Pentraxin 3, a sensitive early marker of hemodialysis-induced inflammation.

BACKGROUND/AIMS: The purpose of this investigation was to determine if the long pentraxin 3 (PTX-3) may be a useful marker of intradialytic inflammation since it is rapidly released in the vasculature. METHODS: PTX-3, interleukin-6, tumor necrosis factor-α and C-reactive protein were measured before and during a hemodialysis session in 22 patients and compared with healthy subjects. The effect of dialysis with low-flux, high-flux membranes and hemodiafiltration on the inflammatory response was compared in 11 patients. RESULTS: C-reactive protein and interleukin-6 levels did not change, while a modest decrease in tumor necrosis factor-α was observed during hemodialysis. The plasma PTX-3 concentration was significantly increased (p < 0.001) after 60 min and peaked at 180 min during hemodialysis. There was no difference in the intradialytic increase in PTX-3 using different dialysis membranes and modalities. CONCLUSION: PTX-3 stands out as a rapid and sensitive marker of hemodialysis-induced inflammation. Membrane flux and hemodiafiltration did not alter the inflammatory response.

Postprandial metabolic response to a fat- and carbohydrate-rich meal in patients with chronic kidney disease.

BACKGROUND: While chronic kidney disease (CKD) is associated with dysmetabolism including a marked insulin resistance, the postprandial response has not comprehensively been studied in CKD patients. METHODS: We conducted an intervention study comparing fasting and postprandial circulating biomarkers of glucose and lipid homeostasis, incretins, anabolic hormones, inflammation and oxidative stress in nine prevalent non-diabetic hemodialysis (HD) patients and 10 matched controls assessed after a standardized meal consisting of 75 g of milk fat, 80 g of carbohydrates and 6 g of proteins/m(2) of body surface area. RESULTS: Glucose and triglyceride increased in a similar manner following the meal, while insulin, C-peptide and glucose-dependent insulinotropic polypeptide increased more in HD patients. HDL and LDL cholesterol decreased slightly with no significant difference between the groups. The elevated baseline growth hormone (GH) in patients dropped, resulting in comparable levels in both groups 240 min after the meal; however, there was no change in insulin-like growth factor 1 (IGF-1) levels. No marked changes of interleukin 6 and tumor necrosis factor-α were observed in either group. An elevation in the DNA oxidative product 8-hydroxydeoxyguanosine was observed in HD patients. CONCLUSIONS: The postprandial state in CKD is characterized by impaired insulin sensitivity with increased incretin levels, along with GH/IGF-1 axis uncoupling and an elevation in an oxidative stress marker.

Left ventricular hypertrophy in incident dialysis patients randomized to treatment with hemofiltration or hemodialysis: results from the ProFil study.

INTRODUCTION: Left ventricular hypertrophy (LVH) is present in a majority of hemodialysis (HD) patients and is among the strongest risk factors for cardiovascular events and mortality. Hemofiltration (HF), a purely convective dialysis treatment, has been associated with enhanced hemodynamic stability compared with HD, possibly as a result of a more physiologic removal of fluid and solutes. METHODS: In a randomized controlled study conducted at ten dialysis centers in Sweden and Denmark, incident patients (HD <3 months) without clinical signs or history of cardiovascular disease were randomized to treatment with either online, predilution HF or low-flux HD. The primary endpoint was change in left ventricular mass index (LVMI), as measured by two-dimensional M-mode and Doppler echocardiography. RESULTS: The analyses included 34 patients (18 HF, 16 HD) followed for up to 2 years. At baseline, 65% of the patients had LVH, but LVMI did not differ between the study groups. In the HF group, LVMI decreased by 22 ± 48 g/m(2) during a mean treatment time of 19 ± 7 months, while in the HD group the decrease was 15 ± 57 g/m(2) during 16 ± 7 months. As analyzed by MANOVA (mixed model), the difference in LVMI over the whole period was statistically significant (p = 0.03) with a more favorable outcome in HF. Blood pressure and other study variables did not differ between the groups, but at baseline and throughout the study, HF patients required heavier antihypertensive treatment. CONCLUSIONS: In incident dialysis patients, long-term predilution HF, a purely convective dialysis treatment, is associated with a significantly more favorable development of LVMI compared with regular low-flux HD. Considering the predictive strength of LVMI as a risk factor, the quantitative difference between the treatments is of clinical importance.

