Fat mass, adipokines and clinical complications of chronic kidney disease

Sammanfattning: Patients with chronic kidney disease (CKD), irrespective of initial etiology, have a risk of cardiovascular morbidity (CVD) and mortality that is many-fold higher than that of a similar person without CKD. While traditional risk factors, such as hyperlipidemia, certainly contribute, these factors cannot by themselves explain the burden of CVD. Recent data suggest that endocrine signaling of fat mass may lead to the complex of CVD risk factors known as the metabolic syndrome. In the following work, we test the hypothesis that an uremic metabolic syndrome caused by aberrant adipose tissue signaling may contribute to inflammation and metabolic disturbances in CKD. Study I. In a cross-sectional study of 187 incident patients starting dialysis therapy we measured several inflammatory cytokines and adipokines and related these to total and truncal fat mass as estimated by dual-energy x-ray absorptiometry (DEXA). We found that truncal, but not non-truncal, fat mass was associated with circulating levels of both interl eukin(IL)-6 and C-reactive protein (CRP). Study II. In a study of 197 incident CKD patients evaluated shortly before the start of dialysis, we showed that patients with elevated fat mass, although having elevated inflammatory markers, are less likely to need recombinant erythropoietin (epoetin), and that epoetin dose is associated with circulating levels of leptin. Study III. This is a post hoc, cross-sectional study comparing 239 CKD patients with varying degrees of renal function impairment with an age- and gender-matched randomly selected control group of 24 individuals. We explored the role of decreased renal function on the adipokine resistin, apparently able to inhibit hepatic insulin action in mice We also investigate possible links with inflammation (CRP, IL-6) and the insulin resistance (QUICKI, HbA1c%) present in patients with CKD. While resistin is strongly related to renal function and inflammation, we could find no links to surrogate markers of insulin resistance. Study IV. In a longitudinal study of 158 CKD, patients with varying degrees of renal failure, we explored the relationship between changes in body fat (DEXA) and tissue resident macrophages (assessed by measuring sCD163), as well as links to systemic inflammation (IL-6, CRP). We concluded that an increase in fat mass is associated with increased sCD163, a surrogate marker of macrophages, and more inflammation in CKD patients. Study V. Again using a cross-sectional design of 189 prevalent CKD patients, we investigated putative links between the adipokine visfatin and insulin resistance in CKD. We conclude that while a reduced renal function and inflammation both independently predict visfatin levels, visfatin is not associated with QUICKI or HbA1c%. However, increased circulating visfatin was associated with endothelial adhesion molecules (sVCAM-1) and a higher mortality rate. Study VI. Using a Mendelian randomization approach in a cohort of 198 incident CKD patients starting dialysis, we show significant differences in serum lipids between functional genotypes of alpha2Heremans-Schmid glycoprotein (AHSG) as well as a significant association between AHSG and fat mass (DEXA). Conclusions. In patients with chronic renal disease, total and, especially, truncal fat mass is associated with increased circulating levels of several cytokines and adipokines that have may influence cardiovascular health and outcome. Thus, further studies are needed to evaluate the impact of fat mass and adipokines on outcome in this patient group.