Lack of reversal effect of EDTA treatment on cadmium induced renal dysfunction: a fourteen-year follow-up

The aim of this study was to evaluate the effect of ethylenediaminetetraacetic acid (EDTA) on cadmium (Cd) induced renal dysfunction. Seventeen workers (14 males, 3 females) were diagnosed with occupational Cd poisoning in 1986. These individuals had between 7 to 39 years of Cd exposure. From 1986 to 1999, patients received periodic EDTA therapy as part of their follow-up, all at the same hospital. Levels of urinary cadmium (UCd) and urinary beta2-microglobulin (B2M) were measured before and after each annual EDTA treatment period. Renal dysfunction was defined as urinary B2M > 0.8 mg/g Cr (creatinine). In these workers, patients with UCd level higher than 10 microg/g Cr in 1986 had abnormal B2M excretions (> or = 0.8 mg/g Cr) or trended to have abnormal B2M levels during the treatment period. However, in subjects with UCd concentration lower than 10 microg/g Cr in 1986, their urinary B2M excretions either remained normal (< 0.8 mg/g Cr) or returned to normal during the treatment period. The prevalence of renal dysfunction increased during the follow up period regardless of whether UCd levels increased or not, indicating a progressive renal dysfunction despite removal from Cd exposure. Our results suggest that reversibility of renal dysfunction caused by Cd related to the level of Cd exposure at the time of removal from exposure: renal dysfunction could be reversed if initial UCd < 10 microg/g Cr, but was irreversible when UCd > 10 microg/g Cr. Repeated examinations on these 17 Cd exposed workers from 1986 to 1999 also revealed that periodic administration of EDTA had no beneficial effects on chronic Cd-induced renal dysfunction.     

Effect of chronic treatment with losartan on streptozotocin induced diabetic rats

Treatment of rats with streptozotocin (STZ, 45mg/kg, i.v.,single dose) produced cardinal symptoms of diabetes mellitus including hyperglycemia, hypoinsulinemia and increase in blood pressure. Treatment with losartan--an angiotensin (AT1) receptor antagonist, 2 mg/kg, po for 6 weeks decreased the blood glucose levels by 16.5%. There was 190% increase in AUCglucose and 59.4% decrease in AUCinsulin in STZ-diabetic rats as compared to control rats. Treatment with losartan caused slight decrease in AUCglucose and slight increase in AUCinsulin. There was no significant difference in insulin sensitivity (K(ITT)) index of STZ-diabetic group as compared to control. Losartan treatment failed to alter these levels significantly. Serum cholesterol and creatinine levels were found to be increased significantly in STZ-diabetic rats. Treatment with losartan significantly prevented the rise in cholesterol and creatinine levels by 20.1 and 81% respectively. The results suggest that losartan produces some beneficial effects in STZ-diabetic rats.     

Environmental epidemiological study and estimation of benchmark dose for renal dysfunction in a cadmium-polluted area in China

We have performed a study aimed at investigating the critical concentration of urinary cadmium (UCd) required for the development of renal dysfunction. We studied population groups (totally 790 persons) living in two cadmium exposed areas and one control area in China. UCd, was determined as an indicator of cadmium exposure and accumulation, while the concentrations of N-acetyl-beta-D-glucosaminidase (NAG), its iso-form B (NAG-B), beta2-microglobulin (B2M), retinol binding protein (RBP), and albumin (ALB) in urine were measured as indicators of the renal effects caused by cadmium. There was a significantly increased prevalence of hyperNAGuria, hyperNAG-Buria, hyperB2Muria, hyperRBPuria and hyperALBuria with increasing levels of Cd excretion in urine. We used the benchmark dose (BMD) procedure to estimate the critical concentration of urinary cadmium in this general population. The lower confidence limit of the BMD (LBMD-05) of urinary cadmium for a 5% level of risk above the background level was estimated for each of the renal effect indicators. The BMD-05/LBMD-05 were estimated to be 4.46/3.99, 6.70/5.87, 8.36/7.31, 7.98/6.98 and 15.06/12.18 microg/g creatinine for urinary NAG-B, NAG, B2M, RBP and ALB, respectively. Our findings suggest, based on the present study, that the Lower Confidence Limit of the Population Critical Concentration of UCd (LPCCUCd-05) of tubular dysfunction for 5% excess risk level above the background may be ca. 3-4 microg/g creatinine, and that cadmium concentration in urine should be kept below this level to prevent renal tubular damage. This report is the first to use the BMD method in this field and to define the concept of critical concentration in urine.     