Comorbidity and acute clinical events as determinants of C-reactive protein variation in hemodialysis patients: implications for patient survival.

BACKGROUND: Patients with chronic kidney disease stage 5 have high comorbidity and are prone to inflammation that may contribute to the high cardiovascular mortality risk. STUDY DESIGN: Three-month observational cohort study of prevalent hemodialysis patients. SETTINGS & PARTICIPANTS: 228 hemodialysis patients (44% women) were included, median age of 66 years, median time on dialysis therapy of 29 months. PREDICTORS & OUTCOMES: In part 1, comorbidity and intercurrent illness were predictors and C-reactive protein (CRP) level was the outcome. In part 2, serial CRP values were predictors and survival was the outcome. MEASUREMENTS: High-sensitivity CRP was measured weekly and interleukin 6 (IL-6), tumor necrosis factor alpha, and IL-10 were measured monthly. Data for comorbidity were collected from patient records to calculate Davies comorbidity score, and self-reported clinical events were recorded weekly. RESULTS: Median baseline CRP level was 6.7 mg/L (25th to 75th percentiles, 2.5 to 21 mg/L). Baseline CRP level correlated with time-averaged CRP (Spearman rho = 0.76) and individual median of serial CRP values (rho = 0.78; both P < 0.001). Part 1: comorbidity score was significantly associated with greater CRP and IL-6 levels. Age, sex, comorbidity, and 7 of 12 clinical events had significant effects on CRP level variation. Part 2: during a mean follow-up of 29 months, 38% of patients died. Median and mean serial CRP levels were associated with a greater hazard ratio for death (1.013; 95% confidence interval, 1.004 to 1.022) and 1.012 (95% confidence interval, 1.004 to 1.020) than baseline, maximum, and minimum CRP values during the study. Other significant covariates were age, Davies risk group, dialysis vintage, and albumin level. LIMITATIONS: The study is based on observational data for prevalent dialysis patients. CONCLUSIONS: Comorbidity and clinical events are strongly associated with inflammation in hemodialysis patients. Despite variability over time, inflammation assessed by using CRP level is a strong predictor of mortality. Serial measurements provide additional information compared with a single measurement.

Inflammation modifies the association of osteoprotegerin with mortality in chronic kidney disease.

BACKGROUND: The production and expression of osteoprotegerin (OPG), a bone regulating protein, is regulated by inflammatory cytokines. METHODS: As clinical and experimental studies have implicated OPG in atherogenesis, we investigated serum OPG in relation to inflammation, endothelial dysfunction and oxidative stress markers in 265 chronic kidney disease (CKD) stage 5 patients. Cardiovascular disease (CVD), carotid plaques (n=69) and mortality (5 years) in relation to OPG were also analyzed, and the impact of inflammation on the association of OPG with mortality was evaluated. RESULTS: OPG correlated positively with circulating surrogate markers of inflammatory, endothelial dysfunction and oxidative stress. Patients with clinical CVD or carotid plaques had higher concentrations of OPG than their respective counterparts. Increased OPG levels per se were related to higher cardiovascular and all-cause mortality even after adjustment for age, sex, C-reactive protein, diabetes mellitus and baseline CVD. Moreover, the presence of inflammation further and independently aggravated the hazard ratios (HR) for both cardiovascular (HR=2.8; 95% confidence interval [95% CI], 1.3-6.4; p=0.01) and all-cause (HR=2.5; 95% CI, 1.4-4.5; p<0.01) mortality. CONCLUSIONS: Elevated OPG levels are associated with surrogate markers of inflammation, endothelial dysfunction, oxidative stress and CVD in CKD patients. Moreover, inflammation and OPG levels seem to have additive effects on survival.

Acute effects of low and high intravenous doses of furosemide on myocardial function in anuric haemodialysis patients: a tissue Doppler study.

