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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2020  |  Volume : 31  |  Issue : 2  |  Page : 353-359
Serum cytokeratin 18 level is associated with dietary intake and serum triglycerides level in hemodialysis patients


1 Laparascopy Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
2 Student Research Committee , School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
3 Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4 Department of Nephrology, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

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Date of Submission04-Jun-2019
Date of Acceptance11-Jul-2019
Date of Web Publication09-May-2020
 

   Abstract 


Cell death leads to increase serum cytokeratin 18 (CK-18) in chronic kidney disease. However, few studies have investigated the serum CK-18 level in relation to nutritional and metabolic biomarkers. We examined the association of dietary intake and lipid profile with serum CK18 level among hemodialysis (HD) patients. Ninety HD patients according to inclusion and exclusion criteria were included in the study. An analysis of clinical characteristics, anthropometric indices, dietary intake, and lipid profile revealed a significant association between serum CK-18 and diabetes, metabolic syndrome, body mass index (BMI), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), energy intake (EI), protein intake (PI), and saturated fatty acid (SFA). In a multiple stepwise regression model, after adjusting for confounders in three models, the association between serum CK-18 and serum TG level, dietary SFA and EI remained significant. The model 3 adjusted for DM, Mets, BMI, ALT, AST, and PI; model 2 adjusted for model 1 + EI; and model 1 adjusted for model 2 + SFA. Our findings suggest that the development of hypertriglyceridemia and inadequate EI contribute to higher serum CK-18, which is a cell death biomarker.

How to cite this article:
Haghighat N, Zare M, Vaziri NM, Hosseini B, Sohrabi Z, Bazyar H, Alipour M, Shafei M. Serum cytokeratin 18 level is associated with dietary intake and serum triglycerides level in hemodialysis patients. Saudi J Kidney Dis Transpl 2020;31:353-9

How to cite this URL:
Haghighat N, Zare M, Vaziri NM, Hosseini B, Sohrabi Z, Bazyar H, Alipour M, Shafei M. Serum cytokeratin 18 level is associated with dietary intake and serum triglycerides level in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 May 25];31:353-9. Available from: http://www.sjkdt.org/text.asp?2020/31/2/353/284009



   Introduction Top


Malnutrition is one of the most common complications in dialysis patients, especially in hemodialysis (HD) patients. Besides, inflammation, another common condition in HD patients, plays a significant role in worsening malnutrition due to a rise in rest energy expenditure, inhibition of muscular and hepatic protein synthesis, resulting in lowering somatic and visceral protein storage.[1] Nutritional treatment is known as an effective strategy to prevent metabolic abnormalities and adverse outcomes in people with chronic diseases.[2] The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines stated that the dietary energy requirement in HD patients is increased. They recommended that enough daily energy intake (EI) maintains the nitrogen balance and prevents protein catabolism and tissue destruction, which could improve nutritional status in HD patients.[3] Nevertheless, the daily intake of macronutrients and micronutrients is widely inadequate in HD patients,[4] which could be in result of anorexia, lifestyle change while receiving dialysis treatment, and some dietary restriction.[2],[3] Therefore, this poor dietary intake, particularly EI may lead to malnutrition that can result in disease exacerbation, clinical complications, and higher morbidity and mortality.

In addition to poor dietary intake, inflammation is a leading cause of tissue destruction in the kidney in chronic kidney disease (CKD) patients.[5] Indeed, cell death and increased systemic stress and inflammation are profound features of CKD.[6] Moreover, in HD patients, the inflammation as a result of an impaired immune system can cause cell death via necrosis or apoptosis.[7] One of the novel surrogate markers for measuring or determining necrosis and apoptosis is cytokeratin- 18 (CK-18) which has been used as a measure for myocardial infarction and hepatic injury diagnosis.[8] The uremic toxins might increase apoptosis[3],[9] and this can, in turn, elevate CK- 18 in HD patients. One of the merits of assessing CK-18 is related to acute kidney injury (AKI) as CK-18 might be increased during AKI caused by apoptosis.[10] Regarding the fundamental effect of inflammation on CK-18 release, this might propose an indirect association between malnutrition and serum CK-18. Most of the studies investigated the changes in serum CK-18 concentration in liver cell damages.[11],[12] However, few studies evaluated the serum CK-18 level and its determinants in HD patients. Moreover, determining the associated factors affecting serum concentration of CK-18 might be of great importance to verify its assessment in the course of CKD prevention or management or any response to the treatment. Due to the association between malnutrition, inflammation, and apoptosis, there might be a significant association between apoptosis and its marker, CK-18, and dietary intake among HD patients that was not evaluated yet. In addition, due to the effects of inflammation on insulin resistance and serum lipids,[13] there might be indirect correlations between serum CK-18 and metabolic disorders that were not investigated yet. Hence, the objective of the current study was to examine the association of serum CK-18 and clinical characteristics, anthro- pometric indices, dietary intake, and metabolic abnormalities among patients who receiving HD treatment.


