Selected microRNA Expression and Protein Regulator Secretion by Adipose Tissue-Derived Mesenchymal Stem Cells and Metabolic Syndrome.

The role of adipose mesenchymal stem cells (Ad-MSCs) in metabolic syndrome remains unclear. We aimed to assess the expression of selected microRNAs in Ad-MSCs of non-diabetic adults in relation to Ad-MSC secretion of protein regulators and basic metabolic parameters. Ten obese, eight overweight, and five normal weight subjects were enrolled: 19 females and 4 males; aged 43.0 ± 8.9 years. Ad-MSCs were harvested from abdominal subcutaneous fat. Ad-MSC cellular expressions of four microRNAs (2-ΔCt values) and concentrations of IL-6, IL-10, VEGF, and IGF-1 in the Ad-MSC-conditioned medium were assessed. The expressions of miR-21, miR-122, or miR-192 did not correlate with clinical parameters (age, sex, BMI, visceral fat, HOMA-IR, fasting glycemia, HbA1c, serum lipids, CRP, and eGFR). Conversely, the expression of miR-155 was lowest in obese subjects (3.69 ± 2.67 × 10-3 vs. 7.07 ± 4.42 × 10-3 in overweight and 10.25 ± 7.05 × 10-3 in normal weight ones, p = 0.04). The expression of miR-155 correlated inversely with BMI (sex-adjusted r = -0.64; p < 0.01), visceral adiposity (r = -0.49; p = 0.03), and serum CRP (r = -0.63; p < 0.01), whereas it correlated positively with serum HDL cholesterol (r = 0.51; p = 0.02). Moreover, miR-155 synthesis was associated marginally negatively with Ad-MSC secretion of IGF-1 (r = -0.42; p = 0.05), and positively with that of IL-10 (r = 0.40; p = 0.06). Ad-MSC expression of miR-155 appears blunted in visceral obesity, which correlates with Ad-MSC IGF-1 hypersecretion and IL-10 hyposecretion, systemic microinflammation, and HDL dyslipidemia. Ad-MSC studies in metabolic syndrome should focus on miR-155.

Uremic pruritus and serum brain-derived neurotrophic factor in diabetic and non-diabetic haemodialysis patients.

INTRODUCTION: Even though uremic pruritus (UP) is very troublesome for haemodialysis (HD) patients, its underlying mechanism is not fully understood. AIM: Due to the possible role of brain-derived neurotrophic factor (BDNF) and its higher serum concentration in haemodialysis diabetic patients compared to non-diabetic ones, this study is aimed to evaluate its association with UP among diabetic and non-diabetic patients on maintenance HD. MATERIAL AND METHODS: A total of 94 patients were enrolled into the study. A visual analogue scale (VAS) was used to assess pruritus. RESULTS: No differences were found between the observed study groups in terms of BDNF serum concentration, other biochemical markers, sleep disturbances, or pruritus presentation. CONCLUSIONS: BDNF serum concentration was not found to be associated with UP among HD patients, however further studies are worth performing on a larger group of individuals.

Mesenchymal Stem Cells-Potential Applications in Kidney Diseases.

Mesenchymal stem cells constitute a pool of cells present throughout the lifetime in numerous niches, characteristic of unlimited replication potential and the ability to differentiate into mature cells of mesodermal tissues in vitro. The therapeutic potential of these cells is, however, primarily associated with their capabilities of inhibiting inflammation and initiating tissue regeneration. Owing to these properties, mesenchymal stem cells (derived from the bone marrow, subcutaneous adipose tissue, and increasingly urine) are the subject of research in the settings of kidney diseases in which inflammation plays the key role. The most advanced studies, with the first clinical trials, apply to ischemic acute kidney injury, renal transplantation, lupus and diabetic nephropathies, in which beneficial clinical effects of cells themselves, as well as their culture medium, were observed. The study findings imply that mesenchymal stem cells act predominantly through secreted factors, including, above all, microRNAs contained within extracellular vesicles. Research over the coming years will focus on this secretome as a possible therapeutic agent void of the potential carcinogenicity of the cells.

Pentoxifylline and Methylprednisolone Additively Alleviate Kidney Failure and Prolong Survival of Rats after Renal Warm Ischemia-Reperfusion.