瓣膜病变合并肾功能不良患者的体外循环管理

目的：探讨瓣膜病变合并肾功能不良患者的体外循环管理方法。方法：2003年1月～6月在我院接受瓣膜置换术且术前肾功能检查指标异常的15名患者作为研究组,2002年1月～6月符合上述条件的18名患者作为对照组。两组患者体外循环管理的不同之处在于：研究组患者在体外循环中应用平衡超滤,严格选用抗生素,少用或不用人工胶体,不用甘露醇,体外循环中避免肾缺血。结果：研究组患者术后肾功能明显好于对照组。结论：在研究组患者中应用的上述措施对术前就用肾功能损伤的患者是有帮助的。     

芦沙坦的降压效应和内、外侧缰核神经元单位放电的关系

目的和方法 :观察腹腔注射 (i.p) 2mg kg和 10mg kg芦沙坦 (losartan)对大鼠股动脉血压 (aterialbloodpressure ,AP)和心率 (heartrate,HR)的影响以及与缰核 (Hb)神经元活动的关系。用玻璃微电极记录内侧缰核 (MHb)、外侧缰核(LHb)神经元单位放电活动 ,观察 10mg kg芦沙坦对其放电频率的影响。结果 :2mg kg芦沙坦对大鼠AP和HR无明显影响 ;(10mg kg芦沙坦可显著降低大鼠动脉血压 ,但对心率无明显影响。 10mg kg芦沙坦可使LHb内 6 6 6 6 % 12 18)神经元单位放电频率增加 ,使MHb内 6 1 90 % (13 2 1)神经元单位放电频率减少。结论 :10mg kg芦沙坦可明显地降低大鼠AP ,但 2mg kg芦沙坦对AP无明显影响 ;10mg kg芦沙坦可兴奋LHb和抑制MHb,产生降压效应     

Development of pressure overload induced cardiac hypertrophy is unaffected by long-term treatment with losartan

Left ventricular hypertrophy with adequate wall thickness, preserved adult phenotype and extracellular matrix may be useful in the prevention of heart failure. Because activation of subtype 1 of angiotensin II (AT₁) receptors is thought to be involved in the hypertrophic response of cardiomyocytes, we tested the potential of systemic AT₁ blockade to modify the development of left ventricular hypertrophy due to pressure overload.Sham-operated rats and rats with ascending aorta constriction were treated with losartan (30 mg/kg/day) for 8 weeks. Left ventricular geometry, dynamics of isovolumic contractions, hydroxyproline concentration as well as myosin isozymes (marker of fetal phenotype) were assessed. Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure-volume relationship was shifted to smaller volumes. An enlarged ventricular pressure-volume area and increased (p < 0.05) peak values of +dP/dtmax and -dP/dtmax demonstrated an enhanced overall ventricular performance. Signs of congestive heart failure were not apparent. In contrast, parameters of myocardial fimction (normalized length-stress area, +d/dtmax and -d/dtmax) were depressed (p < 0.05), indicating an impaired myocardial contractility. The hydroxyproline concentration remained unaltered. However, the proportion of -myosin heavy chains (NMC) was increased (p < 0.05). Administration of losartan decreased (p < 0.05) blood pressure and body weight in sham operated and pressure overloaded rats. By contrast, neither the concentric left ventricular hypertrophy or depressed myocardial function nor the increased -MHC expression were significantly altered. Thus, activation of AT₁ receptors appears not to be involved in the initial expression of the fetal phenotype of pressure overloaded heart which may be responsible for the progressive functional deterioration of the hypertrophied ventricle.     

Risk assessment on renal dysfunction caused by co-exposure to arsenic and cadmium using benchmark dose calculation in a Chinese population

Arsenic and cadmium are important inorganic toxicants in the environment. Humans certainly have the potential to be exposed to the mixtures of arsenic and cadmium, but the toxicological interactions of these inorganic mixtures are poorly defined. A general population co-exposed to arsenic and cadmium, was selected in China. The total number of participants was 245, made up of 122 in the arsenic-cadmium polluted area, 123 in the non polluted area. Urinary arsenic (UAs) and cadmium (UCd) were determined by atomic absorption spectrometry as exposure biomarkers and beta2-microglobulin (Ubeta2MG), albumin (UALB), N-acetyl-beta2-glucosaminidase (UNAG) in urine were determined as effect biomarkers. The benchmark dose (BMD) and the lower confidence limit on the benchmark dose (LBMD) were calculated to estimate the critical concentration of UAs and UCd. UAs and UCd concentrations in the polluted area were significantly higher than those in the non polluted area (P < 0.01). The levels of Ubeta2MG, UALB and UNAG in the polluted area were significantly higher than those in the non polluted area (P < 0.01). The BMD/LBMD of UAs and UCd for a 10% level of risk above the background level were estimated as 121.91/102.11 microg/g creatinine and 1.05/0.88 microg/g creatinine. It was suggested that the lower confidence limit of population critical concentration of UAs and UCd for renal dysfunction for 10% excess risk level above the background, which is obtained from LBMD, may need to be kept below 102 and 0.88 microg/g creatinine in order to prevent renal damage in general population co-exposed to arsenic and cadmium. It is indicated that combined effect of arsenic and cadmium were additive effect and/or synergistic effect, and cadmium may potentiate arsenic nephrotoxicity during the long-term and co-exposure to arsenic and cadmium in humans.     