BACKGROUND: In patients with pulmonary oedema and preserved renal function, furosemide has not only a renal, but also a vascular effect, causing a rapid fall in left ventricular filling pressure accompanied by an increase in venous compliance. Previous studies have shown conflicting findings regarding the vascular effects of furosemide in patients with end-stage renal disease (ESRD). The objective of our study was to investigate whether furosemide induces changes in central cardiac haemodynamics in anuric ESRD patients, using conventional echocardiography and colour tissue Doppler velocity imaging (TVI), a new quantitative and sensitive method. METHODS: Repeated low doses (40 mg followed by an additional dose of 40 mg after 30 min) of i.v. furosemide were administered to 12 (61.6 +/- 16 years, 7 men) and a high dose (250 mg) of i.v. furosemide to 6 (64.1 +/- 3.6 years, 5 men) clinically stable anuric haemodialysis (HD) patients. Conventional two-dimensional echocardiography and colour TVI images were recorded immediately before (0 min) the furosemide infusion in both groups, and in the group receiving the repeated low-dose infusion (at 0 and 30 min), 10, 20, 30, 40, 50 and 70 min after the administration of the first infusion. In the group receiving the single high dose of furosemide the ultrasound investigation was repeated 10, 20, 30 and 40 min after the infusion. The myocardial tissue velocities (v; cm/s) for isovolumetric contraction (IVC), peak systole (PS), early (E') and late (A') myocardial diastolic filling velocities were measured in the left ventricle (LV) at six sites (infero-septal, antero-lateral, inferior, anterior, infero-lateral and antero-septal walls) at the basal region. IVC time (IVCT), IV relaxation time (IVRT), PS time (PSt), RR interval, mitral annulus motion (MAM), strain rate (SR), left ventricular filling pressure (E/E') and cardiac output were also measured. The average of the different walls was used to evaluate global function. Right ventricle (RV) dynamics was evaluated from measurements of IVC velocity (IVCv), peak systolic velocity (PSv), E' and A' from the RV free wall. RESULTS: No significant changes in cardiac output, IVCv, PSv, SR, MAM, E', A', E'/A', IVRT and LV filling pressure were observed, indicating that neither 40 mg (plus additional 40 mg after 30 min) nor 250 mg of furosemide had any measurable effects on LV filling pressure and LV and RV systolic and diastolic function. CONCLUSIONS: In anuric HD patients, low and high doses of furosemide had no significant effects on central cardiac haemodynamics. Therefore, the use of furosemide infusion in anuric ESRD patients with acute pulmonary oedema is not supported by the results of this study.

Proteome patterns in uremic plasma.

In patients with chronic kidney disease (CKD), peptides and proteins circulate at altered concentrations versus in healthy individuals. We have characterized proteome samples from 7 pooled CKD stage 5 patients not yet on dialysis and with no known co-morbidities. We also analyzed pooled plasma samples from 7 healthy age- and sex-matched controls. After immunodepletion of the 6 most abundant plasma proteins, HPLC and SDS-PAGE patterns differed between the healthy and disease groups. The differing proteins were identified by peptide mass fingerprinting using MALDI mass spectrometry and verified with electrospray tandem mass spectrometry sequence analysis. Multiple differences in at least 19 HPLC fractions were observed, from which we identified 29 proteins, 25 in greater yield and 4 in lower yield than in the healthy controls, adding at least 6 protein components to those that were previously known to be altered in CKD.

Comparison of nutritional and inflammatory markers in dialysis patients with reduced appetite.

BACKGROUND: Anorexia is common in chronic kidney disease and worsens as the disease progresses. Sex hormones and inflammatory cytokines may be related to feeding behavior. OBJECTIVE: We hypothesized that appetite would be related to inflammation and outcome in hemodialysis patients but that sex may account for differences in the symptoms associated with poor appetite. DESIGN: A cross-sectional study was conducted in patients undergoing prevalent hemodialysis (n = 223; 127 M; x +/- SD age: 66 +/- 14 y). Anthropometric markers of body composition, handgrip strength, and nutritional and inflammatory status were measured, and 3 groups according to their self-reported appetite were established. Overall mortality was assessed after 19 mo (range: 2-29 mo) of follow-up. RESULTS: Poor appetite was associated with a longer vintage time, increased inflammation (higher serum concentrations of interleukin 6 and C-reactive protein), and a worse nutritional status (lower serum concentrations of insulin-like growth factor I, albumin, urea, and creatinine). However, across worsening appetite scale, handgrip strength was incrementally lower in men but not in women (multivariate analysis of variance). In a multivariate logistic regression analysis (pseudo r(2) = 0.19), appetite loss was associated with sex [odds ratio (OR): 0.41; 95% CI: 0.24, 0.72], insulin-like growth factor I (3.58; 2.10, 6.32), and C-reactive protein > 10 mg/L (2.39; 1.34, 4.11). Finally, appetite loss was associated with worse clinical outcome even after adjustment for age, sex, inflammation, dialysis vintage, and comorbidity (likelihood ratio = 44.3; P < 0.0001). CONCLUSIONS: These results show a close association among appetite, malnutrition, inflammation, and outcome in patients undergoing prevalent hemodialysis. Moreover, our data suggest that uremic men may be more susceptible than are women to inflammation-induced anorexia.

