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Chronic kidney disease (CKD) may progress to end-stage renal disease (ESRD) at different pace. Early markers of disease progression could facilitate and improve patient management. However, conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages. Therefore, we performed untargeted plasma peptidome analysis to select the peptides involved in progression, which are suitable for long prospective studies in future. The study consists of non-CKD (n = 66) and CKD (n = 106) patients with different stages. We performed plasma peptidomics on these subjects using chromatography and mass spectrometric approaches. Initially, we performed LC-ESI-MS and applied least absolute shrinkage and selection operator logistic regressions to select the peptides that are differentially expressed and we generated a peptidomic score for each subject. Later, we identified and sequenced the peptides with MALDI-MS/MS and also performed univariate and multivariate analyses with the clinical variables and peptidomic score to reveal their association with progression of renal disease. A logistic regression model selected 14 substances showing different concentrations according to renal function, of which seven substances were most likely occur in CKD patients. The peptidomic model had a global P value of < 0.01 with R2 of 0.466, and the area under the curve was 0.87 (95% CI, 0.8149–0.9186; P < 0.0001). The predicted score was significantly higher in CKD than in non-CKD patients (2.539 ± 0.2637 vs − 0.9382 ± 0.1691). The model was also able to predict stages of CKD: the Spearman correlation coefficient of the linear predictor with CKD stages was 0.83 with concordance indices of 0.899 (95% CI 0.863–0.927). In univariate analysis, the most consistent association of peptidomic score in CKD patients was with C-reactive protein, sodium level, and uric acid, which are unanticipated substances. Peptidomic analysis enabled to list some unanticipated substances that have not been extensively studied in the context of CKD but were associated with CKD progression, thus revealing interesting candidate markers or mediators of CKD of potential use in CKD progression management. Key messages: • Conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages of chronic kidney disease (CKD). • We performed untargeted plasma peptidome analysis to select the peptides involved in progression. • A logistic regression model selected 14 substances showing different concentrations according to renal function. • These peptides are unanticipated substances that have not been extensively studied in the context of CKD but were associated with CKD progression, thus revealing markers or mediators of CKD of potential use in CKD progression management. [ABSTRACT FROM AUTHOR]

Aims High-density lipoprotein (HDL) is known to have potent anti-inflammatory properties. Monocyte chemoattractant protein-1 is an important pro-inflammatory cytokine in early atherogenesis. There is evidence that HDL can lose its protective function during inflammatory disease. In patients with end-stage renal disease (ESRD), epidemiological studies have documented that the inverse correlation between HDL-cholesterol and cardiovascular risk is lost. Many structural modifications leading to reduced HDL function have been characterized, but the functional consequences are not fully understood. Methods and results We showed that HDL from patients with ESRD has a lower anti-inflammatory potential by reduced inhibition of monocyte chemoattractant protein-1 formation in vascular smooth muscle cells. Via a proteomic approach, we identified proteins in HDL from ESRD patients exerting pro-inflammatory actions. By chromatographic separation of proteins and mass-spectrometric analysis, we found serum amyloid A (SAA) to be one molecule acting as a potent pro-inflammatory protein. SAA is enriched in HDL from ESRD patients, correlating with reduced anti-inflammatory capacity. In SAA signal transduction, activation of formyl-peptide receptor 2 is involved. SAA enrichment in HDL of healthy subjects reduced the anti-inflammatory capacity of HDL and correlated with its decreased function. Conclusion These results suggest that SAA enrichment of HDL during disease conditions contributes to the decreased protective function. It is a novel finding that SAA acts as a pro-inflammatory molecule to reduce the anti-inflammatory properties of HDL. [ABSTRACT FROM PUBLISHER]

We analyzed proteomic profiles in monocytes of chronic kidney disease (CKD) patients and healthy control subjects. Two-dimensional electrophoresis (2-DE) and silver staining indicated differences in protein pattern. Among the analyzed proteins, superoxide dismutase type 1 (SOD1), which was identified both by MS/MS mass-spectrometry and immunoblotting, was reduced in kidney disease. We characterized SOD1 protein amount, using quantitative in-cell Western assay and immunostaining of 2-DE gel blots, and SOD1 gene expression, using quantitative real-time polymerase chain reaction (PCR), in 98 chronic hemodialysis (HD) and 211 CKD patients, and 34 control subjects. Furthermore, we showed that different SOD1 protein species exist in human monocytes. SOD1 protein amount was significantly lower in HD (normalized SOD1 protein, 27.2 ± 2.8) compared to CKD patients (34.3 ± 2.8), or control subjects (48.0 ± 8.6; mean ± SEM; P < 0.05). Analysis of SOD1 immunostaining showed significantly more SOD1 protein in control subjects compared to patients with CKD or HD ( P < 0.0001, analysis of main immunoreactive protein spot). SOD1 gene expression was significantly higher in HD (normalized SOD1 gene expression, 17.8 ± 2.3) compared to CKD patients (9.0 ± 0.7), or control subjects (5.5 ± 1.0; P < 0.0001). An increased SOD1 gene expression may indicate increased protein degradation in patients with CKD and compensatory increase of SOD1 gene expression. Taken together, we show reduced SOD1 protein amount in monocytes of CKD, most pronounced in HD patients, accompanied by increased SOD1 gene expression. [ABSTRACT FROM AUTHOR]

