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1.
Nephron ; 130(1): 35-40, 2015.
Article in English | MEDLINE | ID: mdl-25998865

ABSTRACT

AIM: The evaluation of sodium and potassium intake is part of the optimal management of hypertension, metabolic syndrome, renal stones, and other conditions. To date, no convenient method for its evaluation exists, as the gold standard method of 24-hour urine collection is cumbersome and often incorrectly performed, and methods that use spot or shorter collections are not accurate enough to replace the gold standard. The aim of this study was to evaluate the correlation and agreement between a new method that uses multiple-scheduled spot urine collection and the gold standard method of 24-hour urine collection. METHODS: The urine sodium or potassium to creatinine ratios were determined for four scheduled spot urine samples. The mean ratios of the four spot samples and the ratios of each of the single spot samples were corrected for estimated creatinine excretion and compared to the gold standard. RESULTS: A significant linear correlation was demonstrated between the 24-hour urinary solute excretions and estimated excretion evaluated by any of the scheduled spot urine samples. The correlation of the mean of the four spots was better than for any of the single spots. Bland-Altman plots showed that the differences between these measurements were within the limits of agreement. CONCLUSION: Four scheduled spot urine samples can be used as a convenient method for estimation of 24-hour sodium or potassium excretion.


Subject(s)
Potassium/urine , Sodium/urine , Urine Specimen Collection/methods , Adult , Aged , Chlorides/urine , Creatinine/urine , Female , Healthy Volunteers , Humans , Male , Middle Aged , Reference Standards , Urinalysis/methods , Young Adult
2.
Nutrition ; 31(1): 138-47, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25466658

ABSTRACT

OBJECTIVE: The importance of serum uric acid (SUA) for the maintenance of a hemodialysis (MHD) population has not been well established. The aim of this study was to determine if SUA levels are associated with nutritional risk and consequently with adverse clinical outcomes in MHD patients. METHODS: This was a 2-y prospective observational study, performed on 261 MHD outpatients (38.7% women) with a mean age of 68.6 ± 13.6 y. We measured prospective all-cause and cardiovascular (CV) hospitalization and mortality, nutritional scores (malnutrition-inflammation score [MIS) and geriatric nutritional risk index (GNRI), handgrip strength (HGS), and short-form 36 (SF36) quality-of-life (QoL) scores. RESULTS: SUA positively correlated with laboratory nutritional markers (albumin, creatinine), body composition parameters, HGS (r = 0.26; P < 0.001) and GNRI (r = 0.34; P < 0.001). SUA negatively correlated with MIS (r = -0.33; P < 0.001) and interleukin-6 (r = -0.13; P = 0.04). Patients in the highest SUA tertile had higher total SF-36 scores (P = 0.04), higher physical functioning (P = 0.003), and role-physical (P = 0.006) SF-36 scales. For each 1 mg/dL increase in baseline SUA levels, the first hospitalization hazard ratio (HR) was 0.79 (95% confidence interval [CI], 0.68-0.91) and first CV event HR was 0.60 (95% CI, 0.44-0.82); all-cause death HR was 0.55 (95% CI, 0.43-0.72) and CV death HR was 0.55 (95% CI, 0.35-0.80). Associations between SUA and mortality risk continued to be significant after adjustments for various confounders including MIS and interleukin-6. Cubic spline survival models confirmed the linear trends. CONCLUSIONS: In MHD patients, SUA is a good nutritional marker and associates with body composition, muscle function, inflammation, and health-related QoL, upcoming hospitalizations, as well as independently predicting all-cause and CV death risk.


Subject(s)
Biomarkers/blood , Renal Dialysis , Uric Acid/blood , Aged , Aged, 80 and over , Body Composition , Body Mass Index , Creatinine/blood , Energy Intake , Female , Hand Strength , Hospitalization , Humans , Inflammation/blood , Interleukin-6/blood , Male , Middle Aged , Nutritional Status , Prospective Studies , Quality of Life , Risk Factors , Serum Albumin/metabolism , Skinfold Thickness , Treatment Outcome , Tumor Necrosis Factor-alpha/blood
3.
Nutrition ; 30(3): 297-304, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24484680

ABSTRACT

OBJECTIVE: We hypothesize that longitudinal changes in phase angle (PA) have independent associations with changes in inflammatory parameters over time and consequently with long-term survival in patients on maintenance hemodialysis (MHD). The aim of the present study was to determine the effect of change in nutritional and inflammatory parameters over time on change in PA and on subsequent mortality in patients on MHD. METHODS: A 2-y prospective longitudinal study was performed on 91 prevalent HD patients (57 men and 34 women), followed by an additional 3 y of clinical observations. Dietary intake, biochemical markers of nutrition, body composition, and interleukin (IL)-6 levels were measured at baseline and at 6, 12, 18, and 24 mo following enrollment. RESULTS: In a linear mixed-effect model adjusted for baseline demographic and clinical parameters, each pg/mL increase in IL-6 over time was associated with a decrease in PA levels of 0.001°/2-y (P = 0.003 for IL-6 × time interaction). PA remained associated with the rate of change in IL-6 even after controlling for extracellular water and fat mass. Changes in PA over time were associated with inverse linear changes in IL-6 (adjusted r = -0.32; P = 0.005) and consequently with mortality risk. For each 1° increase in PA, the crude and adjusted mortality hazard ratios using Cox models with effect of time-varying risk were 0.62 (95% confidence interval [CI], 0.54-0.71) and 0.61 (95% CI, 0.53-0.71), respectively. Additionally, longitudinal changes in PA exhibited significant associations with slopes of changes over time in main nutritional markers. CONCLUSIONS: Longitudinal changes in PA appear to be reliable in detecting changes in nutritional and inflammatory parameters over time, a combination that may contribute to the understanding of its prognostic utility.