Renal ischemia-reperfusion injury (IRI) induces local inflammation leading to kidney damage. Since pentoxifylline (PTX) and steroids have distinct immunomodulatory properties, we aimed to evaluate for the first time their combined use in IRI-induced acute kidney injury (AKI) and chronic kidney disease (CKD) in rats. In two experiments, PTX (100 mg/kg body weight subcutaneously) was administered 90 min prior to renal IRI or/and methylprednisolone (MP; 100 mg/kg body weight intramuscularly) was infused 60 min after reperfusion of a solitary kidney (AKI model: 45 min ischemia, 48 male Sprague-Dawley rats) or one kidney with excision of contralateral kidney 2 weeks later (CKD model: 90 min ischemia, 38 rats). Saline was infused in place of PTX or/and MP depending on the group. Renal function (diuresis, serum creatinine, creatinine clearance, sodium and potassium excretion, and urine protein/creatinine) was assessed at 48 h and 120 h post-IRI (AKI model) or 4, 16 and 24 weeks after IRI, along with survival analysis (CKD model). More evidently at early stages of AKI or CKD, treated animals showed higher glomerular filtration and diminished tubular loss of electrolytes, more so with PTX + MP than PTX or MP (serum creatinine (µmol/L) at 48 h of AKI: 60.9 ± 19.1 vs. 131.1 ± 94.4 vs. 233.4 ± 137.0, respectively, vs. 451.5 ± 114.4 in controls, all p < 0.05; and at 4 weeks of CKD: 89.0 ± 31.9 vs. 118.1 ± 64.5 vs. 156.9 ± 72.6, respectively, vs. 222.9 ± 91.4 in controls, p < 0.05 for PTX or PTX + MP vs. controls and PTX + MP vs. MP). Survival was better by >2-fold with PTX + MP (89%) vs. controls (40%; p < 0.05). PTX + MP largely protect from IRI-induced AKI and CKD and subsequent mortality in rats. This calls for clinical investigations, especially in kidney transplantation.

Association between hypoglycemia and the type of insulin in diabetic patients treated with multiple injections: an observational study.

INTRODUCTION: Hypoglycemia may have serious health consequences; therefore, it is important to expand knowledge on the factors that increase its prevalence. OBJECTIVES: The aim of the study was to evaluate the effect of the type of insulin-human vs. analogue-on the incidence of mild and severe hypoglycemia, body weight, and hemoglobin A1c (HbA1c) levels. PATIENTS AND METHODS: A total of 203 diabetic patients treated with intensive insulin therapy completed the questionnaire on hypoglycemia at baseline and at 3 and 6 months of the follow­up. Body weight and HbA1c levels were measured at baseline and at 6 months. Incidence of mild and severe hypoglycemia, body weight, and HbA1c levels were compared between patients treated with short­acting analogue and those treated with short­acting human insulin (regardless of the type of long­acting insulin used) and between patients receiving short- and long­acting analogue insulin and those receiving short- and long­acting human insulin. A multiple logistic regression analysis was used to find independent risk factors of severe hypoglycemia. RESULTS: At baseline, mild hypoglycemia was more common in patients receiving insulin analogue. There were no differences between the subgroups in the incidence of severe hypoglycemia, HbA1c levels, and body weight. Male sex, older age, and the dose of long­acting insulin were independently associated with a higher incidence of severe hypoglycemia. Type 2 diabetes and higher body weight were associated with a lower risk of severe hypoglycemia. CONCLUSIONS: Our results suggest that use of insulin analogues may predispose to more frequent episodes of mild hypoglycemia, but it does not increase the incidence of severe hypoglycemia in patients on intensive insulin therapy. Insulin analogues are not different from human insulin in terms of the effects on HbA1c levels and body mass.

Peritoneal dialysis as a mode of treatment for acute kidney injury in sub-Saharan Africa.

BACKGROUND: Developing sustainable treatment programs for kidney failure in most countries of sub-Saharan Africa continues to remain an imposing challenge. While long-term renal replacement therapies in end-stage renal disease appear beyond national financial capabilities, there exist opportunities for a short-term and affordable treatment of acute kidney injury (AKI). Peritoneal dialysis (PD) is an effective and simpler modality compared to hemodialysis (HD) and can be performed without the need for machinery or electricity, making it an ideal choice in a low-resource setting. METHODS: Since cost of treatment is the major obstacle, the goal is to develop a program that is cost effective. Developing an HD program requires a large capital investment by the hospital, needing water treatment systems and machinery and providing for their ongoing repair and maintenance. Gravity-driven PD is a simple, effective modality and can be performed in low-resource locales. RESULTS: In a pediatric program that we started in the Komfo Anokye Teaching Hospital in Kumasi, Ghana, 28 patients have been treated with PD for AKI so far. Half of them were treated successfully and were discharged having fully recovered kidney function. Seven patients (25%) were determined to have end-stage renal disease, whereas 7 others (25%) died during hospitalization. In these cases, late presentation for dialysis may have contributed to the inability to recover. CONCLUSION: For individuals and governments alike, who are concerned about the cost of providing or paying for dialysis, using PD to treat AKI is an effective and simpler modality compared to HD and can be performed without the need for machinery or electricity, making it an ideal choice in a low-resource setting.