End-stage renal disease (ESRD) patients exhibit increased in vivo oxidative stress conceivably contributing to cardiovascular mortality. The type IIA secretory phospholipase A2 (sPLA2) has proatherogenic activity. We explored the hypothesis that sPLA2 contributes to oxidative stress generation and endothelial dysfunction in ESRD patients and transgenic (tg) mice. Patients with ESRD had increased in vivo oxidative stress as assessed by plasma isoprostane levels ( p < 0.001). Active sPLA2 in plasma was substantially increased compared with healthy controls (1,156 ± 65 versus 184 ± 5 ng/dL, p < 0.001) and correlated with plasma isoprostanes ( r = 0.61, p < 0.001). Correspondingly, human sPLA2 tg mice display increased generation of reactive oxygen species within aortic vascular smooth muscle cells, leading to severe endothelial dysfunction (maximal vasodilation in response to 10 µmol/L acetylcholine, sPLA2 36 ± 8%, controls 80 ± 2% of phenylephrine-induced vasoconstriction). Increased vascular oxidative stress in sPLA2 tg mice is dependent on the induction of vascular cyclooxygenase (COX)2 expression. Conversely, ESRD patients show increased formation of COX2-derived prostaglandins ( p < 0.05) correlated with plasma sPLA2 ( r = 0.71, p < 0.05). Our data indicate that increased expression of sPLA2 might represent a novel causative risk factor contributing to the increased cardiovascular disease morbidity and mortality in ESRD. [ABSTRACT FROM AUTHOR]

Background: Patients with stage 5 chronic kidney disease show increased cardiovascular morbidity and mortality that are partly related to impaired arterial vascular reactivity. We investigated whether intravenous administration of the antioxidant acetylcysteine improves arterial vascular reactivity in these patients. Methods: Arterial vascular reactivity was determined during reactive hyperemia by photoplethysmography of digital pulse waves in a randomized, prospective, placebo-controlled cross-over study of 24 patients with stage 5 chronic kidney disease with and without infusion of acetylcysteine during hemodialysis. Acetylcysteine (5 g in 5% glucose in a final volume of 50 ml) was continuously administered intravenously during one hemodialysis session. Results: In the absence of acetylcysteine, the reflective index was 38.5 ± 9.4 (mean ± SD; n = 24) at baseline and 33.8 ± 9.9 during reactive hyperemia, immediately after the hemodialysis session; thus there was no significant vasodilatation (p > 0.05), indicating impaired arterial vascular reactivity in these patients. However, when the hemodialysis session in the same patients was performed in the presence of acetylcysteine, the reflective index significantly decreased from 37.9 ± 8.6 at baseline to 30.2 ± 10.3 during reactive hyperemia (n = 24; p < 0.01). Conclusion: The present study shows that intravenous administration of acetylcysteine during hemodialysis significantly improves arterial vascular reactivity during reactive hyperemia. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Phenylacetic acid (PAA) is a recently described uremic toxin that inhibits inducible nitric oxide synthase expression and plasma membrane calcium ATPase and may therefore also be involved in remodeling of arteries. Such vascular effects have not been evaluated yet in patients with chronic kidney disease stage 5. Method: We prospectively measured the plasma concentrations of PAA using nuclear magnetic resonance spectroscopy in 50 patients with chronic kidney disease stage 5 (37 men, 13 women) on maintenance hemodialysis. Arterial vascular properties were quantified by the reflective index obtained from digital photoplethysmography. Results: During the hemodialysis session the plasma PAA concentration was reduced from 3.38 ± 0.24 mmol/l (mean ± SEM; median, 2.85 mmol/l; interquartile range, 2.02–4.52 mmol/l) to 2.25 ± 0.11 mmol/l (median, 2.06 mmol/l; interquartile range, 1.62–2.86 mmol/l; n = 50; p < 0.001). There was a significant correlation between the PAA concentration and the reflective index before the start of the hemodialysis session. Conclusion: The study demonstrates an association of PAA and arterial vascular properties in patients with chronic kidney disease stage 5. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Background: Retinol-binding protein 4 (RBP4) levels are elevated in the serum of patients with kidney dysfunction. We recently showed that RBP4 isoforms including apo-RBP4 (RBP4 not bound to retinol) and RBP4 truncated at the C-terminus (RBP4-L, RBP4-LL) are increased in the serum of patients with kidney diseases but not in serum of patients with various liver diseases. The aim of this study was to investigate the effect of renal replacement therapy on RBP4 isoforms. Methods: We investigated serum levels of RBP4, apo-RBP4, holo-RBP4, RBP4-L, RBP4-LL, retinol and transthyretin (TTR) in 18 hemodialysis (HD) patients, 30 patients after renal transplantation (RTx) and in 35 healthy controls. RBP4 and TTR levels were measured by enzyme-linked immunosorbent assay, apo- and holo-RBP4 by native electrophoresis, retinol by high performance liquid chromatography and RBP4-L and RBP4-LL were analyzed by mass spectrometry. Results: HD and RTx patients had elevated RBP4, apo-RBP4 and RBP4-LL levels compared to controls. RTx patients had elevated amounts of RBP4-L compared to controls and elevated RBP4 and apo-RBP4 levels compared to HD patients. Conclusion: The results demonstrate a strong correlation between kidney function and RBP4 isoforms and provide data for investigating the relation of RBP4 and insulin resistance in these patients. [Copyright &y& Elsevier]

