The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development

Clinical and Experimental Nephrology - It is well-established that uremic toxins are positively correlated with the risk of developing chronic kidney disease and cardiovascular disease. In...     

Relationship between uremic toxins and oxidative stress in patients with chronic renal failure

OBJECTIVE: Uremic toxins play a critical role in the manifestation of the uremic syndrome. This is a consequence of retention of such substances in chronic renal failure patients and interactions between them. To date >100 uremic compounds have been discovered. The aim of this study was to elucidate potential relationships between N-methyl-2-pyridone-5-carboxamide (Me2PY) and N-methyl-4-pyridone-5-carboxamide (Me4PY), two uremic compounds, and different parameters of oxidative stress. MATERIAL AND METHODS: Forty-three non-dialyzed patients at the Nephrological Outpatients Clinic of Gdansk were enrolled and divided into two groups: (i) 20 patients with a mean estimated glomerular filtration rate (eGFR) of 22.7 ml/min/1.73 m(2); and (ii) 23 patients with a mean eGFR of 12.4 ml/min/1.73 m(2). In both groups, the plasma concentrations of uremic toxins (Me2PY, Me4PY, creatinine), malonyldialdehyde (MDA) and carbonyl groups and the erythrocyte concentration of glutathione (GSH) were analyzed. Correlations between uremic toxins and oxidative stress markers were calculated using Pearson's correlation. RESULTS: We observed significant correlations between serum creatinine and Me2PY (r=0.68; p=0.00001), eGFR and Me2PY (r=-0.55; p=0.00001), Me4PY and serum creatinine (r=0.64, p=0.00001), Me4PY and eGFR (r=-0.59; p=0.00008), MDA and Me2PY (r=0.42; p=0.006), MDA and Me4PY (r=0.38; p=0.02), GSH and Me2PY (r=-0.37; p=0.02) and GSH and Me4PY (r=-0.46; p=0.005), and in particular in patients with severe renal impairment. CONCLUSIONS: We conclude that there is a relationship between the novel uremic toxins described and oxidative stress markers. However, elucidation of the exact pathogenetic links requires further detailed studies.     

大鼠创伤后胰岛素抵抗与胰岛素信号转导关系的研究

目的 探讨手术创伤引起胰岛素受体后信号转导通路的改变及其与创伤后胰岛素抵抗（insulin resistance，IR）之间的关系。方法 通过对大鼠实施小肠部分切除手术建立创伤模型，分别测定不同时间的大鼠血糖和血清胰岛素浓度并计算胰岛素抵抗指数（HOMA—IR）和胰岛素分泌指数（HOMA-β）；运用高胰岛素-正常血糖钳夹技术评估外周组织葡萄糖廓清率；并对大鼠骨骼肌组织中的胰岛素受体底物-1（insulin receptor substrate 1，IRS-1）和蛋白激酶B（protein kinase B，PKB／AKT）的磷酸化状态进行检测。结果 大鼠小肠部分切除术后血糖浓度明显升高，血清胰岛素浓度则先短暂降低然后升高；创伤组大鼠胰岛素抵抗指数（HOMA-IR）明显高于对照组而胰岛素分泌指数（HOMA-β）则低于对照组；创伤组大鼠外周组织对葡萄糖的整体利用率下降了47％，骨骼肌IRS-1丝氨酸残基磷酸化较对照组增强95％，而酪氨酸残基磷酸化则减弱38％，其下游PKB／AKT磷酸化亦相应减弱48％。结论 大鼠创伤早期即存在胰岛素抵抗现象，胰岛素实际分泌量并未减少，但相对分泌量不足；创伤后胰岛素抵抗的机制与胰岛素受体后信号转导通路受阻、组织葡萄糖利用障碍有关。     

