Hemodialysis International 2015; 19:472–481

Relationship between non-alcoholic fatty liver disease and MIA syndrome Ivana MIKOLASEVIC,1 Davor STIMAC,2 Sanjin RACKI,1 Luka ZAPUTOVIC,3 Bosiljka DEVCIC,1 Ita JELIC,1 Vesna LUKENDA,4 Mladen RADIC,2 Lidija ORLIC1 Departments of 1Nephrology, Dialysis and Kidney Transplantation, 2Gastroenterology, 3Cardiology, University Hospital Center Rijeka, Rijeka, Croatia; 4Department of Internal Medicine, General Hospital “Dr. Josip Bencevic”, Slavonski Brod, Croatia

Abstract Non-alcoholic fatty liver disease (NAFLD) is an important factor in the pathogenesis of cardiovascular diseases in the general population. Recently, it has been shown that NAFLD is highly prevalent in chronic kidney disease (CKD) patients. Ninety-four hemodialysis (HD) patients were followed for a time period of 18 months or until death. Patient’s survival rate was determined in relation to their nutritional and inflammatory state, and the presence of NAFLD. We also investigated the association between the presence of NAFLD and the patients’ nutritional and inflammatory state. We did not find any significant association between the clinical parameters of nutritional status and the mortality rate. However, the mortality rate was statistically significantly higher in patients with low serum albumin and high high-sensitive C-reactive protein (hs-CRP) levels and in those who had NAFLD. Surprisingly, patients who had received enteral nutrition did not have a better survival rate. The severity of liver steatosis was negatively correlated with the serum albumin levels, while it was positively correlated with hs-CRP values. Furthermore, serum albumin levels showed a negative correlation with hs-CRP levels. We did not find any significant association between the presence of NAFLD and clinical parameters of nutrition. We have shown that NAFLD could be one more possible example of reverse epidemiology in patients undergoing HD. NAFLD may be the missing link that causally ties malnutrition, inflammation, and atherosclerosis syndrome to the morbidity and mortality in patients undergoing HD. Key words: Hemodialysis, non-alcoholic fatty liver disease, malnutrition, mortality

INTRODUCTION Mortality rate in hemodialysis (HD) patients, in spite of continuous progress in renal replacement therapy, is still high. Numerous authors have shown that cardiovascular diseases (CVDs) remain the most common cause of morCorrespondence to: I. Mikolasevic, MD, PhD, Department of Nephrology, Dialysis and Kidney Transplantation, University Hospital Centre Rijeka, Tome Strižic´a 3, Rijeka 51000, Croatia. E-mail: [email protected] No financial support, grants or any other funding

bidity and mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) receiving HD. Malnutrition is often present in patients undergoing chronic HD and is associated with increased morbidity and mortality. These findings are opposite to the general population where obesity is associated with increased CVD risk. Malnutrition in patients undergoing dialysis has been attributed to many factors, such as insufficient nutrient intake, dialysis inadequacy, acidosis, hormone derangement, and inflammation. Malnutrition and inflammation are common and usually concurrent in chronic patients undergoing HD; it has been suggested

© 2015 International Society for Hemodialysis DOI:10.1111/hdi.12280

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that in patients with CKD, “inflammation” is the most important factor associated with poor nutritional state.1–6 According to the literature, pro-inflammatory cytokines represent a common link between malnutrition, inflammation, and atherosclerosis (MIA syndrome) in this population of patients. However, as malnutrition occurs in patients undergoing pre-dialysis as well, it is evident that dialysis-unrelated factors e.g., infectious and inflammatory complications and comorbidities may also be important contributors to malnutrition in CKD.3–5 In recent years, the link between CKD and nonalcoholic fatty liver disease (NAFLD) has attracted considerable research interest. It has been shown that NAFLD is highly prevalent in patients with CKD.7–11 Accordingly, we have recently analyzed the association between NAFLD and decreased kidney function in our patients with CKD stage III and IV. Our patients with CKD had a high prevalence of NAFLD. Moreover, the severity of liver steatosis was negatively correlated with kidney function.8 In the next phase of our investigations we were interested in analyzing whether the presence of NAFLD is associated with higher CVD risk in patients undergoing HD.9 We have found that patients undergoing HD with NAFLD show more carotid atherosclerosis. Our patients undergoing dialysis with NAFLD had higher CVD risk as well as higher high-sensitive C-reactive protein (hs-CRP) levels.9 Similar results were found by Lai YC et al. In their analysis NAFLD was an independent risk factor for nonfatal cardiovascular events in patients undergoing chronic HD.12 Neri et al. have found that carotid intima-media thickness was significantly higher in patients with biopsy proven NAFLD.13 NAFLD, which is the most common liver disease in industrialized countries, is associated with obesity, hypertension, dyslipidemia and type-2 diabetes in the general population. NAFLD is thought to be the hepatic manifestation of insulin resistance (IR) (or the metabolic syndrome).14–17 Patients with NAFLD had significantly higher levels of various plasma proinflammatory cytokines and pro-coagulations factors. Sub-chronic liver inflammation in NAFLD patients leads and contributes to dyslipidemia, inflammation, enhanced oxidative stress and endothelial dysfunction. This consequently results in accelerated atherosclerosis. Indeed, there is growing evidence that NAFLD is strongly associated with CVD in general population.14–19 The aim of our study was to determine patients’ survival rate in relation to their nutritional and inflammatory state and the presence of NAFLD. Investigating the association between NAFLD and various clinical and laboratory data regarding nutritional and inflammatory patients’ state was our other endpoint.