[Carbohydrate sweeteners and obesity]. / Weglowodanowe substancje slodzace a otylosc.

The U.S. prevalence of obesity increases since the mid-70s of the 20th century. Around that time high-fructose corn syrup (HFCS)--mixture of fructose and glucose was introduced as a sweetener replacing sucrose in the food production. HFCS containing 55% fructose and 42-45% glucose (HFCS55) has dominated the American soft drink industry and HFCS has recently become commonly used in Poland. The coincidence of HFCS introduction and obesity epidemic raised widely publicized suspicions of a causal relationship between the two. As a possible mechanism, a higher content of fructose in the HFCS55, as compared with sucrose was suggested -fructose is known to increase serum uric acid level, induce hepatic lipogenesis and not stimulate postprandial hyperinsulinemia, a main activator of leptin release. Few comparative studies of HFCS and sucrose have largely failed to reveal any different impacts on the metabolic parameters, yet they were mainly short-term. It has been recently shown that obesity is linked with changes in the intenstinal flora. Among the causes of allegedly different effects of sucrose and HFCS on metabolism, their influence on the gut microbiome has not been examined. Some bacterial types do not hydrolyze sucrose which may determine different compositions of gut flora with the use of both sweeteners. Studies involving quantitative analysis of bacterial DNA in the stool, both in animals and in humans, shall shed light on the issue that has recently so much absorbed the U.S. public opinion.

Expression profile of significant immortalization genes in colon cancer.

Cancer is a disease of genomic instability, a multistep process involving numerous mutations and chromosomal aberrations. Telomeres are highly specialized structures at the ends of chromosomes and function to stabilize and protect the ends of linear chromosomes, therefore determining cellular immortalization. Homeostasis of telomere length is a multifactor-dependent process. Since cellular immortalization is an early and essential step towards cancer, the aim of the present study was to determine immortalization genes that are significant in colon cancer and assess their usefulness in the early diagnosis of this tumor. Expression profiles of 119 transcripts known to be involved in cellular immortalization were assessed with oligonucleotide microarrays in 13 probes of colon adenocarcinoma (low and high clinical stages) and 9 probes of controls (normal colon tissue) and were compared among these groups with the use of the Significant Analysis Microarray (SAM) software and independently verified with the effect size parameter. Eighteen genes with significantly differential expression between high clinical stage colon cancer and the control group, and 21 with differential expression between low clinical stage colon cancer and the control group were identified. Nine genes showing altered expression in both low and high clinical stage colon cancer: ACD (TPP1), DKC1 and ERCC1, MYC, MAX, NBN, NOLA2, PRKDC and HSP82 should, in particular, be the subjects of further studies including QRT-PCR methods.

Impact of switch of vascular access type on key clinical and laboratory parameters in chronic haemodialysis patients.

BACKGROUND: Observational studies demonstrate poor clinical outcomes in chronic haemodialysis patients with venous catheters as vascular access. This longitudinal study examines the impact of vascular access change on key clinical and laboratory parameters. METHODS: We studied 2616 haemodialysis patients who had no or one vascular access change between January 2002 and June 2003. Two hundred and seventy-one patients switched from a catheter to an arteriovenous (AV) access (AV fistula or graft) and 69 patients from an AV access to a catheter. Accesses remained unchanged in 430 patients with catheters, and in 1846 patients with an AV access, who served as controls. Levels of serum albumin, white blood cell count (WBC), enPCR, eKdrt/V, blood haemoglobin and erythropoietin dosage were obtained monthly. Data were averaged over 6 months preceding (pre) and 6 months following the access change (post). Differences between post- and pre-access change were compared to changes in respective parameters between the last and first 6 months of the study period in controls. RESULTS: The change from a catheter to an AV access was associated with a rise of serum albumin (+0.12 g/dL; P < 0.001), enPCR (+0.05 g/kg body weight/day; P = 0.001) and haemoglobin (+0.41 g/dL; P < 0.001) and a decrease in WBC (-370/microL; P = 0.048). Conversely, switching from an AV access to a catheter was followed by a significant fall in albumin (-0.11 g/dL; P = 0.035), enPCR (-0.07 g/ kg body weight/day; P = 0.001) and eKdrt/V (-0.09; P < 0.001) and a rise in erythropoietin dosage (+89 IU/kg body weight/week; P = 0.002), as compared to controls. CONCLUSION: Change from a catheter to an AV access seems to alleviate malnutrition, inflammation and anaemia. Efforts to replace catheters with fistulae or grafts should be intensified.