大鼠创伤后胰岛素抵抗与葡萄糖转运关系的研究

目的探讨创伤后骨骼肌对葡萄糖转运能力的改变及其与创伤后胰岛素抵抗（m）之间的关系。方法通过对大鼠实施小肠部分切除手术建立创伤模型，观察大鼠血糖和血清胰岛素浓度的变化规律。运用高胰岛素-正常血糖钳夹技术评估外周组织葡萄糖廓清率。[^3H]标记葡萄糖示踪法检测创伤后骨骼肌葡萄糖转运能力的变化。最后分别测定大鼠骨骼肌组织中葡萄糖转运蛋白-4（GLUT-4）的mRNA和蛋白表达。结果大鼠小肠部分切除术后血糖浓度明显升高，血清胰岛素浓度则先短暂降低然后升高。创伤组大鼠外周组织对葡萄糖的廓清率下降了47％（P〈0．01）。创伤组大鼠骨骼肌对葡萄糖的转运能力明显低于对照组（P〈0．01）。两组大鼠骨骼肌中GLUT4mRNA和GLUT-4蛋白总量的表达差异无统计学意义（P〉0．05），但是创伤组大鼠骨骼肌细胞膜上的GLUT-4蛋白含量明显少于对照组（P〈0．05）。结论大鼠手术后早期即存在胰岛素抵抗现象，但胰岛素分泌量并未减少。创伤后早期骨骼肌细胞膜上GLUT-4分布减少以及对葡萄糖转运能力降低可能是导致创伤后胰岛素抵抗的机制之一。     

New insights in uremic toxins

The retention in the body of compounds, which normally are secreted into the urine results in a clinical picture, called the uremic syndrome. The retention compounds responsible for the uremic syndrome are called uremic toxins. Only a few of the uremic retention solutes fully conform to a true definition of uremic toxins. Uremic patients develop atheromatotic vascular disease more frequently and earlier than the general population. The classical risk factors seem to be less important. Other factors have been suggested to be at play, and among those uremic toxins are mentioned as potential culprits. The identification, classification and characterization of the solutes responsible for vascular problems seems of utmost importance but is far from complete due to a lack of standardization and organization. The European Uremic Toxin Work Group (EUTox) has as a primary aim to discuss, analyze and offer guidelines in matters related to the identification, characterization, analytical determination and evaluation of biological activity of uremic retention solutes. The final aim remains the development of new strategies to reduce the concentration of the most active uremic solutes. These activities will at first be concentrated on reducing factors influencing cardiovascular morbidity and mortality.     

Relationship between bone mineral density and insulin resistance in polycystic ovary syndrome

The aim of the present study was to evaluate whether there is a relationship between bone mineral density (BMD) and insulin resistance and hyperinsulinemia in women with polycystic ovary syndrome (PCOS). The study consisted of 28 amenorrheic women with PCOS and 11 amenorrheic women without PCOS. Fifteen healthy women with normal ovulatory function, matched for age and body mass index (BMI), served as controls. BMD was measured at the lumbar spine and left femoral neck with dual-energy X-ray absorptiometry. Blood samples were obtained to measure serum levels of insulin, follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin (SHBG), total and free testosterone, androstenedione and estradiol by radioimmunassay. Insulin resistance was estimated by the insulin tolerance test (ITT), and K_ITT was taken as the insulin sensitivity index. In the PCOS group, K_ITT was significantly lower and insulin levels were higher than in either of the control groups (P < 0.001). BMD in the PCOS group was lower than in the healthy group and higher than in the amenorrheic control group (P < 0.05). In the PCOS group, there were positive correlations of BMD of the lumbar spine with insulin (r = 0.42; P < 0.05) and negative correlations of BMD with K_ITT (r = −0.58; P < 0.001) and SHBG (r = −0.38; P < 0.05). The inverse association of BMD and K_ITT was independent of BMI, insulin, SHBG, androstenedione, and free testosterone. In conclusion, insulin resistance and hyperinsulinemia in women with PCOS may be a relative protective factor against bone mineral loss. Received: November 13, 2000 / Accepted: December 28, 2000     

Normal and pathologic concentrations of uremic toxins

An updated review of the existing knowledge regarding uremic toxins facilitates the design of experimental studies. We performed a literature search and found 621 articles about uremic toxicity published after a 2003 review of this topic. Eighty-seven records provided serum or blood measurements of one or more solutes in patients with CKD. These records described 32 previously known uremic toxins and 56 newly reported solutes. The articles most frequently reported concentrations of β2-microglobulin, indoxyl sulfate, homocysteine, uric acid, and parathyroid hormone. We found most solutes (59%) in only one report. Compared with previous results, more recent articles reported higher uremic concentrations of many solutes, including carboxymethyllysine, cystatin C, and parathyroid hormone. However, five solutes had uremic concentrations less than 10% of the originally reported values. Furthermore, the uremic concentrations of four solutes did not exceed their respective normal concentrations, although they had been previously described as uremic retention solutes. In summary, this review extends the classification of uremic retention solutes and their normal and uremic concentrations, and it should aid the design of experiments to study the biologic effects of these solutes in CKD.     

