The Association of Serum Fetuin A Level, Insulin Resistance and Hepatic Fat Content and Their Associations With Overall Survival in Maintenance Hemodialysis and Peritoneal Dialysis Patients

Background:

Fetuin A is a protein secreted by hepatocytes that inhibits insulin receptor tyrosine kinase of adipose and muscle cells (1, 2). Recently, its inhibitory potency on calcium phosphate precipitation has been linked to cardio-vascular (CV) calcification and has predicted CV and non-CV mortality in dialysis patients (3, 4). In most investigations, fetuin A deficiency is associated with higher mortality, worse CV outcomes in dialysis patients. In our recent study, fetuin A deficiency is also linked to vascular access failure in hemodialysis (HD) patients (5). The pathogenesis of worse survival in these fetuin A deficiency dialysis patients is not well-known. Nevertheless, the associations of fetuin A deficiency and progression of vascular calcification and atherosclerosis are thought to be the possible mechanism of the high CV mortality (6, 7).

In general population, fetuin A is associated with insulin resistance, metabolic syndrome and obesity, that is, human with higher fetuin A concentration has higher insulin resistance (8). Insulin resistance, diabetes and metabolic syndrome are all important predictors of long-term CV outcome in general population (9, 10). In an interventional study performed in diabetic human with normal kidney function, treatment with pioglitazone seems to decrease fetuin A levels and enhance insulin sensitivity (11). In an animal model, mice with fatty liver presented up-regulated fetuin A (Ahsg) mRNA expression (1, 2). In non-diabetic subjects, fetuin A is associated with hepatic fat accumulation and insulin resistance (12). Moreover, in a recent investigation, fetuin A concentration was associated with body fat mass in chronic kidney disease (CKD) patients not yet receiving dialysis (13). In our previous investigation, we also found HD patients with higher fetuin A concentration have higher risk to be truncal obesity and hypertriglyceridemia (14). These studies suggested this liver-secreted protein rapidly responds to hepatic fat accumulation which inhibits generation of adiponectin in adipose tissue; therefore higher fetuin-A and lower adiponectin may contribute to obesity-induced insulin resistance and development of diabetes in general population and CKD patients (15). However, this relationship has not been shown in dialysis patients.

Although obesity, metabolic syndrome contributed to higher CV mortality in general population (9, 10); patients under dialysis with higher BMI experienced short-term survival benefit (16). It is so-called "reverse epidemiology" in dialysis patients. Generally speaking, well-nutrition dialysis patients experienced less malnutrition-inflammation complex and therefore, their short-term survival benefit from being well-nutrition overcomes the long-term survival disadvantage brought from over-nutrition such as obesity and insulin resistance. However, ESRD patients with abdominal obesity still have higher CV mortality risk (17).The interesting part of the results these investigations is that, fetuin A deficiency in dialysis patients have worse CV outcome; on the contrary, higher fetuin A level leads to insulin resistance and thereafter higher CV mortality in general population. It is not clear that whether the fetuin A concentration is another "reverse epidemiology" in dialysis patients. But dialysis patients with well-nutrition, presented with higher BMI, more hepatic fat accumulation have better survival. We hypothesize the survival disadvantages of fetuin A deficiency, which is frequently present in dialysis patients, may have a major impact on mortality in a shorter period of time; and increased hepatic fat-accumulation (over-nutrition) may leads to fetuin A secretion and overwhelms the short-term negative effects of fetuin A deficiency on survival, finally, leading to a protective effect of high BMI, hepatic fat accumulation or over-nutrition on overall survival in dialysis patients.

Study purposes: