YKL-40 in patients with end-stage renal disease receiving haemodialysis

Purpose: This study aimed to determine serum YKL-40 in patients with end-stage renal disease (ESRD) on haemodialysis (HD) and to evaluate the prognostic value of serum YKL-40.

Methods: Patients >18?years on maintenance HD were included. Serum YKL-40 was measured using ELISA before and after a single HD treatment.

Results: A total of 306 patients were included. Median serum YKL-40 concentration was 238?µgL^?1 (IQR: 193–291?µgL^?1) before HD treatment and 198?µgL^?1 (IQR: 147–258?µgL^?1) after HD treatment, which corresponded to age-corrected 93th percentile in healthy subjects. All-cause mortality after 2.8?years was 35.9%. Patients with serum YKL-40 in the highest quartile compared with the lowest quartile had a univariate HR of 4.0 (95% CI: 2.2–7.3, p?p?=?0.01) in multivariate analysis. Time-dependent receiver operating characteristic curves showed that serum YKL-40 after HD treatment had significant higher area under the curves from 90?d (p?=?0.004) and throughout the rest of the follow-up period when compared to serum YKL-40 before HD treatment.

Conclusion: YKL-40 was highly elevated in patients with ESRD on HD, and dialysis reduced serum YKL-40 concentrations approximately one-sixth. YKL-40 measured after dialysis was independently associated with mortality in HD patients.     

维持性血液透析终末期肾病患者肠道优势菌群多样性变化研究

目的探讨维持性血液透析终末期肾病患者肠道优势菌群多样性及其与炎症因子的相关性。方法采集维持性血液透析的稳定终末期肾病患者和健康对照受试者的血液和粪便样本,采用荧光实时定量PCR(real-time quantitative PCR,QPCR)检测肠道优势菌群的变化情况,应用酶联免疫吸附技术(enzymelinked immunosorbent assay,ELISA)检测患者血液中的白介素1β(interleukin 1β,IL-1β)、白介素6(interleukin 6,IL-6)、肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)和内毒素(lipoposaccharide,LPS)。结果维持性血液透析终末期肾病患者肠道菌群总菌量差异无统计学意义,但肠道内有益菌群如双歧杆菌属细菌、乳酸杆菌属细菌和粪杆菌属细菌显著降低,而肠道内有害菌如肠杆菌科细菌和肠球菌属细菌均显著升高(P0.05)。维持性血液透析终末期肾病患者血液中IL-6、TNF-α和LPS显著升高,均与双歧杆菌属细菌有显著负相关,与肠杆菌科细菌有显著正相关。肠道内乳酸杆菌属细菌和粪杆菌属细菌与IL-6呈显著负相关,肠球菌属细菌与其呈显著正相关。此外,乳杆菌属细菌与TNF-α呈显著负相关,肠球菌属细菌和LPS呈显著正相关。结论维持性血液透析终末期肾病患者肠道优势菌群多样性发生了显著变化,且与患者炎症因子有密切的相关性。     

Bile acids of patients with renal failure receiving chronic hemodialysis

Bile acids in serum, urine and dialysate of 8 patients with renal failure in chronic hemodialysis were analyzed by gas chromatography and gas chromatography-mass spectrometry. The following results were obtained: 1. Lithocholic acid, 3 beta-hydroxy-5-cholen-24-oic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and cholic acid were identified in hemodialysate as well as in serum and urine. 2. The serum bile acid concentration of the patients was 2.78 +/- 0.57 micrograms/mL before hemodialysis and 1.34 +/- 0.48 micrograms/mL after a 5-h period hemodialysis with cuprophane membrane. The proportions of secondary bile acids in predialysis and postdialysis serum of patients were significantly higher than those of healthy subjects. 3. Two out of 8 patients excreted urine. But the amounts of bile acids in urine of the patients were very small compared to those of healthy subjects. 4. The amount of bile acids removed from blood by hemodialysis was 0.70 +/- 0.25 mg. In dialysate, cholic acid constituted a larger proportion of the total bile acids, and lithocholic acid a smaller proportion, when compared to those in urine of patients and healthy subjects.     

Plasma ghrelin levels in patients with end-stage renal disease

Ghrelin is an acylated peptide stimulating secretion of the growth hormone (GH). It was originally isolated from the rat stomach as an endogenous ligand for the growth hormone secretagogue receptor. Although being predominantly produced by endocrine cells of the gastric fundus, its secretion has been found in various tissues including the kidney. To study the influence of renal failure on plasma ghrelin levels we examined 16 patients with end-stage renal disease (ESRD) receiving hemodialysis (8 men and 8 women) and 19 controls (10 men and 9 women). Both groups were comparable in age and BMI. In all subjects we assessed plasma levels of ghrelin, leptin, soluble leptin receptor, insulin, IGF-I, IGFBP-1, IGFBP-3 and IGFBP-6. Ghrelin levels were significantly higher in the group of dialyzed patients (4.49+/-0.74 vs. 1.79+/-0.15 ng/ml; p<0.001). These patients had significantly higher levels of GH, IGFBP-1, IGFBP-6, leptin and percentage of body fat (p<0.05). In the group of patients with ESRD plasma ghrelin levels positively correlated with IGFBP-1 (p<0.01). In the control group, ghrelin positively correlated with GH concentrations (p<0.01) and negatively correlated with the levels of insulin and creatinine (p<0.05). In conclusion, patients with ESRD have higher ghrelin concentrations, which might be caused by a decreased excretion/metabolism of ghrelin in the kidney during renal failure.     

Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.     

Alteration of plasma total F2-isoprostanes before and after hemodialysis in end-stage renal disease patients

F(2)-isoprostanes are derived in vivo principally from the following: (1) the formation of positional peroxyl radicals of arachidonic acid, (2) endocyclization to prostaglandin G(2)-like structures, and (3) reduction to PGF(2)-like compounds. F(2)-isoprostanes have been proposed as biomarkers of lipid peroxidation, oxidative stress status, and the oxidation of low-density lipoprotein (LDL). Using gas chromatography-ion trap-mass spectrometry, we studied how hemodialysis (HD) affects plasma total F(2)-isoprostanes. We examined the plasma total F(2)-isoprostanes in end-stage renal disease (ESRD) patients, before HD, after HD, between HD, and in control subjects. Plasma concentrations of total F(2)-isoprostanes were significantly higher in the after HD ESRD patients than the before hemodialysis ESRD patients (P < 0.05). There is no difference between before HD ESRD patients and normal controls. Moreover, a positive or negative correlation was seen between LDL and plasma total F(2)-isoprostanes (P < 0.001), and between age and plasma total F(2)-isoprostanes (P < 0.001). This study indicates HD treatment may be the major contributor of oxidative stress in ESRD patients.     

Biomarkers and cardiac disease in patients with end-stage renal disease on dialysis

Very soon after troponin was introduced to routine clinical use in the mid-1990s, it was observed that troponin T was often increased in the blood of asymptomatic patients undergoing chronic dialysis for end-stage renal disease. Observation of these patients showed that the presence of troponin T in blood was predictive of a worse outcome for these patients.Cardiac disease is the major cause of death in dialysis patients. This review considers the heterogeneous cardiac disease that is found in these patients and reviews the role of cardiac biomarkers in identifying patients at risk of an adverse outcome.     

Paraoxonase-1 and ischemia-modified albumin in patients with end-stage renal disease

End-stage renal disease (ESRD) with and/or without treatment by hemodialysis (HD) is associated with accelerated atherosclerosis, leading to cardiovascular disease (CVD) including acute coronary syndromes. Therefore, the regulation of CVD is a crucial issue for ESRD patients. Given the recent reports that paraoxonase-1 (PON-1) and ischemia-modified albumin (IMA) could predict CVD-related mortality in ESRD, the two recent biomarkers may be useful for preventive strategies for CVD. This review paper presents current data on the relationships between PON-1, IMA, and ESRD. Many studies have shown that circulating PON-1 activity is lower in ESRD patients, and we have shown that its levels increase after HD. Although circulating IMA levels can increase before HD in ESRD patients, there remains to be little data. Our pilot study has shown a significant inverse correlation between PON-1 and IMA in ESRD patients. Although the pathogenic link between PON-1 and IMA remains speculative, considering both biomarkers may provide new insights into the prevention of CVD in ESRD patients.     

Inflammatory markers in end-stage renal disease patients on haemodialysis

BackgroundCXC chemokine ligand 16 (CXCL16) is an inflammatory chemokine that mediates renal infiltration of macrophages and activated T cells. Aim: To investigate serum levels of CXCL16 in patients undergoing hemodialysis and their correlation with other inflammatory markers such as C-reactive protein (CRP) and intact parathyroid hormone (iPTH).MethodsThe study included 40 hemodialysis patients (22 males) and 40 age and gender-matched controls (24 males). Fasting blood sugar (FBS), urea, creatinine, calcium and inorganic phosphorous were assayed in participants using routine methods, glycosylated hemoglobin (HbA1c) by quantitative chromatographic spectrophotometry, iPTH by chemiluminescent microparticle immunoassay, CRP by nephelometry and CXCL16 by ELISA technique.ResultsSerum CXCL16, CRP, PTH, FBS, HbA1c, phosphorus, urea, and creatinine levels were significantly higher in hemodialysis patients compared to controls (p<0.00001). No statistically significant differences were observed between patients and controls for calcium. Serum CXCL16 levels correlated positively with CRP (r=0.956, p<0.00001) and iPTH (r=-0.403, p<0.001). Hemodialysis patients (diabetics or hypertensives) had significantly higher CXCL16 levels compared to non-diabetics or non-hypertensives.ConclusionsHigh levels of serum CXCL16, CRP and iPTH reflect the inflammatory status of hemodialysis patients and help avoid complications. Serum CXCL16 could be used as a biomarker together with CRP in these patients.     

Incidence and causes of end-stage renal disease among Aboriginal children and young adults

Background:

Although Aboriginal adults have a higher risk of end-stage renal disease than non-Aboriginal adults, the incidence and causes of end-stage renal disease among Aboriginal children and young adults are not well described.

Methods:

We calculated age- and sex-specific incidences of end-stage renal disease among Aboriginal people less than 22 years of age using data from a national organ failure registry. Incidence rate ratios were used to compare rates between Aboriginal and white Canadians. To contrast causes of end-stage renal disease by ethnicity and age, we calculated the odds of congenital diseases, glomerulonephritis and diabetes for Aboriginal people and compared them with those for white people in the following age strata: 0 to less than 22 years, 22 to less than 40 years, 40 to less than 60 years and older than 60 years.

Results:

Incidence rate ratios of end-stage renal disease for Aboriginal children and young adults (age < 22 yr, v. white people) were 1.82 (95% confidence interval [CI] 1.40–2.38) for boys and 3.24 (95% CI 2.60–4.05) for girls. Compared with white people, congenital diseases were less common among Aboriginal people aged less than 22 years (odds ratio [OR] 0.56, 95% CI 0.36–0.86), and glomerulonephritis was more common (OR 2.18, 95% CI 1.55–3.07). An excess of glomerulonephritis, but not diabetes, was seen among Aboriginal people aged 22 to less than 40 years. The converse was true (higher risk of diabetes, lower risk of glomerulonephritis) among Aboriginal people aged 40 years and older.

