Clinical Study of Serum Fetuin A Level, Insulin Resistance and Hepatic Fat Content in Dialysis Patients
Clinical Study of Serum Fetuin A Level, Insulin Resistance and Hepatic Fat Content in Dialysis Patients
Background Fetuin A, synthesized in hepatocyte, is a circulatory inhibitor of precipitation
 of calcium and phosphate and links to cardiovascular calcification and mortality in dialysis
 patients; besides, it is associated with insulin resistance in general population. Hepatic
 fat accumulation enhanced fetuin A secretion in animal model.

 Objects This study is designed to investigate the association of fetuin A level, insulin
 resistance and hepatic fat content in dialysis patients. Besides, we planed to observe the
 survival of dialysis patient with different hepatic fat content.

 Methods. This is a prospective observational study. Three hundred and fifty ESRD patients
 undergoing maintenance HD or PD will be recruited for this prospective investigation. All the
 participants will receive baseline abdominal ultrasound for estimation of hepatic fat
 content. Hepatic fat content will be estimated as minimal, mild, moderate or severe according
 to the Hepburn classification. Besides, all participants also check baseline fetuin A,
 HOMA-IR, hs-CRP, adiponectin, leptin and lipid profiles (T-CHO, TG, LDL-C, HDL-C),
 nutritional parameter and other biochemical parameters. All participants will be followed for
 4 years for survival analysis. The outcomes are all-cause mortality and composite CV
 mortality.

 Expected results Dialysis patients with higher hepatic fat may have higher fetuin A levels
 which may lead to long-term survival benefits.
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:

 This study is designed to:

 1. To evaluate the association of hepatic fat content and fetuin A concentration in
 maintenance HD/PD patients

 2. To evaluate the association of fetuin A concentration and insulin resistance markers in
 HD/PD patients

 3. To evaluate the overall survival (4-year) of HD/PD patients with different content of
 hepatic fat

 Study designs and methods:

 This is a prospective observational study. Three hundred and fifty ESRD patients undergoing
 maintenance HD or PD for more than 6 months will be recruited for this prospective
 investigation.

 All the participants will receive baseline abdominal ultrasound for estimation of hepatic fat
 content. Hepatic fat content will be estimated as minimal, mild, moderate or severe according
 to the Hepburn classification: absent (affecting 0% to 2% of the hepatocytes), minimal (2% to
 10%), mild (10% to 30%), moderate (30% to 60%), and severe (more than 60% of the
 hepatocytes). We choose abdominal ultrasound as the method of hepatic fat estimation rather
 than MRI and CT which are the gold standard of hepatic fat estimation, because the limited
 use of MRI in dialysis patients and increased cancer risk receiving screening CT. Besides,
 all participants also check baseline fetuin A, HOMA-IR, hs-CRP, adiponectin, leptin and lipid
 profiles (T-CHO, TG, LDL-C, HDL-C), nutritional parameter and other biochemical parameters.
 All participants will be followed for 4 years for survival analysis. The outcomes are
 all-cause mortality and composite CV mortality.
Inclusion Criteria:

 1. ESRD patients undergoing maintenance HD or PD for more than 6 months

 2. Age>20

 Exclusion Criteria:

 1. Recent hospitalization duet active medical or psychiatric problems

 2. Active malignancy

 3. Patient refusal