   Materials and Methods Top


Study design

This cross-sectional study investigated the association between nutritional and metabolic biomarkers and cell death in HD patients.

Participants

Ninety participants aged 30-65 years undergoing HD for at least three months were recruited from HD centers of Shiraz and Ahvaz University of Medical Sciences from January 2018 to July 2018. The patients regularly underwent a thrice-weekly HD treatment and had an equilibrated Kt/V (eKt/V) of 1.2 for the past three months. Patients with known malignancies, amputation, infection, hospitalization one month before the study, previous kidney transplant or likely to receive a transplant, acute or chronic inflammatory disorders, liver disease, use of a central catheter for HD access, using steroidal and/or nonsteroidal anti-inflammatory drugs, intense physical activity, pregnancy, and missing data in their assessments were excluded from the study. Written informed consent was obtained from each participant. The study was carried in accordance with the Declaration of Helsinki. The Research Ethics Committee of Shiraz University of Medical Sciences approved the study protocol (IR.SUMS. REC.1398.937).

Demographic characteristics and anthropometric measurements

Demographic data including age, sex, dialysis vintage, history of diabetes (DM), hypertension (HTN), and metabolic syndrome (MetS) were retrieved. In addition, anthropometric information, comprising height and dry weight, were obtained. Body mass index (BMI) was calculated as dry weight (in kg) divided by the square of the height (in m). In addition, the geriatric nutritional risk index (GNRI), a nutritional screening index, was determined from the serum albumin, body weight, and height of the patients.[14]

Biochemical assays

The predialysis total cholesterol, triglyceride (TG), low-density lipoprotein, high-density lipoprotein, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were retrieved and measured by standard automated techniques. The level of serum CK-18 (M30 antigen) was detected by ELISA kit (PEVIVA, Alexis, Grunwald, Germany).

Dietary intake and physical activity

A licensed nutritionist conducted face-to-face interviews with the patients during the HD process and used a 24-h recall with common household measuring utensils. Three-day (a dialysis day, a nondialysis day, and a weekend) averages of total calories, carbohydrates, proteins, saturated fatty acids, mono-unsatu- rated fatty acids, and PUFAs were analyzed using nutrient analysis software (Nutritionist Edition, Enhancement plus 4, Version 2009). Moreover, dietary energy and protein intake (PI) were normalized to body weight. Physical activity data of the patients were evaluated during an interview using the International Physical Activity Questionnaire. A metabolic equivalent value was indicated according to the levels of physical activity (light, moderate, and intense), which was scored in METs.


   Statistical Analyses Top


The Kolmogorov-Smirnov test was used to assess normality before examining the data.

Linear regression analyses were used to identify metabolic factors significantly correlated with serum CK-18 level. Univariate linear regression was used for identifying CK18 predictors. To examine independent metabolic and dietary factors, variables with P <0.2 in relation to serum CK18 level in univariate analyses were entered into a multi- variate regression model. The stepwise variable selection was used to obtain the candidate final regression model to multivariable analyses. Variables such as DM, MetS, BMI, TG, ALT, AST, EI, PI, and SFA intake were included in the model. P <0.05 was considered to show statistical significance.


   Results Top


Patient characteristics

The characteristics of the studied participants are shown in [Table 1]. In total, 90 patients with ESRD on HD (41 men and 28 women) were identified. The mean age and dialysis vintage of the patients were 48.44 ± 10.69 years (range: 36-59 years) and 6.50 ± 5.37 years (range: 13 months-12 years), respectively. Regarding comorbidity, 68%, 70%, and 40% of the patients undergoing HD have DM, HTN, and MetS, respectively. The serum albumin and GNRI score, indicators of the nutritional status, were 4.0 ± 0.3 mg/dL and 101.0 ± 4.5, respectively.
Table 1: The demographic, clinical and laboratory characteristics of hemodialysis patients.

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To show factors significantly related to serum CK-18 level, linear regression analyses were performed. In univariate regression analysis, we found that the presence of DM, MetS, serum TG, ALT, AST levels, and dietary SFA (% EI) intake were positively associated with serum CK-18; on the contrary, the BMI, dietary PI, and EI were negatively associated [Table 2].
Table 2: Simple linear regression for predicting serum CK18 level in 90 hemodialysis patients.