Control of core temperature and blood pressure stability during hemodialysis.

BACKGROUND AND OBJECTIVES: Cool dialysate may ameliorate intradialytic hypotension (IDH). It is not known whether it is sufficient to prevent an increase in core temperature (CT) during hemodialysis (HD) or whether a mild decline in CT would yield superior results. The aim of this study was to compare both approaches with regard to IDH. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fourteen HD patients with a history of IDH were studied. During three mid-week HD treatments, CT was set to decrease by 0.5 degrees C ("cooling") or to remain unchanged at the baseline level ("isothermic"). "Thermoneutral" HD (no energy is added to or removed from the patient) was used as a control. Central blood volume (CBV), BP, skin temperature, heart rate variability [low and high frequency] were recorded. RESULTS: CT increased during thermoneutral and remained respectively stable and decreased during isothermic and cooling. Skin temperature decreased significantly during isothermic and cooling, but not during thermoneutral. Nadir systolic BP (SBP) levels were lower during isothermic and thermoneutral compared with cooling. CBV tended to be higher during cooling compared with isothermic and thermoneutral. Three patients complained of shivering during cooling. Change in LF/HF was not different between cooling, isothermic, and thermoneutral. CONCLUSIONS: IDH may be slightly improved by cooling compared with the isothermic approach, possibly because of improved maintenance of CBV. The hemodynamic effects of mild blood cooling should be balanced against a potentially higher risk of cold discomfort.

Dry weight: sine qua non of adequate dialysis.

Attainment of dry weight remains a major clinical problem and challenge in current-day dialysis therapies. The vicious cycle of fluid overload and inadequate intradialytic fluid removal with hypotensive episodes, and subsequent poor clinical outcomes, is reinforced by excessive salt accumulation orally as well as during dialysis. Negligence in recognizing the importance of fluid status in dialysis prescriptions with shortened times has contributed to the prevalence of overhydration. The treatment of this problem is exacerbated by the lack of adequate methods to diagnose and manage it. The recent findings of improved fluid status and prognosis with salt restriction, individualized dialysate sodium concentrations, and prolonged hemodialysis times when necessary with well-tolerated fluid removal rates show the path to prolonging survival of dialysis populations. The ongoing development of techniques permitting accurate assessment of hydration status, including those based on bioimpedance analysis, will provide an efficient tool in these efforts.

Fluid dynamics during hemodialysis in relationship to sodium gradient between dialysate and plasma.

Fluid shifts during hemodialysis involve changes in both extracellular and intracellular volumes. This study aimed to determine the effect of intradialytic sodium gradients (GNa), that is, the difference between dialysate and serum sodium concentration, on dynamics of extracellular and intracellular volumes in a group of maintenance hemodialysis patients. Extracellular volume change (deltaECV) between predialysis and postdialysis periods was determined by whole-body bioimpedance spectroscopy; intracellular volume change (deltaICV) was indirectly derived as the difference between deltaECV and the change in body weight, corrected for intradialytically given fluids. A total of 200 bioimpedance measurements were performed in 32 dialysis patients. Extracellular and intracellular volume changes were -2.6 +/- 0.9 L (range: -4.7 to -0.5 L) and -0.2 +/- 0.7 L (range: -2.5 to +1.5 L), respectively. There was a significant correlation between deltaICV and GNa; deltaICV = -0.12 * GNa + 0.26 (p < 0.001). In contrast, GNa was not correlated with deltaECV. We conclude that the sodium gradient between dialysate and plasma has a significant effect on the ICV during dialysis. Hemodialysis with GNa = 0 mmol/L should be sought to prevent ICV shrinking or swelling and to prevent excessive thirst, consequently high interdialytic weight gains, and ultrafiltration rates.

Determinants of serum albumin concentration analyzed in a large cohort of patients on maintenance hemodialysis.