Subject(s)
Electric Impedance , Interleukin-6/blood , Renal Dialysis/adverse effects , Aged , Biomarkers/blood , Body Composition , Energy Intake , Female , Follow-Up Studies , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/therapy , Longitudinal Studies , Male , Middle Aged , Nutritional Status , Proportional Hazards Models , Prospective Studies
4.
Ther Apher Dial ; 18(5): 450-4, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24417873

ABSTRACT

The possibility of developing coronary steal in patients having coronary artery bypass graft (CABG) using internal thoracic artery (ITA) and ipsilateral upper extremity arteriovenous (AV) hemodialysis shunt has been reported. The impact of this phenomenon on clinical outcomes is uncertain. The aim of this study was to investigate an association between the AV dialysis shunt location regarding the side of the ITA CABG and clinical outcomes. This retrospective cohort study included chronic hemodialysis patients having ITA CABG and upper extremity AV shunt. The patients were divided into two groups: those with ipsilateral and those with contralateral location of ITA CABG and AV shunt. The outcomes were: death from any cause, cardiac death and a first cardiac event. In a group of 112 chronic hemodialysis patients having CABG, 32 had an ipsilateral and 25 had a contralateral location of ITA CABG and an upper extremity AV shunt. Significantly more cardiac events occurred in the group with an ipsilateral compared to a contralateral location of ITA CABGs and dialysis AV shunts (hazard ratio, 2.16 [95% CI, 1.11 to 4.19], P = 0.023). There was no difference between the groups in the all cause mortality risk (hazard ratio, 1.005 [95% CI, 0.43 to 2.37], P = 0.990) or the risk of cardiac death (hazard ratio, 2.43 [95% CI, 0.64 to 9.17], P = 0.191). The ipsilateral location of a CABG with the use of ITA and upper extremity AV hemodialysis shunt may be associated with increased risk of cardiac events.


Subject(s)
Arteriovenous Shunt, Surgical/methods , Coronary Artery Bypass/methods , Mammary Arteries/transplantation , Renal Dialysis , Aged , Cohort Studies , Coronary-Subclavian Steal Syndrome/etiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies , Upper Extremity/blood supply
5.
Biomed Res Int ; 2013: 796586, 2013.
Article in English | MEDLINE | ID: mdl-24102059

ABSTRACT

Obestatin, a proposed anorexigenic gut hormone, has been shown to have a number of beneficial cardiotropic effects in experimental studies. We hypothesized that obestatin alteration in hemodialysis patients may link to clinical outcomes. This cross-sectional study with prospective followup for almost 4 years was performed on 94 prevalent hemodialysis patients. Obestatin, leptin, proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6, and various nutritional markers were measured. Patients with low obestatin levels, defined as a level less than median, had a worse all-cause mortality and cardiovascular mortality. The crude all-cause (HR 2.23, 95% CI 1.17 to 4.24) and cardiovascular mortality hazard ratios (HR 4.03, 95% CI 1.27 to 12.76) in these patients continued to be significant after adjustment for various confounders for all-cause mortality. Across the four obestatin-TNF-α categories, the group with low obestatin and high TNF-α (above median level) exhibited a worse outcome in both all-cause mortality and cardiovascular mortality. Clinical characteristics of patients in low obestatin high TNF-α group did not differ from other obestatin-TNF-α categorized groups. In summary, low serum obestatin concentration is an independent predictor of mortality in prevalent hemodialysis patients. Novel interactions were observed between obestatin and TNF-α, which were associated with mortality risk, especially those due to cardiovascular causes.


Subject(s)
Cardiovascular Abnormalities/mortality , Ghrelin/blood , Renal Dialysis/mortality , Tumor Necrosis Factor-alpha/blood , Biomarkers/blood , Cardiovascular Abnormalities/blood , Cardiovascular Abnormalities/complications , Female , Humans , Inflammation/blood , Inflammation/complications , Interleukin-6/blood , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Leptin/blood , Male , Middle Aged
6.
Growth Horm IGF Res ; 23(6): 209-14, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23958273

ABSTRACT

OBJECTIVE: Insulin-like growth factor-1 (IGF-1) and inflammation have both been linked to high cardiovascular risk and mortality in the general population, as well as in hemodialysis (HD) patients. We hypothesized that the association of low IGF-1 with chronic inflammation may increase the mortality risk in HD patients. DESIGN: We investigated the interactions between inflammatory biomarkers (IL-6 and TNF-α) and IGF-1 as predictors of death over a 4 years of follow-up (median--47 months, interquartile range--17.5-75 months) in 96 prevalent HD patients (35% women, mean age of 64.9 ± 11.6 years). RESULTS: A significant interaction effect of low IGF-1 (defined as a level less than median) and high IL-6 (defined as a level higher than median) on all-cause and cardiovascular mortality was found: crude Cox hazard ratios (HR) for the product termed IGF-1 × IL-6 were 4.27, with a 95% confidence interval (CI): 2.10 to 8.68 (P<0.001) and 7.49, with a 95% CI: 2.40-24.1 (P=0.001), respectively. Across the four IGF-1-IL-6 categories, the group with low IGF-1 and high IL-6 exhibited the worse outcome in both all-cause and cardiovascular mortality (multivariable adjusted hazard ratios were 4.92, 95% CI 1.86 to 13.03, and 14.34, 95% CI 1.49 to 137.8, respectively). The main clinical characteristics of patients in the low-IGF-1-high IL-6 group didn't differ from other IGF-1-IL-6 categorized groups besides gender that consequently was inserted in all multivariable models together with the other potential confounders. CONCLUSIONS: An increase in mortality risk was observed in HD patients with low IGF-1 and high IL-6 levels, especially cardiovascular causes.