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The results of multivariate stepwise regression analyses showed that dietary EI, dietary SFA (%EI) intake, and serum TG level remained independent factors related to CK- 18. We examined the possible effect of three models. According to all models, after adjustment for major confounding factors in model 3: BMI, DM, MetS, ALT, AST, and PI; model 2: model 3+ dietary EI; model 1: model 2 + dietary SFA intake [Table 3].
Table 3: Prediction of CK-18 Levels according to the Multivariable Stepwise Linear Regression Analysis for the Correlates of CK-18 level.

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   Discussion Top


The results of the present study demonstrated that serum CK-18 concentration is an appropriate biomarker for the screening of HD patients. In our study indicated that the serum CK-18 was associated positively with serum TG level and dietary SFA intake and negatively with EI among patients undergoing HD.

Although the use of serum CK-18 level for the diagnosis of nonalcoholic fatty liver disease (NAFLD), septicemia, chronic liver diseases and cirrhosis, and acute myocardial infarction has been discussed in the previous studies,[12] few studies have examined the serum CK-18 level in HD patients. Roth et al demonstrated that the level of CK-18 has been raised in serum and urine of CKD patients compared to the healthy controls,[15] which could be due to increased cell death in consequence of inflammation or uremic toxins.[16] Inflammation can cause tissue destruction or ischemia in the kidney in the context of HD.[5] Inflammation and malnutrition are the two significant features of HD patients.[17] Malnutrition and cachexia, in other words low BMI, emanate from inflammation that shows a viscous cycle between cachexia and inflam- mation.[17] On the other hand, as CK-18 is related to inflammation, hence, the negative association between CK-18 and BMI seems logical.

It is noteworthy that after adjusting for BMI and other confounders, an increase in the serum CK-18 level was seen to be significantly and independently associated with a decrease in EI among HD patients. Unfortunately, calorie and PI are compromised in HD due to the effect underlying disease, other diseases, psychosocial factors, and uremic anorexia.[18] On the other hand, low appetite or reduced EI is related to an overlap condition of malnutrition and inflammation called protein- energy wasting, and the successful management of this condition is important for promoting HD patients’ outcome. Maintaining enough EIs can improve HD patients’ prognosis. Hence, because of lower EI and malnutrition and higher grades of inflammation following that[19] and considering the association between inflammation and serum CK- 18,[16] the reason for the relationship between lower EI and higher CK-18 is almost clear.

On the other hand, we found a positive association between dietary SFA intake and serum CK-18 level, which was in line with that of a study by Tabuchi et al. SFA intake and increased serum CK-18 show the relationship between fat intake and necro- inflammation.[20] The positive association between dietary SFA and serum CK-18 might be pertinent to the inhibitory effects of SFA on delta-6-desaturase and delta-5-desaturase[11] and suppression of arachidonic acid metabolism to long-chain metabolites including lipoxins and resolvins that can reduce the pro-inflammatory cytokines. Higher consumption of SFAs in the long-term might cause adipokine imbalance and apoptosis through inducing glucose- dependent insulinotropic polypeptide elevation.[20] A higher SFA intake might induce a SFA molar ratio in plasma phospholipids, and this can increase M30 antigen or CK-18 in turn.[11] In addition, it is noteworthy to state that impaired delta-5-desaturase activity induced by SFA intake might be a causative factor for metabolic syndrome development,[21] which might indirectly explain the association seen between metabolic syndrome and CK-18 in the current study. On the other hand, due to the relationship between glucose metabolism parameters and serum CK-18, reported by some studies,[22],[23] the association between diabetes and serum CK-18 seems inevitable. The main reason for this association might be due to the effect of CK-18 on pancreatic exocrine dysfunction.[24] However, after adjusting for diabetes, metabolic syndrome, BMI, and serum liver enzyme, the association of serum CK-18 and serum TG level remains significant. As CK-18 is a typical marker of NAFLD, it is not surprising that serum CK-18 level and serum TG level are linked since the higher serum TG level is a risk factor for NAFLD development. This finding is confirmed by the result of a study by Cao et al about the association between serum CK-18 and TG in the patients with nonalcoholic steatohepatitis.[12] The possible explanation for this is that inflammation can cause insulin resistance and fat accumulation in the liver and TG elevation.[13] As CK-18 is elevated due to the inflammatory status among HD patients, the relationship between serum CK-18 and TG might be indirectly related to the insulin resistance caused by inflammation in this condition.

The current study had some limitations. First, because of the cross-sectional design, causal relationships or clinical outcomes could not be determined. Therefore, further longitudinal studies are warranted to confirm the cause and effect relationships. Second, for assessing dietary intake, self-reported dietary records were used and this might cause under- or overreporting and this can be a source of error as well.