Interpretation:

The incidence of end-stage renal disease is higher among Aboriginal children and young adults than among white children and young adults. This higher incidence may be driven by an increased risk of glomerulonephritis in this population.Compared with white Canadians, Aboriginal Canadians have a higher prevalence of end-stage renal disease,^1,2 which is generally attributed to their increased risk for diabetes. However, there has been limited investigation of the incidence and causes of end-stage renal disease among Aboriginal children and young adults. Because most incident cases of diabetes are identified in middle-aged adults, an excess risk of end-stage renal disease in young people would not be expected if the high risk of diabetes is responsible for higher overall rates of end-stage renal disease among Aboriginal people. About 12.3% of children with end-stage renal disease in Canada are Aboriginal,³ but only 6.1% of Canadian children (age < 19 yr) are Aboriginal.^4,5A few reports suggest that nondiabetic renal disease is common among Aboriginal populations in North America.^2,6–8 Aboriginal adults in Saskatchewan are twice as likely as white adults to have end-stage renal disease caused by glomerulonephritis,^7,8 and an increased rate of mesangial proliferative glomerulonephritis has been reported among Aboriginal people in the United States.^6,9 These studies suggest that diabetes may be a comorbid condition rather than the sole cause of kidney failure among some Aboriginal people in whom diabetic nephropathy is diagnosed using clinical features alone.We estimated incidence rates of end-stage renal disease among Aboriginal children and young adults in Canada and compared them with the rates seen among white children and young adults. In addition, we compared relative odds of congenital renal disease, glomerulonephritis and diabetic nephropathy in Aboriginal people with the relative odds of these conditions in white people.     

Large-scale mitochondrial DNA deletions in skeletal muscle of patients with end-stage renal disease

End-stage renal disease (ESRD) is associated with enhanced oxidative stress. This disease state provides a unique system for investigating the deleterious effect of exogenous sources of free radicals and reactive oxygen species (ROS) on mitochondrial DNA (mtDNA). To test the hypothesis that uremic milieu might cause more severe damage to mtDNA, we investigated the prevalence and abundance of mtDNA deletions in the skeletal muscles of ESRD patients. The results showed that the frequencies of occurrence of the 4977 bp and 7436 bp deletions of mtDNA in the muscle tissues of the older ESRD patients were higher than those of the younger patients. The frequency of occurrence of the 4977 bp-deleted mtDNA in the muscle was 33.3% for the patients in the age group of < 40 years, 66.6% in the 41-60-year-old group, 100% in the 61-80-year-old group, and 100% in patients >80 years of age, respectively. Only 22% of the normal aged controls carried the 4977 bp mtDNA deletion, whereas 77% (17/22) of the ESRD patients exhibited the mtDNA deletion. Using a semiquantitative PCR method, we determined the proportion of the 4977 bp-deleted mtDNA from the muscles that had been confirmed to harbor the deletion. We found that the proportions of the 4977 bp-deleted mtDNA in the muscle were significantly higher than those of the aged matched controls. Using long-range PCR techniques, a distinctive array of mtDNA deletions was demonstrated in the muscle of uremic patients. In summary, we found diverse and multiple mtDNA deletions in the skeletal muscles of ESRD patients. These deletions are more prevalent and abundant in ESRD patients than those found in normal populations. Accumulation of uremic toxins and impaired free radical scavenging systems may be responsible for the increased oxidative stress in ESRD patients. Such stress may result in oxidative damage and aging-associated mutation of the mitochondrial genome.     

Effects of hemodialysis on serum lipids and phospholipids of end-stage renal failure patients

