65．2％）;两组血清B2．MG、PTH均下降（P〈0．05）,HP／HD组132-MG清除率（69．0±4．3％）显著高于HDF组（57．1±4．1％）,两组在清除PTH方面无显著差异（P〉0．05）。结论：HP／HD和HDF治疗能很好的清除患者体内B2-MG、PTH等中分子物质,改善顽固性皮肤瘙痒症状效果显著,且HP／HD改善效果更明显。     

血液透析深静脉置管并发症的预防及处理

随着血液透析技术的不断完善,尿毒症患者的存活时间越来越长．生活质量也得到了提高。建立稳定、可靠的血管通路是患者进行血液透析的基本保证。对于急诊和动静脉内瘘未建立之前的尿毒症患者,采用留置深静脉双腔透析导管的方法进行血液透析,能保证透析效果．且操作简单,     

耳穴治疗尿毒症血液透析患者皮肤瘙痒的临床分析

目的探讨耳穴治疗尿毒症血液透析患者皮肤瘙痒的临床效果。方法选取80例尿毒症血液透析皮肤瘙痒患者随机分为对照组和观察组各40例,对照组采用常规方法治疗,观察组在常规治疗基础上加用耳穴治疗,观察比较两组临床效果。结果两组患者皮肤瘙痒改善程度比较,观察组明显优于对照组,差异有统计学意义(P0.05)。结论耳穴治疗尿毒症血液透析患者皮肤瘙痒的效果明显,显著提高了患者的睡眠及生活质量,而且该法安全可靠,操作简便,并能避免药物带来的药源性危害,值得临床推广。     

血液透析联合血液灌流及依达拉奉对尿毒症RLS患者外周血清中毒素水平、临床症状及睡眠质量的影响

摘要 目的：探讨高通量血液透析（HFD）联合血液灌流（HP）及依达拉奉对尿毒症不宁腿综合征（RLS）患者外周血清中毒素水平、临床症状、睡眠质量、负性情绪的影响。方法：选择2018年2月至2019年12月我院肾内科收治的174例尿毒症RLS患者,采用随机数字表法将患者分为三组。常规血液透析（HD）组（58例）采用常规血液透析治疗,联合A组（58例）采用HFD联合HP治疗,联合B组（58例）采用HFD联合HP及依达拉奉治疗。观察三组治疗前后肾功能[尿素氮（BUN）、血肌酐（SCr）、尿白蛋白排泄率（UAER）]、血清毒素[甲状旁腺激素（PTH）、硫酸吲哚酚（IS）、硫酸对甲酚（PCS）]水平、RLS评分、睡眠质量、负性情绪以及不良反应的差异。结果：三组治疗后血清BUN、SCr、UAER、PTH、IS、PCS水平、RLS评分、匹兹堡睡眠质量指数（PSQI）评分、汉密尔顿焦虑量表（HAMA)评分、汉密尔顿抑郁量表（HAMD）评分均有所下降（P＜0.05）。联合B组、联合A组治疗后血清BUN、SCr、UAER、PTH、IS、PCS水平低于HD组（P＜0.05）,联合B组、联合A组上述指标比较无统计学差异（P＞0.05）。联合B组治疗后RLS评分、PSQI评分、HAMA评分、HAMD评分均低于联合A组和HD组（P＜0.05）,联合A组低于HD组（P＜0.05）。三组治疗期间不良反应发生率比较无统计学差异（P＞0.05）。结论：HFD联合HP及依达拉奉可改善尿毒症RLS患者的临床症状和肾功能,可降低血清毒素水平,并改善睡眠质量和负性情绪。     

尿毒症皮肤瘙痒患者采取腹膜透析与血液透析治疗的效果探究

目的：探究尿毒症皮肤瘙瘁患者采取腹膜透析与血液透析治疗的临床效果,并为该病的临床治疗提供经验积累。方法：选取我院肾内科于2005年1月-2012年12月收治的52例尿毒症皮肤瘙痒患者,利用随机数字表法进行分组,分别设为研究组和对照组。其中对照组实施血液透析治疗,而研究组开展腹膜透析治疗。记录两组在治疗前和治疗后第8周末血生化客观指标及皮肤瘙痒程度,并做好对比。结果：两组在治疗前的皮肤瘙痒评分、β2-MG、PTH、p3,BUN、SCr值差异无统计学意义（P〉0．05）;治疗后,研究组皮肤瘙瘁评分为（3．4±0．8）分,对照组为（5．8±0．9）分,差异有统计学意义（P〈0．05）。治疗后,研究组β2-MG、PTH及Ps．均低于对照组,差异有统计学意义（P〈0．05）。结论：尿毒症皮肤瘙痒患者的主要致敏因子为大中分子,采取腹膜透析能够有效清除大分子物质,进而达到瘙痒程度的有效改善。     