老年男性2型糖尿病患者胰岛素抵抗与 骨质疏松关系的研究

目的 探讨老年男性2型糖尿病(T2DM)患者骨代谢指标及骨密度(BMD)的临床特点,2型糖尿病危险因素与骨密度之间的关系.方法 入选老年男性T2DM患者116例,其中糖尿病肾病(DN)50例,分为T2DM组和DN组,另设老年男性健康对照组50例,记录年龄、体重指数(BMI)、DM病程,均行双能X线骨密度测定检查,并抽血检测空腹血糖(FPG)、糖化血红蛋白(HbA1C)、空腹胰岛素(Fins)、骨代谢、生化等指标的变化,计算稳态胰岛素评估模型胰岛素抵抗(HOMA-IR)指数.结果 (1)T2DM组、DN组年龄和BMI匹配的对照组比较无显著差异(P＞0.05);DN组病程长于T2DM组,两组比较有统计学意义,(P＜0.05);(2)T2DM组、DN组的BMD和骨矿含量(BMC)、25-羟基维生素D、睾酮(T)和骨钙素(BGP)水平较对照组降低,差异有统计学意义(P＜0.001与P＜0.05);DN组较T2DM组更低,两组比较差异有统计学意义(P＜0.05);(3) T2DM组和DN组的甲状旁腺激素(PTH)、B-胶原系列(B-CL)水平高于对照组,差异有统计学意义(P＜0.001与P＜0.05);然而DN组又高于T2DM组,差异显著(P＜0.05);(4)T2DM组、DN组存在胰岛素抵抗(IR),DN组IR尤其显著.HOMA-IR指数与BMD水平呈负相关(P＜0.05).结论 老年男性糖尿病患者DM病程及IR程度均与骨质疏松程度牟正相关,改善老年男性2型糖尿病患者IR对预防其OP的发生和发展有重大意义.     

Induction of insulin resistance in normal adipose tissue by uremic human serum

An incubation of uremic human serum with normal rat adipose tissue will make the subsequently isolated adipocytes less responsive to insulin. To examine the extent of insulin resistance, we obtained sera from nondiabetic, uremic patients, who had not undergone dialysis therapy. The sera were then dialyzed (3500 molecular-weight cutoff) for 18 hr against a defined culture medium to eliminate possible in vitro effects of altered levels of end-product metabolites, electrolytes, and metabolic substrates. After an incubation of epididymal fat tissue from normal rats, for 3 hr with the dialyzed sera (50% vol/vol), cells were isolated and washed. The insulin stimulation of 14C-glucose (0.2 mM) incorporation to 14CO2 and total lipids was significantly reduced in the adipocytes pretreated with sera from 19 of the 29 uremic patients. Although elevated in the uremic patients, the sera levels of insulin, and parathyroid and growth hormones were not correlated to insulin resistant activity. Furthermore, incubation of adipose tissue for 3 hr with insulin, glucagon, or PTH did not produce resistance. The uremic sera reduced glucose utilization equally at 0.2 and 50 mM glucose, suggesting that the insulin resistance was induced additionally at a site distal to the glucose transport system. However, the concentration of insulin (22 microunits/ml) required for half-maximal stimulation of glucose metabolism was not altered by pretreatment with uremic serum. Also, neither the isoproterenol-stimulated lipolysis nor the inhibition of this cellular event was influenced by pretreatment with uremic sera.(ABSTRACT TRUNCATED AT 250 WORDS)     