Subject(s)
Biomarkers/metabolism , Cardiovascular Diseases/mortality , Inflammation/complications , Insulin-Like Growth Factor I/metabolism , Kidney Failure, Chronic/therapy , Renal Dialysis/adverse effects , Aged , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Enzyme-Linked Immunosorbent Assay , Female , Follow-Up Studies , Humans , Male , Prognosis , Prospective Studies , Risk Factors , Survival Rate
7.
Int Urol Nephrol ; 45(6): 1703-13, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23572414

ABSTRACT

PURPOSE: We tested the hypothesis that the basal nitric oxide (NO) levels in prevalent hemodialysis (HD) patients may associate with inflammatory cytokines, predisposing them to increased mortality risk. METHODS: We performed a prospective cohort study of 76 prevalent HD patients (42 % women), with a mean age of 65.3 ± 11.8 years with a follow-up for almost 4 years (median--47 months, interquartile range -19-75 months). We measured basal NO, proinflammatory cytokines (TNF-α, IL-1, IL-6, and IL-10), dietary intake, biochemical parameters of nutrition, and body composition (anthropometry and bioimpedance analysis). RESULTS: Among various cytokines studied, only IL-6 exhibited a statistically significant linear association (adjusted r = 0.31, p = 0.014) with NO. Statistical interaction analysis showed a departure from multiplicity of effects of high NO (above the median) with high IL-6 (above the median) levels: crude Cox hazard ratios for all-cause and cardiovascular mortality for the product termed IL-6 × NO were 2.73 with a 95 % CI of 1.38-5.40 (p = 0.004) and 5.03 with a 95 % CI of 1.76-14.40 (p = 0.003), respectively. Across the four IL-6 NO categories, the group with high IL-6 and high NO (above their median levels) exhibited worse outcomes in both, all-cause and cardiovascular mortality (multivariable adjusted hazard ratios were 3.06, 95 % CI of 1.24-7.54 and 3.95, 95 % CI of 1.02-15.32, respectively). CONCLUSIONS: Chronic inflammation, as measured by higher serum IL-6 levels, in combination with high basal NO is associated with worse clinical outcomes in terms of all-cause and cardiovascular death in clinically stable prevalent HD patients.


Subject(s)
Cardiovascular Diseases/blood , Cardiovascular Diseases/mortality , Inflammation/blood , Inflammation/mortality , Interleukin-6/blood , Kidney Failure, Chronic/blood , Nitric Oxide/blood , Aged , Body Composition , Body Mass Index , Cause of Death , Diet Records , Female , Follow-Up Studies , Humans , Kidney Failure, Chronic/therapy , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , ROC Curve , Renal Dialysis , Skinfold Thickness
8.
Clin J Am Soc Nephrol ; 8(3): 443-51, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23411424

ABSTRACT

BACKGROUND AND OBJECTIVES: This study aimed to compare the longitudinal performance of the malnutrition-inflammation score (MIS) and the geriatric nutritional risk index (GNRI), two nutritional scores for patients on maintenance hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Nutritional scores, dietary intake, biochemical markers, and body composition analysis were performed at baseline and at 6, 12, and 18 months after enrollment (which took place from January through December 2006) on 75 prevalent hemodialysis patients (43% women, mean age 64.8 ± 11.9 years). The patients underwent simultaneous MIS and GNRI assessments calculated by two independent examiners from baseline. The study period was 46.8 ± 16.4 months. RESULTS: GNRI had higher interobserver agreement (weighted κ-score 0.98) than MIS (weighted κ-score 0.62). Longitudinally, a 1-unit increase in MIS was associated with a 0.41 kcal/kg per day reduction in daily energy intake (P<0.001) and with a 0.014 g/kg per day reduction in nPNA (P=0.02). GNRI did not correlate with the change over time of dietary intake. Longitudinal changes of both scores were associated with appropriate changes over time in levels of nutritional biomarkers, inflammation (IL-6), and body composition parameters. Both scores expressed significant associations with prospective hospitalization, whereas only MIS was associated with mortality in this cohort. The multivariate Cox proportional hazard ratio was 1.15 for death for each 1-unit increase in the MIS (95% confidence interval, 1.03-1.3; P=0.02). CONCLUSIONS: Both MIS and GNRI are valid tools for longitudinal assessment of hemodialysis patients' nutritional status. MIS has lower interobserver reproducibility than GNRI; however, MIS is more comprehensive than GNRI.