Hemodialysis International 2015; 19:472–481

MATERIALS AND METHODS In the present prospective study, we followed 102 patients on maintained HD at the Department of Nephrology, Dialysis and Kidney Transplantation for a time period of at least 6 months. All patients underwent HD three times a week for 4–5 hours using a synthetic polysulfone membrane. The exclusion criteria were: serological evidence of chronic hepatitis B and/or C virus infection, alcohol abuse, presence of other autoimmune or cholestatic liver disease, use of potentially hepato-toxic medications and technical reasons (failed transient elastography). None of the patients in the study group had an acute infection (urinary tract infections, pneumonia or catheter infections) at the time of transient elastography (TE) measurements. Patients with evidence of acute kidney injury and those with evidence of advanced progressive metastatic cancer were excluded. All patients that were included in this study had Kt/V > 1.2. During the follow-up period 8 patients were transplanted. Considering the above, 94 patients took part in the further analysis. Data on patient demographic characteristics, medical history and laboratory data were obtained through medical records. Comorbid conditions included the presence of diabetes mellitus, dyslipidemia and arterial hypertension. This data were obtained using a standard questionnaire. Hypertensive nephropathy (renal vascular disease) was defined as the presence of long-term arterial hypertension, left-ventricular hypertrophy, hypertensive retinopathy, presence of proteinuria and gradual deterioration of kidney function. Laboratory data included albumin, cholesterol and hs-CRP levels by standard clinical chemistry techniques. This data were recorded within 1 week of TE measurements. For the assessment of the nutritional status we used various anamnestic, clinical and laboratory parameters according to ISMNR criteria.20 Anamnestic data were regarding appetite was classified as poor, mild or good and were obtained using standard questions. Clinical nutritional status was assessed by measuring fat mass (FAT), waist girth, hip and upper arm, loss of upper arm girth > 10% during a 6-month period and calculating the body mass index (BMI). The BMI was calculated as weight (kg) divided by height (m) squared. Waist circumference was categorized according to median values separately in males (103 cm) and females (93 cm) in primary analyses and according to recommended standards (100 cm in men and 90 cm in women) in sensitivity analyses. Fat mass was assessed by skinfold caliper measurement (the result was correlated with total body fat, FAT). Laboratory

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nutritional state data were obtained using serum albumin levels and cholesterol values. Poor nutritional status was defined as a BMI of 5 mg/L were defined as “high.” Of the patients, 85.1% received supportive enteral nutrition (pharmacological compositions suitable for patients with ESRD). At the beginning of the study, a transient elastography was performed in all of the patients. Liver stiffness was selected as the parameter to quantify liver fibrosis. Furthermore, the controlled attenuation parameter (CAP) was used to detect and quantify liver steatosis with the help of TE (Fibroscan®, Echosense, Paris, France). The cut-off value for defining liver steatosis was CAP ≥238 dB/m and the cut-off value for defining the presence of fibrosis was a liver stiffness of >7 kPa. The diagnosis of NAFLD was defined according to the TE findings with the CAP ≥238 dB/m, with or without any stage of fibrosis and with exclusion of other secondary causes of chronic liver disease. Measurements were performed using the M probe (at 3.5 MHz) on the right lobe of the liver trough intercostal spaces with the patients lying in dorsal decubitus position with the right arm in maximal abduction. Ten successful measurements were performed on each patient and only cases with 10 successful acquisitions were taken into account for this study. The success rate was calculated as the number of successful measurements divided by the total number of measurements. The final CAP value, which ranges from 100 to 400 dB/m, is the median of individual measurements. The ratio of the interquartile Table 1 Recommended values of fat mass according to the age and gender of the patients Age (years) 20–29 30–39 40–49 50–59 Women Very low (%) Low (%) Optimal (%) Moderate (%) High (%) Men Very low (%) Low (%) Optimal (%) Moderate (%) High (%)