Circulating levels of visfatin/pre-B-cell colony-enhancing factor 1 in relation to genotype, GFR, body composition, and survival in patients with CKD.

BACKGROUND: Visfatin, also known as pre-B-cell colony-enhancing factor 1 (PBEF-1), recently was shown to be secreted from adipocytes and have insulin-mimetic properties in mice. Because renal failure per se is associated with both increased levels of circulating peptides and marked insulin resistance, even in the absence of diabetes mellitus, we hypothesized that visfatin could be a factor linking inflammation, kidney disease, and insulin resistance in this patient group. METHODS: Altogether, we studied 189 patients with chronic kidney disease (CKD), comprising 149 patients with CKD stage 5 (glomerular filtration rate [GFR] < 15 mL/min; mean, 7 +/- 2 mL/min [<0.25 mL/s; mean, 0.12 +/- 0.03 mL/s]; 61% men; mean age, 54 +/- 12 years) and 40 patients with CKD stages 3 to 4 (GFR, 15 to 60 mL/min; mean, 33 +/- 21 mL/min [0.25 to 1.00 mL/s; mean, 0.55 +/- 0.35 mL/s]; 72% men; age, 59 +/- 15 years). We compared these with 30 randomly selected population controls (mean GFR, 85 +/- 16 mL/min [1.42 +/- 0.27 mL/s]; 69% men; age, 64 +/- 11 years). Serum visfatin was measured by using commercially available enzyme-linked immunosorbent assay, and we also performed genotyping of 3 verified polymorphisms in the visfatin gene (-423A/G, -1001T/G, and -1535C/T). Body fat was estimated by using dual-energy x-ray absorptiometry. RESULTS: Serum visfatin levels were greater in patients with CKD stage 5 (41.3 +/- 18.0 ng/mL) than in those with CKD stages 3 to 4 (34.0 +/- 9.8 ng/mL; P < 0.01 versus CKD stage 5) or healthy controls (29.3 +/- 8.1 ng/mL; P < 0.0001). However, there were no significant differences between patients with and without diabetes, and the significant differences in circulating visfatin levels between genotypes disappeared after adjustment for differences in age, sex, GFR, and serum albumin level. In univariate analysis, visfatin level correlated with levels of GFR (rho = -0.22; P = 0.001), interleukin 6 (IL-6; rho = 0.17; P = 0.01), high-sensitivity C-reactive protein (rho = 0.14; rho < 0.05), and soluble vascular cell adhesion molecule 1 (sVCAM-1; rho = 0.39; P < 0.0001), but not total or truncal fat mass, insulin resistance, or hemoglobin A(1c) level. High plasma visfatin level predicted mortality in patients with CKD, also after adjustment for age and sex (likelihood ratio, 18.2; P < 0.0001), but not after additional correction for GFR, sVCAM-1, serum albumin, and serum IL-6 levels. CONCLUSION: Circulating levels of the cytokine visfatin/PBEF-1 are influenced by renal function, but are not associated with fat mass or surrogate markers of insulin resistance in patients with CKD. Visfatin was associated independently with level of sVCAM-1, a marker of endothelial damage.

Overestimation of advanced oxidation protein products in uremic plasma due to presence of triglycerides and other endogenous factors.