Subject(s)
Geriatric Assessment , Inflammation/diagnosis , Malnutrition/diagnosis , Nutrition Assessment , Nutritional Status , Renal Dialysis/adverse effects , Aged , Biomarkers/blood , Body Composition , Diet , Female , Hospitalization , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/mortality , Inflammation/physiopathology , Male , Malnutrition/blood , Malnutrition/etiology , Malnutrition/mortality , Malnutrition/physiopathology , Middle Aged , Multivariate Analysis , Observer Variation , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Prospective Studies , Renal Dialysis/mortality , Reproducibility of Results , Risk Assessment , Risk Factors , Time Factors
9.
World J Transplant ; 3(4): 91-8, 2013 Dec 24.
Article in English | MEDLINE | ID: mdl-24392313

ABSTRACT

Interleukin-10 (IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute kidney injury and in the development of chronic renal failure. We further discuss IL-10-induced cellular and molecular pathways and their link to the progression of kidney injury.

10.
Clin J Am Soc Nephrol ; 6(9): 2253-63, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21852667

ABSTRACT

BACKGROUND AND OBJECTIVES: The influence of serum IL-6 levels on nutritional status in chronic hemodialysis (HD) patients remains to be elucidated. The present report describes a prospective longitudinal study of IL-6 levels and nutritional parameters to determine whether high IL-6 levels are independently associated with nutritional status over time in a cohort of prevalent hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 85 clinically stable hemodialysis patients (37.6% women), with a mean age of 66.5 ± 10.6 years, were studied after exclusion of patients with BMI < 20 kg/m(2) and/or serum albumin <35 g/L. IL-6, dietary energy and protein intake, and biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18, and 24 months following enrollment. Observation of this cohort was continued over 2 additional years. RESULTS: IL-6 levels increased with time in both unadjusted (linear estimate: 2.57 ± 0.44 pg/ml per 2 yrs; P = 0.001) and adjusted models (linear estimate: 2.35 ± 0.57 pg/ml per 2 yrs; P = 0.049). Significant reductions of daily energy intake, laboratory markers (albumin, transferrin, cholesterol, creatinine), and body composition (fat mass) with higher IL-6 levels were observed over the duration of the longitudinal observation period. However, none of the studied parameters were associated with changes in IL-6 levels over time (IL-6-by-time interactions were NS). Furthermore, cumulative incidences of survival were correlated with the baseline serum IL-6 levels (P = 0.004 by log-rank test). Finally, for each pg/ml increase in IL-6 level, the hazard ratio for death from all causes was 1.06 (95% CI 1.01 to 1.10) after adjustment for demographic and clinical parameters. CONCLUSIONS: Our results suggest that higher serum IL-6 levels are associated with all-cause mortality without additional changes in clinical and laboratory markers of nutritional status in clinically stable HD patients.


Subject(s)
Interleukin-6/blood , Nutritional Status , Renal Dialysis/mortality , Aged , Female , Humans , Longitudinal Studies , Male , Middle Aged , Prevalence , Proportional Hazards Models , Prospective Studies , ROC Curve
11.
Nutr J ; 10: 68, 2011 Jun 15.
Article in English | MEDLINE | ID: mdl-21676262

ABSTRACT

BACKGROUND: The influence of serum leptin levels on nutritional status and survival in chronic hemodialysis patients remained to be elucidated. We conducted a prospective longitudinal study of leptin levels and nutritional parameters to determine whether changes of serum leptin levels modify nutritional status and survival in a cohort of prevalent hemodialysis patients. METHODS: Leptin, dietary energy and protein intake, biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18 and 24 months following enrollment, in 101 prevalent hemodialysis patients (37% women) with a mean age of 64.6 ± 11.5 years. Observation of this cohort was continued over 2 additional years. Changes in repeated measures were evaluated, with adjustment for baseline differences in demographic and clinical parameters. RESULTS: Significant reduction of leptin levels with time were observed (linear estimate: -2.5010 ± 0.57 ng/ml/2 y; p < 0.001) with a more rapid decline in leptin levels in the highest leptin tertile in both unadjusted (p = 0.007) and fully adjusted (p = 0.047) models. A significant reduction in body composition parameters over time was observed, but was not influenced by leptin (leptin-by-time interactions were not significant). No significant associations were noted between leptin levels and changes in dietary protein or energy intake, or laboratory nutritional markers. Finally, cumulative incidences of survival were unaffected by the baseline serum leptin levels. CONCLUSIONS: Thus leptin levels reflect fat mass depots, rather than independently contributing to uremic anorexia or modifying nutritional status and/or survival in chronic hemodialysis patients. The importance of such information is high if leptin is contemplated as a potential therapeutic target in hemodialysis patients.


Subject(s)
Dietary Proteins/administration & dosage , Kidney Failure, Chronic/blood , Leptin/blood , Renal Dialysis , Aged , Biomarkers/blood , Body Composition , Body Mass Index , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Linear Models , Longitudinal Studies , Male , Middle Aged , Multivariate Analysis , Nutritional Status , Prospective Studies , Survival Analysis
12.
Nephrol Dial Transplant ; 25(8): 2662-71, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20190238