There is a link between diabetes and oxidative stress. Hyperglycaemia leads to free radical generation and alterations of endogenous antioxidants. Our aim is to study the effect of orally administered L-tryptophan (TRP), the melatonin precursor, an endogenous antioxidant, on circulating levels of glycaemia, insulin and melatonin, and on the superoxide dismutase and catalase antioxidant systems in non-diabetic (ND) and type 2 diabetic (n5-STZ) male Wistar rats. At 19:30 every day for 15 days, TRP (125 mg/kg body weight) was administered orally. At 09:00 every two days the glycaemia was measured and every day the intake of food and water was recorded. At the beginning and end of treatment (at 09:00; 21:00; 02:00) plasma insulin and melatonin levels were measured, and (at 09:00) the enzymatic activities of catalase and superoxide dismutase (SOD) in erythrocytes were also measured. Glycaemia values were greater (p < 0.01) in n5-STZ rats than in ND rats, while insulin levels were lower (p < 0.05) at all times studied and these parameters were not altered by the TRP administration. Melatonin levels at 02:00 were lower in n5-STZ than in ND rats (p < 0.05). The TRP administration did not modify the circulating melatonin levels in ND rats, but raised (p < 0.01) the levels at 02:00 in the treated n5-STZ group. In ND rats after TRP administration there was a decline in catalase activity (p < 0.05), while in n5-STZ rats there was a rise (p < 0.01) at the end of treatment. However, there were no significant changes in SOD activity. There was increased food intake (g/day) in the treated n5-STZ group (p < 0.01). In conclusion, the oral administration of TRP did not modify glycaemia or insulinaemia levels, but raised melatonin levels in diabetic rats at 02:00, lowered catalase activity in ND rats but raised it in n5-STZ rats, and increased food intake in n5-STZ rats.     

Effect of intravenous vitamin C on cytokine activation and oxidative stress in end-stage renal disease patients receiving intravenous iron sucrose

Reticuloendothelial blockade in hemodialysis patients prevents optimal intravenous (IV) iron utilization. Vitamin C has emerged as a potential therapy to improve anemia treatment by enhancing iron mobilization. However, Vitamin C can act as a pro-oxidant in the presence of iron. This was a prospective, open-label, crossover study. Thirteen patients with end-stage renal disease on hemodialysis and four healthy controls were assigned to receive 100?mg of IV iron sucrose (IS) or 100?mg of IV IS co-administered with 300?mg of IV Vitamin C (IS?+?C) in random sequence. Serum samples for IL-1, IL-6, TNF-α and IL-10 and non-transferrin bound iron were obtained at baseline, 45?min and 105?min post study medication administration. Peripheral blood mononuclear cells were isolated at the same time points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential (Δψm) by flow cytometry. Lipid peroxidation was assessed by plasma F2-isoprosatane concentration. Both IS and IS?+?C were associated with increased plasma F2-isoprostanes concentrations post-infusion. Maximal plasma F2-isoprostane concentrations after IS?+?C were significantly elevated from baseline (234?±?0.04 vs. 0.198?±?0.028?ng/mL, p?=?0.02). After IS?+?C, IL-1, IL-6, IL-10, and TNF-alpha were significantly elevated compared to baseline. After IS alone only IL-6 was noted to be elevated. Intracellular production of H(2)O(2) and loss of mitochondrial membrane potential (Δψm) was observed after IS while IS?+?C was associated with increased O (2) (·-) production. Both IS and IS?+?C induced serum cytokine activation accompanied by lipid peroxidation, however, IS?+?C induced higher plasma concentrations of F2-isoprostanes, IL-1, IL-10, and TNF-α post-infusion. Long-term safety studies of IV iron co-administered with Vitamin C are warranted.     

Bone marrow-derived mesenchymal stromal cells from patients with end-stage renal disease are suitable for autologous therapy

Background aimsMesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive and reparative properties in vitro and in vivo. Although autologous bone marrow (BM)-derived MSCs are already clinically tested in transplant recipients, it is unclear whether these BM cells are affected by renal disease. We assessed whether renal failure affected the function and therapeutic potential of BM-MSCs.MethodsMSCs from 10 adults with end-stage renal disease (ESRD) and 10 age-matched healthy controls were expanded from BM aspirates and tested for phenotype and functionality in vitro.ResultsMSCs from ESRD patients were >90% positive for CD73, CD90 and CD105 and negative for CD34 and CD45 and showed a similar morphology and differentiation capacity as MSCs from healthy controls. Of importance for their clinical utility, growth characteristics were similar in both groups, and sufficient numbers of MSCs were obtained within 4 weeks. Messenger RNA expression levels of self-renewal genes and factors involved in repair and inflammation were also comparable between both groups. Likewise, microRNA expression profiling showed a broad overlap between ESRD and healthy donor MSCs. ESRD MSCs displayed the same immunosuppressive capacities as healthy control MSCs, demonstrated by a similar dose-dependent inhibition of peripheral blood mononuclear cell proliferation, similar inhibition of proinflammatory cytokines tumor necrosis factor-α and interferon-γ production and a concomitant increase in the production of interleukin-10.ConclusionsExpanded BM-MSCs procured from ESRD patients and healthy controls are both phenotypically and functionally similar. These findings are important for the potential autologous clinical application of BM-MSCs in transplant recipients.     