BACKGROUND: Advanced oxidation protein products (AOPP), a suggested protein biomarker of oxidative stress, are elevated in patients with chronic kidney disease (CKD), who also often suffer from hypertriglyceridemia. METHODS: The analysis included plasma AOPP, TG, cholesterol, albumin and total protein, inflammation and oxidative stress markers from healthy subjects, non-dialyzed CKD, HD and CAPD patients. We studied, at two different European centres, effects of a meal, comparison between serum and plasma, L-index (indicating turbidity), spiking with fat and protein, and centrifugation on the AOPP concentrations. AOPP was measured at 340 nm and expressed as chloramine-T equivalents. RESULTS: AOPP correlated with TG levels not only in CKD patients, but also in healthy subjects. Weak to absent correlations were observed between AOPP and markers of inflammation and oxidative stress in CKD patients. A meal increased the TG levels several-fold paralleled by a rise in measured AOPP to patient levels. Spiking of the plasma with Intralipid or protein resulted in increased absorbances at 340 nm, due to turbidity or real absorbance, while centrifugation similarly decreased the apparent AOPP and TG levels. CONCLUSIONS: AOPP concentration, especially due to the influence of turbidity at all levels of TG concentration, but also due to other factors on top of TG, is overestimated in all plasma samples, including controls at fasting and non-fasting conditions. Thus, AOPP is a questionable biomarker of oxidative stress and inflammation in CKD patients.

Plasma reduced homocysteine and other aminothiol concentrations in patients with CKD.

BACKGROUND: Hyperhomocysteinemia, a risk factor for cardiovascular disease, is present in the majority of patients with chronic kidney disease (CKD). Several studies indicated that the moiety of homocysteine (Hcy) with an unbound -SH group (reduced Hcy [rHcy]) is the atherogenic molecule. This study is designed to examine the relation between different forms of Hcy and other aminothiols in hemodialysis (HD) patients, peritoneal dialysis (PD) patients, and nondialyzed patients with CKD. METHODS: rHcy, free Hcy (fHcy), and total Hcy (tHcy), as well as different forms of cysteine, cysteinyl-glycine, and glutathione, were studied by using a high-performance liquid chromatography technique in 19 HD patients, 12 PD patients, 47 patients with CKD, and 15 control subjects. RESULTS: In PD patients, tHcy levels were 2.8 times greater compared with controls, and in HD patients and those with CKD, 2.1 and 1.9 times greater, respectively. Mean rHcy/tHcy ratios were significantly greater in both HD (P < 0.05) and PD patients (P < 0.01), but did not differ in patients with CKD compared with controls. The decrease in rHcy levels during 1 HD treatment was smaller than that in tHcy and fHcy levels, and rHcy/tHcy ratio increased (before HD, 1.25% +/- 0.44%; after HD, 1.44% +/- 0.66%; P < 0.05). CONCLUSION: Levels of rHcy and other aminothiols are markedly increased in patients with impaired renal function. In dialysis patients, rHcy/tHcy ratio is markedly elevated and shows greater variability than in patients with CKD and controls. We conclude that because rHcy is believed to induce endothelial dysfunction and may be part of the accelerated atherogenic process in patients with CKD, plasma rHcy level could be a more relevant marker of cardiovascular disease risk than tHcy level.

Effect of bicarbonate on muscle protein in patients receiving hemodialysis.

BACKGROUND: Metabolic acidosis stimulates whole-body net protein breakdown in healthy adults and patients with kidney failure, but few studies investigated how acidosis affects protein metabolism in individual tissues, such as skeletal muscle. METHODS: We evaluated the effect of metabolic acidosis on protein turnover in skeletal muscle, assessed by means of phenylalanine kinetics and free amino acid concentrations in plasma and muscle. Long-term hemodialysis patients (n = 16) were divided into 2 groups in an open crossover study design. In group A, we administered bicarbonate supplements and increased blood standard bicarbonate levels from 17.8 +/- 0.03 to 27.1 +/- 1.2 mEq/L (17.8 +/- 0.03 to 27.1 +/- 1.2 mmol/L). In group B, we decreased bicarbonate supplements, which caused a decrease in standard bicarbonate levels from 26.6 +/- 0.7 to 18.6 +/- 0.3 mEq/L (26.6 +/- 0.7 to 18.6 +/- 0.3 mmol/L). RESULTS: Net phenylalanine efflux from leg tissues (muscle) was significantly less when acid-base balance was corrected compared with acidosis (10.8 +/- 1.5 versus 18.6 +/- 3.8 nmol/min/100 g tissue; P = 0.014), as was the rate of phenylalanine appearance (28.3 +/- 3.0 versus 38.4 +/- 5.9 nmol/min/100 g tissue; P = 0.016); the rate of phenylalanine disposal was unchanged. Cortisol and C-reactive protein levels in blood were unchanged after correction of acidosis, as were levels of messenger RNAs encoding components of the ubiquitin-proteasome pathway in muscle biopsy specimens. CONCLUSION: Our findings indicate that acidosis increases protein breakdown in skeletal muscle, but additional studies are needed to identify the pathways stimulated to degrade muscle protein in response to acidosis.