OBJECTIVE: Serum albumin concentration is a powerful predictor of mortality in patients on chronic hemodialysis (CHD). This study sought to investigate variables associated with serum albumin concentration. DESIGN AND STUDY POPULATION: Cross-sectional study in prevalent chronic hemodialysis patients treated at the Renal Research Institute between July 1, 2005 and October 31, 2005. A total of 4,798 (2,199 females) patients were studied. MAIN OUTCOME MEASURES: Univariate and multivariate relationships of serum albumin concentration with age, sex, race (black, white, other), vascular access type (arteriovenous fistula/graft, catheter), white blood cells, neutrophils, lymphocytes, equilibrated normalized protein catabolic rate (enPCR), dialysis efficacy (eKdrt/V), hemoglobin, phosphate, bio-intact parathyroid hormone [bioPTH], creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). RESULTS: Age, access type, and variables of 3 domains, namely, nutrition (enPCR; creatinine), eKdrt/V, and inflammation (white blood cells; neutrophil:lymphocyte ratio; hemoglobin), were related to serum albumin. It is interesting to note that AST was the strongest negative predictor of albumin levels. CONCLUSION: In CHD patients, serum albumin concentration is defined by a complex interaction of inflammation, nutrition, and dialysis efficacy. The relationship between AST and albumin deserves additional study.

Size matters: body composition and outcomes in maintenance hemodialysis patients.

In hemodialysis patients a low body mass index (BMI) is correlated with an unfavorable clinical outcome, a phenomenon known as "reverse epidemiology". Mechanisms underlying this observation are unclear. We propose the following: uremic toxin generation occurs predominantly in visceral organs and the mass of key uremiogenic viscera (gut, liver) relative to body weight is higher in small people. Consequently, the rate of uremic toxin generation per unit of BMI is higher in patients with a low BMI. Body water, mainly determined by muscle mass, serves as a dilution compartment for uremic toxins. Therefore, the concentration of uremic toxins is higher in small subjects. Uremic toxins are taken up by adipose and muscle tissues, subsequently metabolized and stored. Thus, the larger the ratio of fat and muscle mass to visceral mass, the lower the concentration of uremic toxins and the better the survival. To test this hypothesis, studies on uremic toxin kinetics in relation to body composition are needed.

Selected climatic variables and blood pressure in Central European patients with chronic renal failure on haemodialysis treatment.

UNLABELLED: BACKGROUND/AIMS;Higher blood pressure (BP) in winter has been documented in healthy and hypertensive adults. It may potentially contribute to the observed excess winter cardiovascular mortality in the general population. The aim of the study was to assess whether BP varies similarly among patients with chronic renal failure on haemodialysis treatment, who present an increased risk of cardiovascular death. METHODS: We retrospectively analysed values of pre-dialysis BP and parameters of fluid retention--pre-dialysis body weight and inter-dialytic weight gain measured in 49 patients (23 male, 26 female; aged 46.0+/-13.5 years) from 1995 to 1998. For each patient we calculated deviations of monthly mean values of systolic BP, diastolic BP, pre-dialysis body weight and inter-dialytic weight gain from the lowest monthly means of these parameters in a given year. Monthly means of these deviations for the whole study group (dSBP, dDBP, dBW, dWG, respectively) were subsequently computed. Monthly means of air temperature (T), air relative humidity (H) and atmospheric pressure (AP) were provided by the local Institute of Meteorology. The Wilcoxon paired test was applied to compare mean values of BPs and parameters of fluid retention of every patient in three warmest and three coldest months of each year. Spearman rank correlation analysis was employed to evaluate relationships between dSBP, dDBP and climatic variables, dBW or dWG. RESULTS: Systolic BP was higher in summer than in winter (146.6+/-20.5 vs 143.4+/-18.9 mmHg; p<0.00001). Diastolic BP was also higher in summer than in winter (82.6+/-8.5 vs 79.6+/-7.3 mmHg; p<10(-9)). Pre-dialysis body weight and inter-dialytic weight gain did not differ between summer and winter (66.0+/-13.2 vs 66.0+/-13.2 kg; p=0.98 and 2.27+/-0.6 vs 2.29+/-0.5 kg; p=0.53). There was a positive correlation between dSBP and T (RS=0.424, p<0.003), as well as dDBP and T (RS=0.591, p<0.00001) and an inverse correlation between dSBP and H (RS=-0.372, p<0.01), as well as dDBP and H (RS=-0.408, p<0.004). There were no significant associations between BPs and AP, dBW or dWG. CONCLUSIONS: In haemodialysed patients from southern Poland, BP is higher in summer than in winter. Changes in BP are related to seasonal changes in climatic variables--air temperature and air relative humidity. Seasonal variation in BP is not associated with variation in fluid retention. Possible alteration of cardiovascular reactivity to changes in climatic environment in haemodialysed chronic renal failure patients may be one of the potential explanations of these observations.