   Conclusion Top


The higher SFA or lower EI intake might be associated with elevated serum CK-18 independently from serum liver enzyme levels, presence of diabetes and metabolic syndrome, BMI and PI, due to inflammatory status in HD patients. On the other hand, serum TG level is significantly associated with increased serum CK-18. Serum CK-18 might provide a broader basis for deciding about the best treatment in HD patients, as it is more easily measured and noninvasive. Moreover, serum CK-18 might be a good measure for monitoring the course of disease or response to the treatment. Further investigations, especially large clinical studies, are warranted to elucidate the exact mechanism regarding these associations and to evaluate the role of CK-18 in HD patients to find better strategies in the management or secondary prevention of malnutrition, cachexia, and inflammation in HD patients.

Conflict of interest: None declared.



 
   References Top

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Sohrabi Z, Eftekhari MH, Eskandari MH, Rezaianzadeh A, Sagheb MM. Intradialytic oral protein supplementation and nutritional and inflammation outcomes in hemodialysis: A randomized controlled trial. Am J Kidney Dis 2016;68:122-30  Back to cited text no. 1
    
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Kopple JD. National kidney foundation K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 2001;37 Suppl 2:S66-70  Back to cited text no. 3
    
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Leers MP, Kolgen W, Bjorklund V, , et al. Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 1999;187:567-72  Back to cited text no. 8
    
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Haghighat N, Mohammadshahi M, Shayanpour S, Haghighizadeh MH. Effect of synbiotic and probiotic supplementation on serum levels of endothelial cell adhesion molecules in hemodialysis patients: A randomized control study. Probiotics Antimicrob Proteins 2019;11: 1210-8  Back to cited text no. 9
    
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Tabuchi M, Tomioka K, Kawakami T, et al. Serum cytokeratin 18 M30 antigen level and its correlation with nutritional parameters in middle-aged Japanese males with nonalcoholic fatty liver disease (NAFLD). J Nut Sci Vitaminol 2010;56:271-8  Back to cited text no. 11
    
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Cao W, Zhao C, Shen C, Wang Y. Cytokeratin 18, alanine aminotransferase, platelets and tri- glycerides predict the presence of nonalcoholic steatohepatitis. PLoS One 2013;8:e82092  Back to cited text no. 12
    
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Civera M, Urios A, Garcia-Torres ML, Ortega J, Martinez-Valls J, Cassinello N, et al. Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity. Diabetes Metab Res Rev 2010;26:187-92  Back to cited text no. 13
    
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Yamada K, Furuya R, Takita T, Maruyama Y, Yamaguchi Y, Ohkawa S, et al. Simplified nutritional screening tools for patients on maintenance hemodialysis. Am J Clin Nutr 2008;87:106-13  Back to cited text no. 14
    
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Roth GA, Lebherz-Eichinger D, Ankersmit HJ, Hacker S, Hetz H, Vukovich T, et al. Increased total cytokeratin-18 serum and urine levels in chronic kidney disease. Clin Chim Acta 2011; 412:713-7  Back to cited text no. 15
    
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Hunkerler Z, Koken T, Koca B, Kahraman A. Role of uremic toxins on apoptosis with varying periods of hemodialysis. Ther Apher Dial 2017;21:38-42  Back to cited text no. 16
    
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Ekramzadeh M, Sohrabi Z, Salehi M, Ayatollahi M, Hassanzadeh J, Geramizadeh B, et al. Adiponectin as a novel indicator of malnutrition and inflammation in hemodialysis patients. Iran J Kidney Dis 2013;7:304-8  Back to cited text no. 17
    
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Musso G, Gambino R, Pacini G, De Michieli F, Cassader M. Prolonged saturated fat-induced, glucose-dependent insulinotropic polypeptide elevation is associated with adipokine imbalance and liver injury in nonalcoholic steato- hepatitis: Dysregulated enteroadipocyte axis as a novel feature of fatty liver. Am J Clin Nutr 2009;89:558-67  Back to cited text no. 20
    
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Warensjo E, Riserus U, Vessby B. Fatty acid composition of serum lipids predicts the development of the metabolic syndrome in men. Diabetologia 2005;48:1999-2005  Back to cited text no. 21
    
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Cusi K, Chang Z, Harrison S, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with nonalcoholic fatty liver disease. J Hepatol 2014; 60:167-74  Back to cited text no. 22
    
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Miyasato M, Murase-Mishiba Y, Bessho M, Miyawaki M, Imbe H, Tsutsumi C, et al. The cytokeratin-18 fragment level as a biomarker of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Clin Chim Acta 2014;433:184-9  Back to cited text no. 23
    
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Guardado Mendoza R, Perego C, Finzi G, et al. Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas). Diabetologia 2015;58:1814-26.  Back to cited text no. 24
    

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Correspondence Address:
Zahra Sohrabi
Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz
Iran
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DOI: 10.4103/1319-2442.284009

PMID: 32394907

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