基于特异性生物识别分子的黄曲霉毒素快速分析方法研究进展

黄曲霉毒素是黄曲霉菌和寄生曲霉菌分泌的次级代谢产物,容易污染粮食作物及其制品,主要存在于发霉的粮食、豆类、坚果及与其相关食品中。黄曲霉毒素,具有极强的毒性和致癌性,尤其是黄曲霉毒素B1,是目前已发现的最强的天然致癌物质,严重威胁人类健康。目前食品中黄曲霉毒素的检测以高效液相色谱、液质联用等仪器分析方法为主,然而仪器分析方法具有设备昂贵、操作繁琐、需要专业人员等不足。近年来以特异性生物分子(抗体、重组抗体、适配体等)识别黄曲霉毒素,并结合不同的信号报告分子,建立了一系列黄曲霉毒素分析方法,检测快速、灵敏并易于操作,在食品安全领域广泛应用。着重从黄曲霉毒素的生物识别分子和信号报告分子两方面介绍目前黄曲霉毒素的快速检测手段,并对其进行比较和评价,同时对黄曲霉毒素快速检测方法的发展方向进行展望。     

Generation and characterization of monoclonal antibody against Advanced Glycation End Products in chronic kidney disease

Advanced Glycation End Products (AGEs) are toxins that are involved in structural and functional alterations of several organs and tissues, resulting in various pathologies. Several types of AGEs have been described but carboxymethyllysine (CML) is the major antigenic AGE compound. In this study, three different immunogenic carrier proteins (KLH, keyhole limpet hemocyanin; BSA, bovine serum albumin; and HSA, human serum albumin) were modified by glycation. The glycated molecules were used to produce epitope-specific monoclonal antibodies able to recognize the CML domain and to detect uremic toxins in the serum of patients with chronic kidney disease (CKD). A competitive ELISA was standardized in order to quantify CML in the sera of CKD patients. An increase in uremic toxins can compromise the clinical condition of these patients, thus, the detection and quantification of these toxins should contribute to a better management and understanding of this disease.     

Involvement of organic anion transporters in the efflux of uremic toxins across the blood-brain barrier

Renal failure causes multiple physiological changes involving CNS dysfunction. In cases of uremia, there is close correlation between plasma levels of uremic toxins [e.g. 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), hippurate (HA) and indoleacetate (IA)] and the degree of uremic encephalopathy, suggesting that uremic toxins are involved in uremic encephalopathy. In order to evaluate the relevance of uremic toxins to CNS dysfunction, we investigated directional transport of uremic toxins across the blood-brain barrier (BBB) using in vivo integration plot analysis and the brain efflux index method. We observed saturable efflux transport of [(3)H]CMPF, [(14)C]HA and [(3)H]IA, which was inhibited by probenecid. For all uremic toxins evaluated, apparent efflux clearance across the BBB was greater than apparent influx clearance, suggesting that these toxins are predominantly transported from the brain to blood across the BBB. Saturable efflux transport of [(3)H]CMPF, [(14)C]HA and [(3)H]IA was completely inhibited by benzylpenicillin, which is a substrate of rat organic anion transporter 3 (rOat3). Taurocholate and digoxin, which are common substrates of rat organic anion transporting polypeptide (rOatp), partially inhibited the efflux of [(3)H]CMPF. Transport experiments using a Xenopus laevis oocyte expression system revealed that CMPF, HA and IA are substrates of rOat3, and that CMPF (but not HA or IA) is a substrate of rOap2. These results suggest that rOat3 mediates brain-to-blood transport of uremic toxins, and that rOatp2 is involved in efflux of CMPF. Thus, conditions typical of uremia can cause inhibition of brain-to-blood transport involving rOat3 and/or rOatp2, leading to accumulation of endogenous metabolites and drugs in the brain.     

Search for peptidic "middle molecules" in uremic sera: isolation and chemical identification of fibrinogen fragments

According to the "middle molecule" (MM) hypothesis, the uremic solutes ranging from 500 to 5,000 Da are insufficiently eliminated by conventional hemodialysis and may act as uremic toxins. However, because of the methodological difficulties of MM purification, their chemical analysis is complicated and the precise structure of these molecules remains obscure. In the present study, a new micro-preparative procedure including SDS electrophoresis and liquid chromatography was applied for isolation of MM peptides from uremic sera. Microsequencing and MS/MS analyses of these peptides showed that most of the identified MM (22 out of 23) represented the N- and C-terminal fragments of the alpha- and beta-chains of fibrinogen. The obtained data provide new information on the precise structure of fibrinogen fragments accumulating in uremic serum as MM.     

Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients - the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125

BACKGROUND: The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated. METHODS: CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events. CONCLUSION: The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD.     