ABSTRACT

BACKGROUND: Evaluation of nutritional risk, one of the strongest predictors of morbidity and mortality in maintenance haemodialysis (HD) patients, is a difficult process especially in patients with compounding conditions that prevent subjective assessment by subjective global assessment or malnutrition-inflammation score (MIS). METHODS: In this study, we developed and characterized a score for the assessment of nutritional status in dialysis patients based solely on objectively measurable criteria. Our prospective observational cohort included 81 prevalent HD patients (53 men and 28 women) with a mean age of 64.3 +/- 11.9 years. The study period encompassed 26.9 +/- 14.3 months. The quantitative and comprehensive scoring system, named Objective Score of Nutrition on Dialysis (OSND), was calculated by combining anthropometric measurements (the change in end-dialysis dry weight in the past 3-6 months, body mass index, skinfold thickness and mid-arm circumference) with three laboratory tests: albumin, transferrin and cholesterol levels. The sum of all seven components of OSND results in a score from 5 (severely malnourished) to 32 (normal). We compared our OSND system with the accepted MIS and phase angle (PA) measurements derived by bioelectric impedance analysis. RESULTS: The OSND correlated significantly with hospitalization days (r = -0.334; P = 0.002) and frequency of hospitalization (r = -0.373; P = 0.001), as well as with lean body mass and fat mass, MIS, PA and interleukin-6 levels. The Cox proportional hazard-calculated relative risk for death for each five-unit decrease in the OSND was 2.2 (95% CI, 1.3 to 3.8; P = 0.003) comparable with the predictions provided by MIS [for each five-unit increase in MIS, hazard ratio (HR) was 1.8 with 95% CI, 1.2 to 2.8; P = 0.007] and PA (for each 1-unit decrease in PA, HR was 2.9 with 95% CI, 1.5 to 5.6; P = 0.001). CONCLUSIONS: The OSND thus provides a comprehensive scoring system with significant associations with prospective hospitalization and mortality in chronic HD patients as well as measures of nutrition and inflammation.


Subject(s)
Health Status Indicators , Inflammation/epidemiology , Kidney Failure, Chronic/therapy , Malnutrition/epidemiology , Nutritional Status , Renal Dialysis/adverse effects , Severity of Illness Index , Adult , Aged , Body Composition , Body Mass Index , Cholesterol/blood , Cohort Studies , Female , Humans , Kaplan-Meier Estimate , Kidney Failure, Chronic/blood , Male , Middle Aged , Outcome Assessment, Health Care , Prospective Studies , Regression Analysis , Risk Factors , Serum Albumin/metabolism , Transferrin/metabolism
13.
Nephrol Dial Transplant ; 24(8): 2328-38, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19321762

ABSTRACT

BACKGROUND: Compensatory tubular cell hypertrophy following unilateral nephrectomy is a cell cycle-dependent process. Our previous study showed that treatment of unilaterally nephrectomized rats with the immunomodulator AS101 partially inhibits compensatory hypertrophy of the remaining kidneys through the inhibition of IL-10-induced TGF-beta secretion by mesangial cells. The present study is focused on understanding the intracellular mechanism(s) of this phenomenon. METHODS: A total of 120 male Sprague-Dawley rats were unilaterally nephrectomized or sham-operated and treated with AS101 or PBS. Kidney weight and protein/DNA ratio were assessed for each experimental animal. The expression of TGF-beta, PCNA, CDK 2, pRb, ppRb, p21(Waf1), p27(kip1) and p57(kip2) proteins in renal tissues was determined by western blot analysis and immunohistochemistry, and the immunoprecipitation of cyclin E complexes was performed. RESULTS: Compensatory renal growth is initiated by proliferation of resident renal cells that precedes hypertrophy. Changes in TGF-beta expression were positively correlated with the amounts of p57(kip2), but not with p21(Waf1) and p27(kip1) expression in the remaining kidneys. Moreover, there was a marked abundance of p57(kip2) but not p21(Waf1) and p27(kip1) binding to the cyclin E complex in PBS-treated unilaterally nephrectomized rats compared to sham-operated animals. Treatment of uninephrectomized rats with AS101 reduced kidney weight and protein/DNA ratio, inhibited TGF-beta and p57(kip2) expression in the remaining kidneys, and decreased the level of p57(kip2) binding to cyclin E complexes. CONCLUSION: These results demonstrate that TGF-beta-induced compensatory tubular cell hypertrophy is regulated in vivo by p57(kip2) but not by the p21(Waf1) and p27(kip1) cyclin kinase inhibitor proteins.


Subject(s)
Adjuvants, Immunologic/pharmacology , Cyclin-Dependent Kinase Inhibitor p57/metabolism , Ethylenes/pharmacology , Kidney Tubules/pathology , Transforming Growth Factor beta/metabolism , Animals , Blotting, Western , Cells, Cultured , Cyclin E/metabolism , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA/metabolism , Gene Expression Regulation , Hypertrophy , Immunoenzyme Techniques , Immunoprecipitation , Interleukin-10/metabolism , Kidney Tubules/metabolism , Male , Nephrectomy , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Sprague-Dawley , Retinoblastoma Protein/metabolism
14.
J Ren Nutr ; 19(3): 238-47, 2009 May.
Article in English | MEDLINE | ID: mdl-19243974