Changes in fat mass correlate with changes in soluble sCD163, a marker of mature macrophages, in patients with CKD.

BACKGROUND: Recently, adipose tissue was shown to contain macrophages capable of contributing to systemic inflammation and cardiovascular disease (CVD). Here, we investigate this putative relationship in patients with chronic kidney disease (CKD) by using the novel macrophage marker soluble (s)CD163. METHODS: One hundred twenty patients with CKD stage 5 (mean glomerular filtration rate [GFR], 7 +/- 1 mL/min [0.12 +/- 0.02 mL/s; mean age, 53 +/- 1 years; 65% men), 38 patients with CKD stages 3 to 4 (mean GFR, 33 +/- 3 mL/min [0.55 +/- 0.05 mL/s]; mean age, 67 +/- 2 years; 68% men), and 28 healthy controls (mean GFR, 89 +/- 3 mL/min [1.48 +/- 0.05 mL/s]; mean age, 63 +/-2 years; 69% men) were characterized post hoc with a follow-up of up to 5 years (mean, 47 +/- 1 months). sCD163 levels, body composition (dual-energy x-ray absorptiometry), clinical parameters, and levels of circulating inflammatory markers (enzyme-linked immunosorbent assay) were assessed at baseline and, in a subset population, after 1 year of dialysis therapy (hemodialysis, n = 19; peritoneal dialysis, n = 30). RESULTS: sCD163 level increased in patients with both severe (median, 4.3 mg/L; range, 1.3 to 23.4 mg/L) and moderate (median, 3.6 mg/L; range, 1.6 to 9.8 mg/L) CKD compared with controls (median, 2.6 mg/L; range, 0.8 to 7.6 mg/L; P < 0.001). Furthermore, sCD163 levels correlated with both truncal (rho = 0.17; P < 0.05) and total (rho = 0.17; P < 0.05) fat mass, as well as with all measured markers of inflammation and endothelial adhesion molecules. After 1 year, patients who increased body fat mass (average, 11% +/- 5% versus -5% +/- 5%; P < 0.05) also showed a significant increase in sCD163 levels (median, 2.2 versus -0.97 mg/L; P < 0.01). Finally, patients with sCD163 levels greater than 4.0 mg/L had a statistically significantly worse outcome than patients with sCD163 levels less than this value, even after adjustment for age, sex, and diabetes mellitus (chi-square = 19.98; P < 0.001). However, this effect was lost after adjustment for either inflammation or CVD. CONCLUSION: We show that increasing fat mass is associated with increasing levels of sCD163, a circulating marker of macrophages also associated with inflammatory biomarkers. We thus hypothesize that adipose tissue macrophages may have a role in the proinflammatory state observed in patients with renal disease. Finally, we propose the term "uremic-metabolic syndrome" to describe this state of increased adipose tissue signaling in patients with uremia, a phenomenon that may share some characteristics with the metabolic syndrome of obesity.

Inflammation contributes to low plasma amino acid concentrations in patients with chronic kidney disease.