健康男性的胰岛素抵抗指数、肥胖、血清PSA水平间的关系

本研究旨在确定血清PSA水平低于4ngmL^-1的健康男性的胰岛素抵抗指数、肥胖和血清前列腺特异性抗原（PSA）水平之间的关系。调查对象为韩国水力原子力株式会社的11827名健康男性职员,在2003年1月到2008年12月间接受了体检,体检项目包括空腹血糖水平、空腹胰岛素水平和血清PSA水平。用稳态模式评估法（HOMA;[空腹血糖水平×空腹胰岛素水平]／22．5）和定量胰岛素敏感性检验指数（QUICKI;1／[10g（空腹胰岛素水平）＋log（空腹血糖水平）]）测定胰岛素抵抗指数。协方差分析（ANOVA）和Duncan’s多重比较试验显示,随着用HOMA和OuICKI测定的胰岛素抵抗指数四分位的上升,年龄标化体重指数（BMI）也显著增加（P〈0．001）。多变量线性回归分析表明,相对于血清PSA水平,年龄、BMI、以及用HOMA或QUICKI测得的胰岛素抵抗指数都是显著的独立变量（P〈0．001）。本研究说明胰岛素抵抗指数和BMI都是血清PSA水平的独立变量,在健康男性体内,两者都与血清PSA水平呈负相关,两者之间呈正相关。     

体外循环缺血再灌注心肌胰岛素抵抗与心功能障碍的关系

目的：探讨体外循环缺血再灌注心肌胰岛素抵抗与心功能障碍的关系。方法：12条雄性杂种狼犬，按体外循环主动脉阻断时间不同分为两组，组I（6条）：主动脉阻断25min；组Ⅱ（6条）：主动脉阻断150min。分别于转流前、开放主动脉后10、30、60min时同时采集动脉、冠状静脉窦血标本并行右房心肌组织活检，测定血浆葡萄糖、乳酸、胰岛素、C肽、胰高血糖素、皮质醇、生长激素浓度和心肌组织糖原含量，同时监测围手术期血流动力学。结果：缺血再灌流后血浆葡萄糖、乳酸、胰岛素、C肽、胰高血糖素、皮质醇及生长激素浓度均不同程度明显增高，于再灌注10－30min达峰值（与转流前比较，P值均＜0．05），同时心肌糖原分解明显增强，而对葡萄糖的摄取、利用严重障碍。与组I比较，组Ⅱ心肌胰岛素抵抗程度更重、持续更久且终止体外循环后心脏指数、每搏指数及左室每搏工作指数均显著降低（P值均＜0．05）。结论：体外循环缺血再灌注心肌胰岛素抵抗程度与心功能障碍的发生密切相关，提示心肌胰岛素抵抗很可能是触发心肌葡萄糖氧化减少而造成心功能障碍的重要因素。     

Two cases of spontaneous fistula between urinary tract and gastrointestinal tract

This is a report of two cases of a fistula between the urinary and gastrointestinal tracts. One case was a 56-year-old female patient with a right pyeloduodenal fistula, and the other was a 38-year-old female with a left ureterodescending colon fistula. The chief complaint was right lumbago in the first case, and fever and left lumbago in the second case. Both cases were diagnosed by retrograde pyelography. In both cases, the ailing kidney appeared to be non-functioning, and the former was operated by nephrectomy, fistulectomy, and duodenectomy in the cuneate form, while the latter was operated by nephrectomy and fistulectomy. The cause of the formation of the fistula was considered to be chronic pyelonephritis accompanied by renal stones in the first case, and rupture of the colon diverticulitis in the second case. Postoperative prognosis was satisfactory in both cases.     