Effect of Acacia gum on blood pressure in rats with adenine-induced chronic renal failure

Chronic renal failure (CRF) occurring naturally in patients or induced by subtotal nephrectomy in rats induces several alterations in the cardiovascular system (CVS). However, the effect of chemically induced CRF in rats on the CVS is less well known. We induced CRF in rats by feeding adenine (0.75%, w/w, four weeks) and investigated the effect of the ensuing CRF on the systolic and diastolic blood pressure (BP) and heart rate (HR). Further, we investigated the effect of giving acacia gum (AG, 10%, w/v) in the drinking water concomitantly with adenine on the above parameters. AG has been previously shown to ameliorate the severity of CRF in humans and rats. We confirmed here that adenine-induced CRF significantly increased the plasma concentrations of urea and creatinine, and reduced creatinine clearance. Additionally, it significantly increased both systolic and diastolic BP, with no significant effect on HR. Both of these actions were significantly mitigated by AG treatment. The antihypertensive angiotenisn-converting enzyme inhibitor lisinopril (10 mg/kg) was given by gavage to rats concomitantly with adenine, significantly reduced the rise in blood pressure induced by adenine. In conclusion, adenine-induced CRF in rats significantly increased BP, and this was significantly mitigated by administration of AG. Possible mechanisms of these changes and the protective effect of AG will be investigated.     

氯沙坦对肾血管性高血压大鼠血清中血管紧张素Ⅱ-1受体自身抗体产生的影响

目的和方法：采用两肾一夹型肾血管性高血压（RVH）模型,以合成的大鼠血管紧张素Ⅱ－1受体（AT1R）细胞外第二环165－191位氨基酸序列作为特异性抗原,用ELISA法检测大鼠血清中血管紧张素Ⅱ－1受体自身抗体,动态观察（13周）氯沙坦（术后第2周开始,5mg/kg dig,连续12周）治疗对模型大鼠AT1R自身抗体产生的影响。结果：RVH组大鼠血清中AT1R自身抗体从术后1周起阳性率、滴度逐渐升高;给予氯沙坦治疗不仅可抑制模型大鼠心脏功能和结构的改变,而且使血清AT1R自身抗体的阳性率和滴度明显低于肾血管性高血压组。结论：氯沙坦有抑制AT1R自身抗体产生而达到降压的作用。     

The influence of aging on renal response to cadmium in Syrian hamsters

To determine the renal effects of cadmium (Cd) in older animals, we administered subcutaneously a single dose of cadmium, 3.0 mg/kg/BW, to Syrian hamsters aged 16 wk (“young”) and 60 wk (“old”). Marked morphologic changes in the kidney and renal dysfunction were observed, especially in the older animals. The concentration of MDA in the renal cortex was significantly increased only in young hamsters treated with cadmium. Concentrations of glutathione (GSH) in the renal cortex were increased in the old hamsters on d 6. Increased levels of renal MDA after cadmium treatment may induce the production of GSH in the kidney thus preventing renal damage. Aging can increase the susceptibility to the renal effects of cadmium.     

Renal dysfunction of cadmium-exposed workers residing in a cadmium-polluted environment

Human exposure to cadmium may occur in both occupational and general environments. We were interested in determining whether a combination of occupational and environmental exposure to cadmium results in different levels of severity of renal dysfunction relative to that arising from environmental or occupational exposure alone. We selected 44 residents, who once were employed in a smelter and lived in a cadmium-polluted area, as group A. Another 88 subjects, who never worked in the plant, but lived in the same area, were selected as group B. Group C consisted of 88 subjects who had no history of occupational exposure to cadmium and lived in a non-cadmium-polluted area. Statistical analysis demonstrated that there was no significant difference in age or gender among the three groups, nor were there significant differences in smoking habits. The prevalence of renal dysfunction as indicated by increased excretion of beta2-microglobulin (B2M), N-acetyl-beta-D-glucosaminidase (NAG) and albumin (ALB), was higher in group A than in group B. This finding suggests that exposure to cadmium both occupationally and environmentally results in a higher prevalence of renal dysfunction, relative to those who are exposed to cadmium only in the general environment. Therefore, this specific population, who once were occupationally exposed to cadmium and lived in polluted areas, should be identified. Furthermore, health examinations of this population should be conducted in time to prevent further health damage induced by cadmium exposure.     