BACKGROUND: Inflammation and malnutrition are common in chronic kidney disease (CKD) patients, and plasma concentrations of free amino acids (AAs) in these patients are often abnormal. Malnutrition contributes to alterations in AA concentrations. OBJECTIVE: The objective was to study the effects of inflammation on plasma AA concentrations. DESIGN: Concentrations of plasma AAs, serum albumin, and several inflammatory markers were analyzed in 200 fasting, nondiabetic CKD patients who were close to the start of renal replacement therapy. The nutritional status of these patients was assessed by a subjective global assessment. RESULTS: The patients with inflammation [C-reactive protein (CRP) concentrations >10 mg/L] or malnutrition had lower AA concentrations than did the patients with no inflammation or malnutrition. The presence of both inflammation and malnutrition was associated with more marked reductions in AA concentrations than was malnutrition alone. Significant inverse correlations were observed between the plasma concentrations of most of the essential and nonessential AAs and inflammatory markers, whereas serum albumin concentrations were positively correlated with several AA concentrations. A stepwise multivariate regression analysis showed that serum CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs. An analysis of all-cause mortality with a Kaplan-Meier test showed that the patients with higher AA concentrations had significantly better survival than did the patients with lower AA concentrations. CONCLUSIONS: Plasma AA concentrations are low in CKD patients with inflammation and are inversely correlated with concentrations of inflammatory markers. Although inflammation and malnutrition are closely related, CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs, which suggests an independent role of inflammation as a cause of low plasma AA concentrations in CKD patients.

Hyperhomocysteinemia in relation to plasma free amino acids, biomarkers of inflammation and mortality in patients with chronic kidney disease starting dialysis therapy.

BACKGROUND: Plasma levels of total homocysteine (tHcy) and free amino acids (AAs) are influenced by nutritional status in patients with chronic kidney disease (CKD), whereas the role of chronic inflammation is not clear. METHODS: In a cross-sectional analysis, fasting levels of plasma tHcy, total cysteine (tCys), AA, serum albumin (Alb), and several inflammation markers, including C-reactive protein (CRP), were analyzed in a cohort of 250 patients with CKD starting renal replacement therapy. Patients were followed up during a 4-year period to assess overall mortality in relation to basal tHcy level. RESULTS: Ninety-three patients (37%) with signs of inflammation (CRP > or = 1 mg/dL) had significantly lower levels of tHcy, tCys, and serum Alb than 157 noninflamed patients. tHcy and tCys levels correlated positively with serum Alb levels and negatively with CRP levels (rho = -0.24; P < 0.0001; rho = -0.15; P < 0.05, respectively) and other inflammation markers. tHcy and tCys correlated significantly with levels of several AAs. The presence of both inflammation and malnutrition was associated with lower tHcy levels than when malnutrition was present without inflammation. Multivariate analysis showed that serum Alb, CRP, plasma folate, and vitamin B12 levels were independently associated with tHcy levels after adjustment for other variables. tHcy, but not tCys, level was significantly greater in survivors than nonsurvivors, and Kaplan-Meier analysis showed that greater tHcy level was associated with better survival. CONCLUSION: Plasma tHcy and tCys levels are interrelated to plasma AA levels and were lower in patients with inflammation. Thus, inflammation may contribute to the reverse association between tHcy level and mortality in patients with CKD starting renal replacement therapy.

Combined hypertriglyceridemic and insulin-glucose clamps for the characterization of substrate oxidation and plasma elimination of a long-chain triglyceride emulsion in healthy men.

This study examines the effect of glucose and insulin on the plasma elimination rate and oxidation of a fat emulsion by using indirect calorimetry in conjunction with lipid and insulin-glucose clamp techniques. Ten healthy subjects were studied on 2 occasions in a randomized, open, crossover study. On one occasion, a hypertriglyceridemic (HTG) clamp was administrated alone; and, on the other, HTG and insulin-glucose (IG) clamps were administrated simultaneously. During HTG clamps, serum triglyceride (TG) concentration was maintained at 4 mmol × L(-1). During the IG clamp, insulin was administered at a rate of 20 mU × m(-2) × min(-1); and the glucose level was maintained at 7 mmol × L(-1). Continuous indirect calorimetry was carried out throughout the study period. The infusion rate required to maintain stable serum TG concentrations did not differ between the 2 clamps. Mean free fatty acid concentration was lower during the HTG/IG than during the HTG clamp (0.40 ± 0.04 vs 0.82 ± 0.07 mmol × L(-1); P < .001). However, the increases in ß-OH-butyrate levels were significantly lower in the HTG/IG compared with the HTG clamp (0.09 ± 0.04 vs 0.55 ± 0.09 mmol × L(-1); P < .001). Energy expenditure and the respiratory quotient were significantly higher at steady state in the HTG/IG than in the HTG clamp: 1.47 ± 0.06 vs 1.34 ± 0.04 kcal × min(-1) (P < .01) and 0.85 ± 0.01 vs 0.79 ± 0.01 (P < .01), respectively. Insulin and glucose did not significantly change plasma TG disposal rate (P = .0987) or total lipid oxidation (P = .3204) in this metabolic situation with an abundant supply of both carbohydrates and lipids. ß-OH-butyrate increased during both clamps, indicating an ongoing hepatic fatty oxidation despite the administration of glucose/insulin.

