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Mineral Metabolism and Inflammation in Chronic Kidney Disease Patients: A Cross-Sectional Study
Authors:Juan F. Navarro-González  Carmen Mora-Fernández  Mercedes Muros  Haridian Herrera  Javier García
Affiliation:*Nephrology Service.;Research Unit, and ;§Clinical Biochemistry Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; and ;Centre of Biological Research, National Spanish Research Council, Madrid, Spain
Abstract:Background and objectives: Mineral metabolism abnormalities and inflammation are concerns in chronic kidney disease (CKD). Interrelationships among these parameters have not been analyzed.Design, setting, participants, & measurements: The study included 133 patients with CKD not on dialysis and not receiving calcium (Ca) supplements, phosphate binders, or vitamin D. Estimated GFR (eGFR) was 34.1 ± 6.8 ml/min/1.73 m2; 107 participants had stage 3 CKD, and 26 had stage 4.Results: Patients were classified by tertiles of Ca, phosphorus (P), Ca-P product (Ca x P), and parathyroid hormone (PTH). After adjustment for age, gender, and eGFR, the levels of C-reactive protein (CRP) and IL-6 (IL-6) of the third tertile of P, Ca x P, and PTH were significantly higher than those of the first and second tertiles. Serum P and Ca x P directly correlated with CRP and IL-6, whereas HDL-cholesterol and eGFR inversely correlated with the levels of the inflammatory parameters. After partial correlation analysis, the previous associations between CRP and eGFR, and serum P, as well as the relationship between IL-6 and eGFR, and serum P, remained significant. Multiple regression analysis demonstrated that eGFR and serum P were independently associated with CRP and IL-6. Finally, logistic regression analysis using the presence/absence of an inflammatory state as the dependent variable showed that eGFR was a protective factor, whereas serum P was an independent risk factor for the presence of an inflammatory state.Conclusions: Elevated serum P might play a role in the development of inflammation in CKD.Alteration of mineral metabolism is a prevalent condition in chronic kidney disease (CKD). Large epidemiologic studies have shown a strong relationship between elevated levels of calcium (Ca), phosphorus (P), Ca-P product (Ca x P), and parathyroid hormone (PTH) with cardiovascular morbidity and mortality (13). Among abnormalities of mineral metabolism, one of the most prominent and relevant is hyperphosphatemia. Elevated serum P has been related to cardiovascular morbidity and mortality in both hemodialysis and predialysis patients. Vascular and coronary artery calcification have been suggested as the link between abnormal mineral metabolism in general, and hyperphosphatemia in particular, and cardiovascular events in this population (46). Hyperphosphatemia has been pointed out as the primary culprit in the process of cardiovascular calcification (4,810), an event already present in the early phases of renal failure (7,8). More interesting, a significant association between the progression of coronary artery calcification and serum P concentration was observed in CKD patients, despite serum P being in the normal range. Faster progression was found in patients with a high-normal serum P, which was accompanied by more frequent cardiovascular events (11). However, despite these previous findings, the mechanisms by which serum P contributes to cardiovascular disease are not completely known.Vascular and coronary artery calcification are markers of atherosclerotic disease. In the last decades, intensive investigations have led to a paradigm shift in the interpretation of atherosclerosis, from a purely metabolic process (i.e., mainly driven by hypercholesterolemia) to a disease where inflammation is the dominant pathophysiological and biochemical alteration (12). Cardiovascular disease is up to 20-fold more frequent in ESRD patients and accounts for up to 50% of all deaths, with accelerated atherosclerosis being consistently implicated in this process (13). Traditional cardiovascular risk factors cannot completely explain the prevalence of atherosclerosis, the elevated cardiovascular risk, and the disproportional predisposition for adverse cardiovascular outcomes in this population. Therefore, novel emergent cardiovascular risk factors are suggested to contribute to atherogenesis and have been associated with cardiovascular risk. Among these, it is now known that inflammation is a highly prevalent condition in CKD patients, with diverse studies having documented increased concentrations of inflammatory mediators in dialysis patients as well as subjects with advanced renal failure (14,15). More importantly, it has been demonstrated that several inflammatory parameters, mainly C-reactive protein (CRP) and IL-6 (IL-6), are strong and independent predictors of all-cause and cardiovascular mortality (1619).In spite of the important prevalence and relevance of alterations of mineral metabolism and inflammation in CKD patients, the interrelationships among these factors have been scarcely analyzed, especially in predialysis patients. Most previous studies have been performed in hemodialysis, with a limited number of subjects, and with the potentially confounding effect of concomitant treatment with Ca supplements, phosphate binders, or vitamin D derivates (20,21). The aim of this study was to examine the interrelationships among the main parameters of mineral metabolism (Ca, P, Ca x P, and PTH) and inflammation (CRP and IL-6) in patients with advanced CKD.
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