ABSTRACT

OBJECTIVE: The study tested whether obese hemodialysis (HD) patients have a better nutritional and inflammatory state than those with overweight or normal body mass index (BMI). DESIGN: This was a single-center, cross-sectional study. SETTING AND PATIENTS: Ninety-six stable HD patients from a local HD unit were divided into 3 groups according to BMI (normal, overweight, and obese). MAIN OUTCOME MEASURES: Anthropometry, body composition by multifrequency bioelectrical impedance analysis, biochemical nutritional markers, as well as interleukins (IL-1, IL-6, and IL-10), tumor necrosis factor, leptin, and soluble leptin receptor (sOB-R) were measured. RESULTS: Serum creatinine was significantly elevated in the highest BMI category. Albumin and transferrin were significantly elevated in higher BMI groups after adjustment for age, sex, and diabetes status. The higher BMI group had greater lean body mass (P = .001) and fat mass (P = .0001), higher phase angle (PA), and lower extracellular mass-to-body-cell-mass ratio (ECM/BCM) (P < .05). Inflammatory cytokine levels were not different in the 3 BMI groups. In parallel with increasing BMI, a gradual increase in serum leptin and a trend for decreasing sOB-R were detected (P = .0001 and P = .055, respectively). Both PA (r = 0.295, P = .008) and ECM/BCM (r = -0.345, P = .002) significantly correlated with serum leptin concentration. According to a multiple linear regression analysis, with PA as the dependent variable, age (beta = 0.274, P = .008), creatinine (beta = 0.355, P = .001), and log sOB-R/leptin ratio (beta = -0.465, P = .008) were significant independent predictors of PA. CONCLUSION: HD patients with elevated BMI demonstrate better nutritional status compared to normal BMI or overweight patients, whereas the severity of inflammation is not related to BMI in HD patients.


Subject(s)
Body Mass Index , Health Status , Inflammation/blood , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/therapy , Nutritional Status , Renal Dialysis/methods , Aged , Albumins/metabolism , Biomarkers/blood , Body Composition , Creatinine/blood , Cross-Sectional Studies , Cytokines/blood , Electric Impedance , Female , Humans , Inflammation/complications , Interleukins/blood , Israel , Kidney Failure, Chronic/complications , Leptin/blood , Male , Middle Aged , Transferrin/metabolism , Tumor Necrosis Factor-alpha/blood
15.
Nephrology (Carlton) ; 14(2): 189-97, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19143945

ABSTRACT

AIM: Peroxisome proliferator-activated receptor (PPAR)-gamma activation by rosiglitazone decreases manifestation of intrarenal inflammatory hallmarks. Inflammation significantly aggravates renal injury following urinary tract obstruction. The effect of rosiglitazone on renal inflammation following unilateral ureteral obstruction was investigated. METHODS: Ninety-six Sprague-Dawley rats were subjected to unilateral ureteral ligation, or to sham operation. Half of each group received rosiglitazone, 5 mg/kg bodyweight per day. The animals were killed and their kidneys allocated following 1 h, 24 h or 2 weeks, for pathological examination or for intrarenal transforming growth factor (TGF)-beta, interleukin (IL)-4, IL-6, IL-10 and nitric oxide (NO) assessment by specific enzyme-linked immunosorbent assays. Apoptosis rates, extracellular matrix deposition, PPAR-gamma, alpha-smooth muscle actin (alpha-SMA) expression and macrophage infiltration were assessed by specific immunohistological stainings. RESULTS: PPAR-gamma receptor expression was downregulated, and infiltration of macrophages decreased, in all rosiglitazone-treated kidneys. Rosiglitazone significantly decreased apoptosis, TGF-beta, IL-6, alpha-SMA expression and NO availability in obstructed kidneys. Synthesis of IL-10 was unaltered, while IL-4 augmented by Rosiglitazone. Rosiglitazone also affected NO and IL-4 production in sham-operated controls. CONCLUSION: (i) Rosiglitazone attenuates profibrotic and pro-inflammatory responses in a rat model of ureteral obstruction-induced renal inflammation; (ii) rosiglitazone stimulates counteractive anti-inflammatory responses in the damaged kidneys; (iii) in part, rosiglitazone exerts comparable anti-inflammatory effects on obstructed kidneys and unobstructed healthy controls. Taken together, this ascertains the importance of the anti-inflammatory role of rosiglitazone treatment in amelioration of ureteral obstruction-induced renal damage.


Subject(s)
Anti-Inflammatory Agents/pharmacology , PPAR gamma/agonists , Thiazolidinediones/pharmacology , Ureteral Obstruction/complications , Animals , Disease Models, Animal , Immunohistochemistry , Interleukin-10/biosynthesis , Interleukin-4/biosynthesis , Interleukin-6/biosynthesis , Kidney/pathology , Male , Nitric Oxide/metabolism , Rats , Rats, Sprague-Dawley , Rosiglitazone , Transforming Growth Factor beta/biosynthesis
16.
J Hypertens ; 27(2): 365-75, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19155791

ABSTRACT

OBJECTIVE: Poor glycemic control contributes to development of diabetic nephropathy. However, for a majority of clinical situations, the mechanisms responsible for high glucose-induced aggravation of renal tissue injury are not fully elucidated. We investigated responsiveness to pressure of various renal cell subsets subjected to hyperglycemic environment in an in-vitro model of malignant hypertension. METHODS: Rat renal mesangium, epithelium and endothelium were exposed to high glucose-containing medium for 10 days and then subjected to high hydrostatic pressure for 1 h to simulate the incidence of malignant hypertension. In some cultures, renin-angiotensin system was experimentally suppressed prior to pressure application. Proliferation, apoptosis, intrarenal p53, H2O2 and angiotensin-II synthesis were subsequently assessed. RESULTS: By contrast to cultures not exposed to high glucose, in all hyperglycemic cells p53 expression, angiotensin-II synthesis and apoptosis were increased, whereas proliferation depressed, irrespective of pressure enforcement. H2O2 release was enhanced by high pressure per se, and increased further following exposure to high glucose. In all diabetic cultures, inhibition of p53 by a specific inhibitor pifithrin concomitantly significantly decreased apoptosis. CONCLUSION: Hyperglycemic environment alters responsiveness of renal cells to in-vitro simulation of malignant hypertension. The main consequence of either malignant hypertension or hyperglycemia is exaggerated apoptosis. However, the operating mechanisms differ: Malignant hypertension stimulates renal cell apoptosis via increased angiotensin-II, whereas hyperglycemia elicits apoptosis via augmented p53. By contrast to pressure-induced excessive proliferation of normoglycemic cells, hyperglycemia prohibits elevated proliferation in response to pressure. Angiotensin-II production is maximally augmented by hyperglycemic environment and is not stimulated further by pressure application.