Glucose intolerance in uremic patients: the relative contributions of impaired beta-cell function and insulin resistance

Glucose tolerance and tissue sensitivity to insulin were examined in 19 renal failure patients on chronic regular hemodialysis (group U) and in 6 matched control subjects with normal renal function (group A). Based on glucose tolerance as assessed by an oral glucose tolerance test (OGTT), glucose tolerance was normal in 5 (group U:N), borderline in 5 (group U:BL) and decreased in 9 uremic subjects (group U:D). Compared with group A the uremics demonstrated significantly (p less than 0.01) impaired insulin sensitivity as assessed by a continuous mixed infusion of somatostatin, insulin and glucose (SIGIT). In addition 19 non-diabetic subjects with normal fasting blood glucose and normal renal function, matching the uremic patients with respect to glucose tolerance as assessed by OGTT, were studied (group B). In group B impairments in both insulin secretion and insulin sensitivity tended to be more pronounced in subjects with decreased OGTT as compared with those with borderline OGTT. In contrast, insulin resistance was present to a similar degree in uremic subjects of group U:N, U:BL and U:D. During SIGIT endogenous insulin, glucagon and growth hormone (GH) were suppressed in both uremic and control subjects. This implies that insulin resistance in uremia is most likely not due to hyperglucagonemia or abnormal GH metabolism. During OGTT subjects of group U:N had significantly higher insulin response than subjects of group U:BL (p less than 0.02) and group U:D (p less than 0.01). Insulinogenic index was significantly higher in group U:N than in group U:BL (p less than 0.02) and group U:D (p = 0.01) and was higher in group U:BL than in group U:D (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction

Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular diseases than the general population. Endothelial dysfunction, which participates in accelerated atherosclerosis, is a hallmark of CKD. Patients with CKD display impaired endothelium-dependent vasodilatation, elevated soluble biomarkers of endothelial dysfunction, and increased oxidative stress. They also present an imbalance between circulating endothelial populations reflecting endothelial injury (endothelial microparticles and circulating endothelial cells) and repair (endothelial progenitor cells). Endothelial damage induced by a uremic environment suggests an involvement of uremia-specific factors. Several uremic toxins, mostly protein-bound, have been shown to have specific endothelial toxicity: ADMA, homocysteine, AGEs, and more recently, p-cresyl sulfate and indoxyl sulfate. These toxins, all poorly removed by hemodialysis therapies, share mechanisms of endothelial toxicity: they promote pro-oxidant and pro-inflammatory response and inhibit endothelial repair. This article (i) reviews the evidence for endothelial dysfunction in CKD, (ii) specifies the involvement of protein-bound uremic toxins in this dysfunction, and (iii) discusses therapeutic strategies for lowering uremic toxin concentrations or for countering the effects of uremic toxins on the endothelium.     

Relationship between BMI, total testosterone, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men

The objective of this work was to evaluate the relationship between sex steroid hormones, sex hormone-binding-globulin, leptin, insulin and insulin resistance in obese men. Anthropometrical indexes, total testosterone (Tt), free testosterone (fT), estradiol (E), sex hormone-binding-globulin (SHBG), glucemia, insulin and leptin were measured in 77 men, with ages between 20 and 60 years. According to their body mass index (BMI), subjects were grouped into three categories: normal body weight (< 24.9 kg/m2), overweight (25-29.9 kg/m2) and obese group (> 30 kg/m2). Insulin resistance index was obtained by the homeostasis assessment model for insulin resistance (HOMA-IR). Total testosterone and SHBG concentrations were lower in the obese group compared with normal and overweight subjects (p < 0.05). The mean insulin concentration was significantly higher in the obese group compared with the other groups (p < 0.05). T was negatively correlated with the BMI (r = -0.447; p < .01), WC (r = -0.464); p < .01, leptin (r = -0.382; p < .01), insulin (r = -0.391; p < 0.01) and also with the HOMA-IR (r = -0.416; p < 0.01). The SHBG negatively and significantly correlated with BMI (r = -0.334; p < 0.01) and WC index (= -0.322; p < 0.01), as well with insulin levels (r = -0.313; p < 0.01) and insulin resistance (= -0.266; p < 0.05). Our results shows that in a sample of men, Tt and SHBG concentrations proportionally diminished with both the increase of BMI and insulin resistance index.     

血清脂联素水平与尿毒症患者炎性反应状态的关系

脂联素具有抗炎、抗动脉粥样硬化、抗胰岛素抵抗等多种重要的作用。本研究观察慢性肾衰患者血清脂联素（ADPN）水平,分析其与慢性肾衰竭患者营养不良、炎性反应和动脉粥样硬化（MIA）综合征的关系。