Exercise pressor reflex in humans with end-stage renal disease

Previous work has suggested that end-stage renal disease (ESRD) patients may have an exaggerated sympathetic nervous system (SNS) response during exercise. We hypothesized that ESRD patients have an exaggerated blood pressure (BP) response during moderate static handgrip exercise (SHG 30%) and that the exaggerated BP response is mediated by SNS overactivation, characterized by augmented mechanoreceptor activation and blunted metaboreceptor control, as has been described in other chronic diseases. We measured hemodynamics and muscle sympathetic nerve activity (MSNA) in 13 ESRD and 16 controls during: 1) passive hand movement (PHM; mechanoreceptor isolation); 2) low-level rhythmic handgrip exercise (RHG 20%; central command and mechanoreceptor activation); 3) SHG 30%, followed by posthandgrip circulatory arrest (PHGCA; metaboreceptor activation); and 4) cold pressor test (CPT; nonexercise stimulus). ESRD patients had exaggerated increases in systolic BP during SHG 30%; however, the absolute and relative increase in MSNA was not augmented, excluding SNS overactivation as the cause of the exaggerated BP response. Increase in MSNA was not exaggerated during RHG 20% and PHM, demonstrating that mechanoreceptor activation is not heightened in ESRD. During PHGCA, MSNA remained elevated in controls but decreased rapidly to baseline levels in ESRD, indicative of markedly blunted metaboreceptor control of MSNA. MSNA response to CPT was virtually identical in ESRD and controls, excluding a generalized sympathetic hyporeactivity in ESRD. In conclusion, ESRD patients have an exaggerated increase in SBP during SHG 30% that is not mediated by overactivation of the SNS directed to muscle. SBP responses were also exaggerated during mechanoreceptor activation and metaboreceptor activation, but without concomitant augmentation in MSNA responses. Metaboreceptor control of MSNA was blunted in ESRD, but the overall ability to mount a SNS response was not impaired. Other mechanisms besides SNS overactivation, such as impaired vasodilatation, should be explored to explain the exaggerated exercise pressor reflex in ESRD.     

Determinants of premature atherosclerosis in children with end-stage renal disease

Cardiovascular disease is a major cause of morbidity and mortality in young adults with end-stage renal disease (ESRD), but its basis is still not well understood. We therefore evaluated the determinants of atherosclerosis in children with ESRD. A total of 37 children with ESRD (with 31 who had undergone transplantation) were examined and compared to a control group comprising 22 healthy children. The common carotid intima-media thickness (CIMT) was measured by ultrasound as a marker of preclinical atherosclerosis. The association of CIMT with anthropometrical data, blood pressure, plasma lipid levels, and other biochemical parameters potentially related to cardiovascular disease was evaluated. Children with ESRD had significantly higher CIMT, blood pressure, and levels of lipoprotein (a), urea, creatinine, ferritin, homocysteine, and serum uric acid as well as significantly lower values of apolipoprotein A. The atherogenic index of plasma (log(triglycerides/HDL cholesterol)) was also higher in patients with ESRD; however, this difference reached only borderline significance. In addition, a negative correlation was found between CIMT and serum albumin and bilirubin in the ESRD group, and this correlation was independent of age and body mass index. In the control group, a significant positive correlation was observed between CIMT and ferritin levels. Factors other than traditional cardiovascular properties, such as the anti-oxidative capacity of circulating blood, may be of importance during the early stages of atherosclerosis in children with end-stage renal disease.