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60+

28 35

range (IQR) in CAP values to the median (IQR/MCAP) was used as an indicator of variability for the final CAP.21,22 All scans were performed by the same investigator. All patients were followed for a minimum of 18 months or until death. We were interested to determine patient’s survival rate in relation to their nutritional and inflammatory state and the presence of NAFLD. Investigating the association between NAFLD and various clinical and laboratory data regarding nutritional and inflammatory patients’ state was our other endpoint. Survival was defined as the time period between the study initiation to death (or end of study, if still alive). Patients were informed of the purpose and method of the research and the study was done in accordance with the Declaration of Helsinki. All patients gave their written informed consent prior to their inclusion in the study. The study was approved by local ethical commission. Statistical analysis of data was performed using descriptive statistics. Categorical variables were tested by chisquare test. The difference in patients’ survival rate was analyzed with Kaplan–Meier’s method of mortality risk. The Pearson or Spearman’s correlation coefficient was used to express correlations among variables. P value 238 dB/m and thus by definition had NAFLD. Patients who had died had a statistically significant higher levels of hs-CRP and CAP (Table 2). We were interested in exploring whether age (older or younger than 65 years) and gender had an influence on the survival of our patients. There were no statistically

significant difference in survival rate according to age or gender (P = NS). Analyzing the influence of anamnestic (appetite) parameters of nutritional status on the mortality rate, we did not find any significant association among the loss of appetite and the mortality rate. On the other hand, 13 (13.8%) of our patients had a loss of upper arm girth of more than 10% during a 6-month period. Those patients had a significantly higher mortality rate in comparison with the patients who did not lose their upper arm girth during the observed period (hazard ratio [HR] 3.1523; 95% confidence interval [CI] 0.9766–10.1714; P = 0.003; Figure 1). According to the BMI values, 65 (69.1%) of our patients had BMI < 23 kg/m2, 51 (54.3%) out of 94 patients had FAT below reference values for age and gender, while 35 (37.2%) had a waist circumference below median. We did not find any significant association among the BMI, FAT values and waist circumference and mortality rate. Furthermore, the mortality rate was statistically significantly higher in patients with low serum albumin levels (HR 9.6556; 95% CI 4.5258–20.5998; Figure 2), while there was no statistically significant association among cholesterol levels and mortality rate.

Table 2 Baseline characteristics of the study patients

Age, years Duration of HD (months) Patients with residual renal function, n (%) Vascular accesses Arteriovenous fistula Central venous catheter Kt/V Appetite, n (%) Poor Mild Good Enteral nutrition, n (%) Albumins (g/L) Cholesterol (mmol/L) hs-CRP (mg/L) BMI (kg/m) FAT (%) Dry body weight, (kg) Waist circumference (cm) Hip circumference (cm) Upper arm girth (cm) CAP (dB/m) NAFLD, n(%)

All (n = 94)

Alive (n = 66)

Died (n = 28)

P

69.1 ± 12 64.1 ± 58.1 18 (19.1%)

68.6 ± 9.1 66.1 ± 62.6 12 (18.1%)

69.2 ± 7.7 59.2 ± 46.4 6 (21.4%)

NS NS NS

71 (75.5%) 23 (24.5%) 1.33 ± 0.12

51 (77.3%) 15 (22.7%) 1.35 ± 0.11

20 (71.4%) 8 (28.6%) 1.31 ± 0.12

NS NS NS

16 (17%) 10 (10.6%) 68 (72.3%) 80 (85.1%) 37.1 ± 5.2 4.1 ± 1.1 9.6 ± 11.2 24.7 ± 4 20.4 ± 5.6 70.9 ± 15 95.4 ± 15.2 102.1 ± 10.5 27.2 ± 3.5 244.1 ± 39 53 (56.4%)

8 (12.1%) 7 (10.6%) 51 (77.3%) 56 (84.8%) 39.6 ± 3.2 4. ± 4.4 5.3 ± 4.4 24.8 ± 4.1 20.2 ± 5.1 70.8 ± 14.7 95 ± 16.2 102.3 ± 11.3 27.2 ± 3.6 230.9 ± 33.5 27 (40.9%)

8 (28.6%) 3 (10.7%) 17 (60.7%) 24 (85.7%) 33.1 ± 5.5 4.1 ± 1 16.5 ± 14 24.1 ± 3.7 20.2 ± 5.5 69.8 ± 16.1 96.2 ± 12.9 101.2 ± 8 27 ± 3.3 279.6 ± 26 26 (92.9%)

NS

Relationship between non-alcoholic fatty liver disease and MIA syndrome.

Non-alcoholic fatty liver disease (NAFLD) is an important factor in the pathogenesis of cardiovascular diseases in the general population. Recently, i...
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