肾康注射液联合血液透析治疗慢性肾功能衰竭的临床效果及对肾功能、营养指标的影响

目的 探讨肾康注射液联合血液透析治疗对慢性肾功能衰竭患者的肾功能、营养指标及临床疗效的影响.方法 选取2018年3月～2019年2月我院肾内科收治的116例慢性肾功能衰竭患者作为研究对象,随机分为对照组和观察组各58例.对照组给予单纯血液透析治疗,观察组给予肾康注射液联合血液透析治疗,治疗16周后观察两组患者的肾功能及...     

Reversibility of renal tubular dysfunction in streptozotocin-induced diabetes in the rat.

Enzymuria and specific proteinuria were examined over a period of 19 days in 4 groups of 5 rats: a control group, a nondiabetic polyuric group, a group of streptozotocin-induced diabetic rats treated with insulin as of the 10th day after the injection of the drug, and a similar group of untreated diabetic rats. Increased urinary excretion of beta-N-acetyl-D-glucosaminidase, lactate dehydrogenase, and alanine aminopeptidase was observed shortly after the induction of diabetes. It was partly or totally reversible following insulin treatment. Nondiabetic polyuria had a slight effect on the excretion of alanine aminopeptidase only. The urinary excretion of beta 2-microglobulin also rapidly increased after the onset of diabetes to a level approximately 50 times the control values. This effect was largely reversible with insulin treatment and was absent in the nondiabetic polyuric group. A small but significant 3-fold increase in albumin excretion was also noted but was not affected by insulin treatment. We conclude that streptozotocin-induced diabetes causes an early tubular dysfunction that is unrelated to polyuria and is reversible upon insulin treatment. This tubular dysfunction is best revealed by the urinary excretion of the low molecular weight protein beta 2-microglobulin. Our results suggest that it would be of interest to further examine the usefulness of sensitive markers of tubular dysfunction, especially low molecular weight proteinuria, in the detection of early stages of diabetic nephropathy.     

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.     

Investigation of albumin properties in patients with chronic renal failure

The aim of this study was the investigation of HSA properties and its structural changes after modification induced in vivo among patients with CRF who underwent haemodialysis. Application of different fluorescent dyes allowed the investigation of different regions of albumin molecule using ANS, bis-ANS, piren, piren maleimide and fluorescein isothiocyanate. As markers of oxidative modification, the total protein thiol, carbonyls, glycosylated plasma proteins and hydroperoxide were estimated in plasma. Additionally, this study investigated plasma viscosity and total antioxidant capacity (TAC) of the plasma. Results show that haemodialysis provoked significant changes in conformational properties of plasma albumin, which resulted in the loss of its biological functions. These findings suggest that oxidative stress and glycation of proteins in plasma are developed during haemodialysis. The results depict that one of the features of uraemia is the presence of signs of oxidative stress before haemodialysis. Nevertheless, oxidative stress and glycation of proteins in plasma are exacerbated during haemodialysis and are a complex process.     

Effect of prolonged treatment with tyramine on glucose tolerance in streptozotocin-induced diabetic rats

The biogenic amine tyramine has been reported to stimulate in vitro glucose transport in adipocytes, cardiomyocytes and skeletal muscle, and to improve in vivo glucose utilization in rats. These effects were dependent on amine oxidation, since they were blocked by inhibitors of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO). We thus tested in this work whether a prolonged treatment with tyramine could improve glucose tolerance in streptozotocin-induced diabetic rats. First, tyramine content of standard rodent chow was determined by HPLC and daily tyramine intake of control rats was estimated to be around 26 micromol/kg body weight. Then, tyramine was administred during 3 weeks in streptozotocin-induced diabetic rats at 29 micromol/kg by daily i.p. injection alone or together with vanadate 0.02 micromol/kg. In another group of diabetic rats, tyramine was subcutaneously delivered at 116 micromol/kg/day by osmotic minipumps. All tyramine treatments resulted in a decrease of the hyperglycemic responses to an i.p. glucose load. Adipocytes isolated from either untreated or treated diabetic rats were sensitive to the stimulation of glucose uptake by tyramine. However, diabetic animals receiving tyramine for three weeks did not recover from their hyperglycemia, hypoinsulinemia and glucosuria. These results show that the improvement of glucose tolerance induced by prolonged tyramine administration occurs in an insulin-depleted model and probably results from peripheral insulin-like actions of the oxidation of MAO/SSAO substrates, such as the stimulation of glucose uptake into adipocytes.     