Oxidatively-modified and glycated proteins as candidate pro-inflammatory toxins in uremia and dialysis patients

End stage renal disease (ESRD) patients accumulate blood hallmarks of protein glycation and oxidation. It is now well established that these protein damage products may represent a heterogeneous class of uremic toxins with pro-inflammatory and pro-oxidant properties. These toxins could be directly involved in the pathogenesis of the inflammatory syndrome and vascular complications, which are mainly sustained by the uremic state and bioincompatibility of dialysis therapy. A key underlying event in the toxicity of these proteinaceous solutes has been identified in scavenger receptor-dependent recognition and elimination by inflammatory and endothelial cells, which once activated generate further and even more pronounced protein injuries by a self-feeding mechanism based on inflammation and oxidative stress-derived events. This review examines the literature and provides original information on the techniques for investigating proteinaceous pro-inflammatory toxins. We have also evaluated therapeutic - either pharmacological or dialytic - strategies proposed to alleviate the accumulation of these toxins and to constrain the inflammatory and oxidative burden of ESRD.     

Upregulation of BAD, a pro-apoptotic protein of the BCL2 family, in vascular smooth muscle cells exposed to uremic conditions

Chronic kidney disease (CKD) has recently emerged as a major risk factor for cardiovascular pathology. CKD patients display accelerated atherosclerotic process, leading to circulatory complications. However, it is currently not clear how uremic conditions accelerate atherosclerosis. Apoptosis is an important homeostatic regulator of vascular smooth cells under pathological conditions. In the present study, we explored the regulation of apoptosis in cells of the vascular wall in the uremic context. We analysed the expression and regulation of the proteins of the BCL2 family that play an essential role in apoptosis. Our results, obtained in mice and primary human smooth muscle cells exposed to two uremic toxins, point to the existence of an alteration in expression and function of one pro-apoptotic member of this family, the protein BAD. We explore the regulation of BAD by uremic toxins and report the sensitization of vascular smooth muscle cells to apoptosis upon BAD induction.     

Uremic toxins inhibit transport by breast cancer resistance protein and multidrug resistance protein 4 at clinically relevant concentrations

During chronic kidney disease (CKD), there is a progressive accumulation of toxic solutes due to inadequate renal clearance. Here, the interaction between uremic toxins and two important efflux pumps, viz. multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) was investigated. Membrane vesicles isolated from MRP4- or BCRP-overexpressing human embryonic kidney cells were used to study the impact of uremic toxins on substrate specific uptake. Furthermore, the concentrations of various uremic toxins were determined in plasma of CKD patients using high performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Our results show that hippuric acid, indoxyl sulfate and kynurenic acid inhibit MRP4-mediated [(3)H]-methotrexate ([(3)H]-MTX) uptake (calculated Ki values: 2.5 mM, 1 mM, 25 μM, respectively) and BCRP-mediated [(3)H]-estrone sulfate ([(3)H]-E1S) uptake (Ki values: 4 mM, 500 μM and 50 μM, respectively), whereas indole-3-acetic acid and phenylacetic acid reduce [(3)H]-MTX uptake by MRP4 only (Ki value: 2 mM and IC(50) value: 7 mM, respectively). In contrast, p-cresol, p-toluenesulfonic acid, putrescine, oxalate and quinolinic acid did not alter transport mediated by MRP4 or BCRP. In addition, our results show that hippuric acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid and phenylacetic acid accumulate in plasma of end-stage CKD patients with mean concentrations of 160 μM, 4 μM, 129 μM, 1 μM and 18 μM, respectively. Moreover, calculated Ki values are below the maximal plasma concentrations of the tested toxins. In conclusion, this study shows that several uremic toxins inhibit active transport by MRP4 and BCRP at clinically relevant concentrations.     

Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients – the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]

Background

The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated.

Methods

CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events.

Conclusion

The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD.     

Impact of the Uremic Milieu on the Osteogenic Potential of Mesenchymal Stem Cells

Human mesenchymal stem cells (hMSCs), the precursors of osteoblasts during osteogenesis, play a role in the balance of bone formation and resorption, but their functioning in uremia has not been well defined. To study the effects of the uremic milieu on osteogenic properties, we applied an in vitro assay culturing hMSCs in osteogenic medium supplemented with serum from healthy donors and from uremic patients on hemodialysis. Compared to control, serum from uremic patients induces, in hMSC cultures, a modification of several key regulators of bone remodeling, in particular a reduction of the ratio Receptor Activator of Nuclear factor Kappa B Receptor (RANKL) over osteoprotegerin, indicating an adaptive response of the system to favor osteogenesis over osteoclastosis. However, the levels of osteopontin, osteocalcin, and collagen type I, are increased in cell medium, while BMP-2, and alizarin red staining were decreased, pointing to a reduction of bone formation favoring resorption. Selected uremic toxins, such as p-cresylsulfate, p-cresylglucuronide, parathyroid hormone, indoxyl sulfate, asymmetric dimethylarginine, homocysteine, were able to mimic some of the effects of whole serum from uremic patients. Serum from cinacalcet-treated patients antagonizes these effects. Hydrogen sulfide (H2S) donors as well as hemodialysis treatment are able to induce beneficial effects. In conclusion, bone modifications in uremia are influenced by the capability of the uremic milieu to alter hMSC osteogenic differentiation. Cinacalcet, H2S donors and a hemodialysis session can ameliorate the hampered calcium deposition.