Novel links between the long pentraxin 3, endothelial dysfunction, and albuminuria in early and advanced chronic kidney disease.

BACKGROUND AND OBJECTIVES: Albuminuria and inflammation predict cardiovascular events. Pentraxin 3, an inflammatory mediator produced by, among others, endothelial cells, may have a role in atherogenesis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In 207 Swedish patients with stage 5 chronic kidney disease and 79 Turkish patients with type 2 diabetes and proteinuria and normal renal function, whether serum pentraxin 3 levels are associated with albuminuria and endothelial dysfunction was studied. RESULTS: Patients with stage 5 chronic kidney disease and a high degree of albuminuria more often had diabetes and higher levels of pentraxin 3, vascular cellular adhesion molecule-1, and blood pressure. Moreover, pentraxin 3 was independently associated with 24-h urinary albumin excretion. In patients with type 2 diabetes, pentraxin 3 was significantly higher than in control subjects. Patients with type 2 diabetes and more proteinuria had higher pentraxin 3, C-reactive protein, glycosylated hemoglobin, insulin, and homeostasis model assessment index as well as lower flow-mediated dilation and serum albumin. Pentraxin 3 was positively correlated with C-reactive protein, homeostasis model assessment index, and carotid intima-media thickness and negatively with flow-mediated dilation. Pentraxin 3 and glomerular filtration rate were independently associated with 24-h urinary protein excretion. Only pentraxin 3 and proteinuria were significantly and independently associated with flow-mediated dilation. CONCLUSIONS: In two different renal cohorts, one of stage 5 chronic kidney disease and one of type 2 diabetes and normal renal function, pentraxin 3 was independently associated with proteinuria. Moreover, both pentraxin 3 and proteinuria were associated with endothelial dysfunction in patients with type 2 diabetes.

Plasma pentraxin 3 in patients with chronic kidney disease: associations with renal function, protein-energy wasting, cardiovascular disease, and mortality.

BACKGROUND AND OBJECTIVES: Plasma protein pentraxin 3 concentrations are elevated in a wide range of diseased states. However, no study has evaluated protein pentraxin 3 in patients with chronic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma protein pentraxin 3 concentrations were analyzed in relation to GFR, inflammation, cardiovascular disease, and protein-energy wasting in 71 patients with stages 3 to 4 chronic kidney disease, 276 patients with stage 5 chronic kidney disease, and 61 control subjects. Survival (5 yr) in patients with stage 5 chronic kidney disease was analyzed in relation to protein pentraxin 3 levels. RESULTS: Both patient groups with chronic kidney disease had higher protein pentraxin 3 concentrations than control subjects, with the highest concentration in patients with stage 5 chronic kidney disease. In all patients with chronic kidney disease, protein pentraxin 3 correlated negatively with GFR and positively with inflammatory markers. Patients with protein-energy wasting, inflammation, and cardiovascular disease had higher concentrations of protein pentraxin 3 than their counterparts. Patients with high protein pentraxin 3 levels had higher all-cause and cardiovascular mortality. After adjustment for age, gender, C-reactive protein, and cardiovascular disease, all-cause mortality was still significantly higher in patients with high protein pentraxin 3. Finally, protein pentraxin 3 showed a predictive value of mortality similar to that of IL-6 and better than C-reactive protein. CONCLUSION: Plasma protein pentraxin 3 increases as GFR declines and is associated with the presence of cardiovascular disease and protein-energy wasting. Furthermore, in patients with chronic kidney disease, elevated protein pentraxin 3 predicted all-cause mortality.