Subject(s)
Endothelial Cells/physiology , Epithelial Cells/physiology , Hyperglycemia/physiopathology , Hypertension, Malignant/physiopathology , Mesangial Cells/physiology , Angiotensin II/biosynthesis , Animals , Apoptosis , Cell Line , Cell Proliferation , Hydrogen Peroxide/metabolism , Hydrostatic Pressure , Kidney/cytology , Rats , Rats, Sprague-Dawley , Tumor Suppressor Protein p53/biosynthesis
17.
Am J Nephrol ; 29(3): 181-91, 2009.
Article in English | MEDLINE | ID: mdl-18781062

ABSTRACT

BACKGROUND: Vasoconstriction and reactive oxygen species (ROS) accumulation following contrast media (CM) injection are the key factors triggering CM-induced nephropathy. We compared the effects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction and ROS generation in a rat model of CM-induced nephropathy. METHODS: Following a 3-day dehydration, Sprague-Dawley rats received CM (Telebrix) or sham 'CM' injection of 0.9% saline. Part of them received NAC, theophylline or bicarbonate prior to CM. Medullar renal blood flow was estimated by laser Doppler. The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated and intrarenal STAT-8 isoprostane, PGE(2) and NO assessed. RESULTS: Vasoconstriction was significantly attenuated by NAC. Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffective following 30 min. Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE(2). NAC, theophylline but not bicarbonate, gradually increased intrarenal NO. In all experimental variables, CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed. CONCLUSIONS: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but not bicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE(2) synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.


Subject(s)
Acetylcysteine/pharmacology , Kidney/drug effects , Renal Insufficiency/drug therapy , Sodium Bicarbonate/pharmacology , Theophylline/pharmacology , Vasoconstriction/drug effects , Acetylcysteine/therapeutic use , Animals , Contrast Media/adverse effects , Dinoprostone/biosynthesis , Free Radical Scavengers/pharmacology , Free Radical Scavengers/therapeutic use , Hypoxia/drug therapy , Hypoxia/metabolism , Iothalamic Acid/adverse effects , Iothalamic Acid/analogs & derivatives , Isoprostanes/biosynthesis , Kidney/blood supply , Kidney/metabolism , Microcirculation/drug effects , Nitric Oxide/metabolism , Rats , Rats, Sprague-Dawley , Renal Insufficiency/chemically induced , Renal Insufficiency/metabolism , Sodium Bicarbonate/therapeutic use , Theophylline/therapeutic use , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use
18.
Nephrol Dial Transplant ; 23(7): 2213-22, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18400820

ABSTRACT

BACKGROUND: Hypoxia resultant from haemorrhagic shock is the primary cause of kidney damage. Application of normobaric hyperoxia therapy (NHT) is an acceptable treatment for acute haemorrhagic shock. We investigated the effect of NHT on amelioration of haemorrhagic shock-induced rat renal failure. METHODS: Twenty-four Sprague-Dawley rats were subjected to gradual blood withdrawal/reperfusion, followed by 12-h, 24-h or 48-h NHT. Verification/monitoring of intrarenal hypoxia was performed using Hypoxyprobe-TM-1. Subsequently, cystatin C, urea and creatinine were assessed in serum by a Hitachi autoanalyser, and NO, 3-nitro-tyrosine, STAT-8-isoprostane and NF-kB in renal medullae and cortices by specific ELISAs. RESULTS: In rats subjected to haemorrhagic shock, 12- to 48-h NHT significantly reduced intrarenal Hypoxyprobe-TM-1 stained areas and attenuated augmentation of urea, creatinine and cystatin C. Haemorrhagic shock resulted in a 10-fold drop of intrarenal NO availability. 12-h and 24-h, but not 48-h, NHT significantly increased cortical/medullar NO synthesis, the latter, however, not approaching the pre-shock values. Significant shock-induced accumulation of STAT-8-isoprostane and 3-nitro-tyrosine was further exacerbated by NHT. Haemorrhagic shock activated NF-kB in ischaemic tissues, which was not attenuated by NHT. CONCLUSIONS: (1) 12- to 48-h NHT decreased intrarenal hypoxia signs and ameliorated deterioration of renal functions in a rat model of haemorrhagic shock-induced renal failure. (2) 12- to 24 h NHT improved bioavailability of NO in cortices/medullae of kidneys recuperating from haemorrhagic shock. (3) If any anti-inflammatory activities were stimulated by NHT, they would not be mediated via the NF-kB pathway. (4) Despite NHT-associated elevation of reactive oxygen species (ROS), early oxygen supply proved mandatory for effective recuperation of ischaemic kidney from detrimental consequences of haemorrhagic shock.


Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Hyperoxia , Shock, Hemorrhagic/complications , Acute Kidney Injury/physiopathology , Animals , Blood Pressure/physiology , Creatinine/blood , Cystatin C , Cystatins/blood , Dinoprostone/metabolism , Disease Models, Animal , Kidney/metabolism , Kidney/pathology , Male , Nitric Oxide/metabolism , Oxidative Stress/physiology , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Shock, Hemorrhagic/physiopathology , Transcription Factor RelA , Tyrosine/analogs & derivatives , Tyrosine/metabolism , Urea/blood
19.
Am J Nephrol ; 28(2): 238-45, 2008.
Article in English | MEDLINE | ID: mdl-17975301

ABSTRACT

BACKGROUND/AIMS: Following kidney donation, living kidney donors have been reported to develop anemia and pronounced inflammation. Therapeutic strategies for ameliorating unilateral nephrectomy-induced inflammation would be beneficiary for the living donors. We applied rosiglitazone to attenuate inflammatory processes ongoing within the remaining kidney following contralateral nephrectomy. METHODS: 20 Sprague-Dawley rats were subjected to left unilateral nephrectomy and 20 others to sham operation. Half of each group was treated for 2 weeks with rosiglitazone (5 mg/kg body weight). After sacrifice, intrarenal transforming growth factor (TGF)-beta, angiotensin-II (A-II), interleukin (IL)-6, IL-10, IL-4 and nitric oxide (NO) were assessed, and histologic sections stained to assess the inflammatory cell infiltration. Renal function was evaluated by creatinine, urea, cystatin C measurements. RESULTS: Intrarenal IL-6, A-II and TGF-beta were significantly augmented, while NO was significantly decreased in kidneys remaining after contralateral nephrectomy. Rosiglitazone treatment abrogated augmented IL-6, A-II and TGF-beta synthesis and restored intrarenal NO availability in the remaining kidneys. Rosiglitazone also augmented anti-inflammatory IL-4 cytokine synthesis, while IL-10 production, leukocyte infiltration and renal function parameters remained unchanged. CONCLUSIONS: Rosiglitazone treatment attenuates the proinflammatory responses, represented by augmented IL-6, A-II and TGF-beta production, developing in the remaining kidney following contralateral nephrectomy. In addition, by stimulating IL-4 synthesis and restoring NO availability, rosiglitazone treatment initiates counteractive anti-inflammatory responses in the remaining kidney.


Subject(s)
Inflammation/drug therapy , Kidney Transplantation/methods , Nephrectomy/methods , Thiazolidinediones/therapeutic use , Animals , Anti-Inflammatory Agents/therapeutic use , Biomarkers/metabolism , Blood Pressure Determination , Cytokines/metabolism , Hypoglycemic Agents/therapeutic use , Inflammation/etiology , Kidney , Living Donors , Male , Rats , Rats, Sprague-Dawley , Rosiglitazone
20.
Nephron Exp Nephrol ; 106(4): e107-12, 2007.
Article in English | MEDLINE | ID: mdl-17622738

ABSTRACT

BACKGROUND/AIM: The angiotensin II level is elevated in subjects genetically prone to develop hypertension, triggering renal hypercellularity, cytokine production, and matrix deposition. Angiotensin-converting enzyme inhibition and/or angiotensin II type 1 receptor blockade attenuate renal damage. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist possessing antihypertensive and anti-inflammatory properties, was demonstrated to provide better renal protection than angiotensin-converting enzyme inhibitors. We studied the effects of in vivo peroxisome proliferator-activated receptor gamma activation by rosiglitazone on angiotensin II synthesis, proliferation, and apoptosis of mesangial cells of spontaneously hypertensive rats versus normotensive Sprague-Dawley rats. METHODS: The animals consumed either a high-sodium diet (8% Na) or a normal-sodium diet (0.5% Na). Half of each group received rosiglitazone at 5 mg/kg/day. After 3 weeks, all rats were sacrificed and the mesangial cells isolated and cultured. Angiotensin II was assessed by radioimmunoassay, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and cell proliferation by [(3)H]thymidine incorporation. RESULTS: Only the spontaneously hypertensive rats which consumed the high-sodium diet developed hypertension (185 +/- 6 mm Hg vs. basal 128 +/- 5 mm Hg; p = 0.0007) which was attenuated by rosiglitazone (to 126 +/- 4 mm Hg; p = 0.34). Angiotensin II synthesis, proliferation, and apoptosis were exaggerated in mesangial cell cultures from Sprague-Dawley rats and, more so, spontaneously hypertensive rats fed the high-sodium diet, but were inhibited in cultures from rosiglitazone-treated animals. CONCLUSIONS: Peroxisome proliferator-activated receptor gamma activation, in addition to lowering blood pressure, suppresses angiotensin II synthesis and downregulates angiotensin-II-mediated proliferation and apoptosis of mesangial cells. In the context of hypertension-induced renal damage, this would mean that the renoprotective role of rosiglitazone extends beyond glycemic and lipidemic control.


Subject(s)
Angiotensin II/metabolism , Apoptosis/drug effects , Hypertension/metabolism , Mesangial Cells/metabolism , Mesangial Cells/pathology , PPAR gamma/agonists , Thiazolidinediones/administration & dosage , Animals , Cell Proliferation , Cells, Cultured , Dose-Response Relationship, Drug , PPAR gamma/metabolism , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Rosiglitazone
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