Effects of losartan on the collagen degradative enzymes in hypertrophic and congestive types of cardiomyopathic hamsters

The present study was undertaken to determine the effects of AT1 receptor blockade which occurred in response to losartan, on the extracellular matrix (ECM) degradation process in the Bio 14.6 (n = 12) and Bio 53.58 (n = 12) strains which are referred as models of hypertrophic and dilated cardiomyopathy, respectively. The administration of losartan (30 mg/kg/day) in hamsters from 10–20 weeks of age reduced the accumulation of the left ventricular collagen matrix in both of the Bio 14.6 and the Bio 53.58 strains. According to the RTPCR, the levels of mRNA for matrix metalloproteinase (MMP) and the tissue inhibitor of MMP (TIMP) were examined. MMP1, 2, 3, and 9 were more enhanced in both myopathic strains than in the control F1 strains. With losartan, the levels of MMP1, 2, 9, TIMP1 and 2 decreased in the both strains but those for MMP3 did not in Bio 14.6 strains. TIMP3 and 4 mRNA levels did not change in any of the experimental hamsters, whether treated or untreated with losartan. The Western blots also showed similar observations in the both strains as seen in mRNA expressions although MMP2 in the Bio 53.58 strains did not differ between treated and untreated with losartan. Although losartan has an inhibitory effect on collagen accumulation in the development of cardiomyopathy, MMPs (1, 2, 9) and TIMPs (1, 2) seem to be susceptible to responding to losartan in Bio cardiomyopathic hamsters.     

诺沙坦改善非胰岛素依赖型糖尿病大鼠胰岛素敏感性的作用机制

本文研究血管紧张素Ⅱ受体拮抗剂诺沙坦对非胰岛素依赖型糖尿病(non-insulin-dependent diabetes mellitus,NIDDM)大鼠胰岛素敏感性的改善作用,并探讨其作用机制。从饮水中给予正常或高脂喂养加小剂量链脲佐菌素(STZ)诱发的NIDDM大鼠诺沙坦(4 mg/kg),连续6周。分离骨骼肌,用免疫印迹法检测诺沙坦对胰岛素受体底物1(insulin receptor substrate 1,IRS-1)、蛋白激酶B(protein kinase B,PKB)和葡萄糖转运因子4(glucose transporter 4,GLUT4)的表达,以及IRS-1的磷酸化、IRS-1与磷脂酰肌醇3激酶(phosphatidylinositol(PI)3-kinase)的结合。口服葡萄糖耐量试验表明,口服诺沙坦可改善糖尿病大鼠胰岛素敏感性。在骨骼肌组织,NIDDM和正常大鼠的IRS-1、PKB和GLUT4蛋白表达无差异,且不受诺沙坦处理的影响。NIDDM大鼠胰岛素刺激后的骨骼肌IRS-1酪氨酸磷酸化水平、PI 3-kinase结合IRS-1的活性和PKB活性较对照组显著降低(P<0.01),且不能被诺沙坦改善。诺沙坦显著增加NIDDM大鼠肌细胞质膜(plasma membrane,PM)和T管(T-tubules,TT)胰岛素诱导的GLUT4的 含量(P<0.05)。与该结果一致的是,诺沙坦处理的NIDDM大鼠血糖水平较未处理NIDDM大鼠下降(P<0.05)。结果表明,诺沙坦可改善胰岛素抵抗状态,主要是通过非PI 3-kinase依赖的     

Effects of losartan on expression of monocyte chemoattractant protein-1 (MCP-1) in hyperuricemic nephropathy rats

Abstract

The monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of progression of renal failure. This is based on the observations done both in various animal models of renal damage and in different types of human renal disease. During the development of non-infectious kidney stones, crystals are formed and deposited on the kidneys and the kidneys are surrounded by monocytes/macrophages. We have proposed that in response to crystal exposure, renal epithelial cells produce chemokines, which attract the monocytes/macrophages to the sites of crystal deposition. In this study, we investigated the expression of MCP-1 protein by SD rats exposed to oxonic acid (OA). Our study showed that hyperuricemia accelerates renal progression via a mechanism linked to high MCP-1 which may mediate the inflammation reaction of renal diseases induced by hyperuricemia. Losartan may retard the progression of advanced renal dysfunction, and the mechanism was partly due to blocking of renal inflammation induced by the uric acid. Because the number of experiments performed here is very few, results must be confirmed by more extensive studies with a larger sample size.