Describes the characterization of p-hydroxy-hippuric acid as inhibitor of Ca[sup 2+]-ATPase inhibitor in end-stage renal failure. Role of adenosine triphosphatase in uremic toxicity; Purification of membrane from human red blood cells of normotensive patients; Analysis of purified fractions by gas chromatography and mass spectrometry.

Regulation of the Na+/H+ antiporter in patients with mild chronic renal failure: Effect of glucose. Background.The aim of this study was to determine the glucose-dependent regulation of the sodium-proton-antiporter (Na+/H+ antiporter) in patients with mild chronic renal failure (CRF). Methods.We measured plasma glucose concentrations, plasma insulin concentrations, plasma C peptide concentrations, arterial blood pressure, cytosolic pH (pHi), cellular Na+/H+ antiporter activity, and cytosolic sodium concentration ([Na+]i) in 19 patients with CRF and 41 age-matched healthy control subjects (control) during a standardized oral glucose tolerance test. Intracellular pHi, [Na+]i, and Na+/H+ antiporter activity was measured in lymphocytes using fluorescent dye techniques. Results.Under resting conditions, the pHi was significantly lower, whereas the Na+/H+ antiporter activity was significantly higher in CRF patients compared with controls (each P < 0.0001). The oral administration of 100 g glucose significantly increased the Na+/H+ antiporter activity in CRF patients from 13.35 ± 1.26 × 10-3 pHi/second to 16.44 ± 1.37 × 10-3 pHi/second after one hour and to 14.06 ± 1.36 × 10-3 pHi/second after two hours (mean ± sem, P = 0.008 by Friedmans’s two-way analysis of variance). In controls, the administration of 100 g glucose significantly increased the Na+/H+ antiporter activity from 4.23 ± 0.20 × 10-3 pHi/second to 6.00 ± 0.56 × 10-3 pHi/second after one hour and to 6.65 ± 0.64 × 10-3 pHi/second after two hours (P = 0.0003). The glucose-induced... [ABSTRACT FROM AUTHOR]

Examines the correlation between sodium-dependent chloride-bicarbonate exchanger in patients with chronic renal failure. Measurement of activity of ion transport systems in blood cells; Consequences of the altered metabolic profile of the patients; Stimulation of transport system regulating pH.

Background: Radiographic contrast agents can cause a reduction in renal function that may be due to reactive oxygen species. Whether the reduction can be prevented by the administration of antioxidants is unknown. Methods: We prospectively studied 83 patients with chronic renal insufficiency (mean [±SD] serum creatinine concentration, 2.4±1.3 mg per deciliter [216± 116 μmol per liter]) who were undergoing computed tomography with iopromide, a nonionic, low-osmolality contrast agent. Patients were randomly assigned either to receive the antioxidant acetylcysteine (600 mg orally twice daily) and 0.45 percent saline intravenously, before and after administration of the contrast agent, or to receive placebo and saline. Results: Ten of the 83 patients (12 percent) had an increase of at least 0.5 mg per deciliter (44 μmol per liter) in the serum creatinine concentration 48 hours after administration of the contrast agent: 1 of the 41 patients in the acetylcysteine group (2 percent) and 9 of the 42 patients in the control group (21 percent; P=0.01; relative risk, 0.1; 95 percent confidence interval, 0.02 to 0.9). In the acetylcysteine group, the mean serum creatinine concentration decreased significantly (P<0.001), from 2.5±1.3 to 2.1±1.3 mg per deciliter (220±118 to 186±112 μmol per liter) 48 hours after the administration of the contrast medium, whereas in the control group, the mean serum creatinine concentration increased nonsignificantly (P=0.18), from 2.4±1.3 to 2.6±1.5 mg per deciliter (212±114 to 226± 133 μmol per liter) (P<0.001 for the comparison between groups). Conclusions: Prophylactic oral administration of the antioxidant acetylcysteine, along with hydration, prevents the reduction in renal function induced by iopromide, a nonionic, low-osmolality contrast agent, in patients with chronic renal insufficiency. (N Engl J Med 2000;343:180-4.) [ABSTRACT FROM AUTHOR]