Non-inflamed Patients Research Articles

Leptin, adiponectin, and ghrelin dysregulation in chronic kidney disease

In the past 10 years, 3 new metabolic compounds, leptin, adiponectin, and ghrelin, involved in energy metabolism, body composition, and appetite regulation, have been discovered. We have assessed their characteristics in 46 patients with stage 3 to 4 chronic kidney disease to evaluate the role of decreased renal function in the abnormal handling reported in more severe end-stage renal disease patients. In addition to the usual correlations with body mass index and body fat mass, the results show unexpected positive correlations between leptin and insulin, leptin and adiponectin, a weak inverse relationship between adiponectin and glomerular filtration rate, and no influence of C-reactive protein on either leptin or adiponectin in these noninflamed patients. Serum ghrelin was inversely correlated with body mass index and with glomerular filtration rate as measured by inulin clearance. Thus, ghrelin and leptin, 2 antagonist signals for energy balance, both seem to increase when glomerular filtration rate is reduced, potentially neutralizing their respective biologic effects in severe renal insufficiency.

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

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. 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. 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. 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.

Gene Expression Analysis in Inflamed and Non-inflamed Hemodialysis (HD) Patients Using a cDNA Microarray

Systemic inflammation is an independent predictor of mortality in HD patients, and a better understanding of its pathogenetic pathways and identification of targets for intervention are needed. The cDNA microarray technology has recently been used to profile gene expression, and examines simultaneously a broad variety of genes that could determine biological and pathogenetic processes. To investigate the gene expression profile in white blood cells of eight persistently inflamed (CRP > 10 mg/L for 12 months) HD patients compared to eight non-inflamed patients (CRP < 10 mg/L for 12 months), we designed a pilot study using a cytokine expression array (R&D Systems), including 398 different cloned cDNAs, printed as PCR products, on a positively charged nylon membrane. mRNA was extracted from leucocytes and pooled for each group, which were matched for age, gender, primary renal disease, and time on HD. Comparison of the signals from the two samples allowed identification of differentially expressed mRNA. A 10x increase in mRNA expression between the groups was defined as up-regulation. The results showed that 32 genes were up-regulated in the inflamed group compared to the non-inflamed group. Highly up-regulated genes belonged to the following groups: members of the TGF-β superfamily (5 genes), proteolytic enzymes (5), integrin (4), genes involved in nitric oxide metabolism (3), TNF superfamily (3), interleukin receptors (3), cell surface proteins (2), orphan receptors (2), neurothrophic factor (1), fibroblast growth factor family (1), cytokine receptor (1), cytokine (1), and chemokine (1). In conclusion, circulating lymphocytes of inflamed HD patients had markedly up-regulated expression of inflammation-related genes, providing a molecular fingerprint of gene function on the RNA level. These genes should be considered as candidates for genotype analysis or targets for intervention studies.