Impact of Metabolic Syndrome and Malnutrition on Mortality in Chronic Hemodialysis Patients Radojica V. Stolic, MD, PhD,* Goran Z. Trajkovic, MD, PhD,† Vladan M. Peric, MD,* Dragica Z. Stolic, MD,‡ Sasa R. Sovtic, MD, PhD,* Jovanovic N. Aleksandar, MD, PhD,* and Gordana Dj. Subaric-Gorgieva, MD, PhD* Objective: Metabolic abnormalities contribute to increases in the mortality rate of patients on hemodialysis. Here, we estimate the importance and influence of metabolic syndrome and malnutrition on mortality rate. Design: This was a follow-up study. Methods: We examined the demographic characteristics of time on dialysis, body mass index, indications for hospitalization, treatment outcomes, and biochemical parameters over a 4-year period. Results: Whereas 31.7% of patients had metabolic syndrome, 26.7% showed evidence of malnutrition. More than two thirds of the malnourished patients died. Many patients (46%) with malnutrition were hospitalized because of problems with vascular access, whereas hospitalization of half of the examined patients with metabolic syndrome was attributable to cardiovascular disorders. Differences between groups in the parameters of anemia, total proteins, albumin, and low-density lipoprotein cholesterol also occurred, with the lowest values in malnourished patients. Glycemia, total cholesterol, and fibrinogen were significantly higher in patients with metabolic syndrome, whereas those with malnutrition had a markedly higher concentration of C-reactive protein. The mean survival was 24 months with metabolic syndrome and 17.5 months with malnutrition, which was significantly shorter. Conclusions: More than half of the examined patients had metabolic abnormalities. Patients with malnutrition had a lower rate of survival compared with those who had metabolic syndrome. Two thirds of our malnourished patients died, and the total rate of mortality in the examined sample was 38%. Ó 2010 by the National Kidney Foundation, Inc. All rights reserved.
T
HE FIRST DESCRIPTION of metabolic syndrome was made in 1988 by Gerry Reaven, who demonstrated the simultaneous existence of several metabolic disorders based on primarily on atherosclerosis.1 The National Cholesterol Education Programs defined metabolic syndrome as the presence of at least 3 of the following 5 criteria: morning glycemia .6.1
*Kosovska Mitrovica Internal Clinic, University of Pristina/K. Mitrovica, Faculty of Medicine Pristina/K. Mitrovica, Anri Dinana bb, Kosovska, Mitrovica, Serbia. †Institute of Medical Statistics and Informatics, Faculty of Medicine Pristina/Kosovska Mitrovica, University of Pristina/K. Mitrovica, Kosovska, Mitrovica, Serbia. ‡Health Center Pristina, Gracanica, Serbia. Address reprint requests to Radojica Stolic, MD, PhD, Kosovska Mitrovica Internal Clinic, Faculty of Medicine, Anri Dinana bb, 38220 Kosovska, Mitrovica,Serbia. E-mail:
[email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/10/2001-0006$36.00/0 doi:10.1053/j.jrn.2009.01.021
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mmol/L, serum triglycerides .1.7 mmol/L, serum high-density lipoprotein (HDL) cholesterol ,1.04 mmol/L, blood pressure .130/85 mm Hg, and waist size $102 cm for males and $88 cm for females. The World Health Organization defined metabolic syndrome as the existence of elevated insulin or a morning glucose concentration of 5.6 to 6.0 mmol/L, combined with 2 or more of the following criteria: central obesity, dyslipidemia, and arterial hypertension.2 The expected incidence of metabolic syndrome is 8.8% to 14.3% in Europe, and 22.6% to 23.7%, in the United States, with a tendency toward growth. In Australia, 29% of the population older than 25 years and about 40% of those older than 40 years have elements of metabolic syndrome.3 The prevalence of metabolic syndrome in the population requiring dialysis is not sufficiently known. However, one study included 3 criteria to confirm metabolic syndrome, and found a rate of 69.3% in patients on chronic hemodialysis (HD).4 Journal of Renal Nutrition, Vol 20, No 1 (January), 2010: pp 38–43
IMPACT OF METABOLIC SYNDROME AND IN CHRONIC HD PATIENTS
Protein-caloric malnutrition in patients on HD is manifested by reduced values of total proteins, serum albumin, transferrin, and cholesterol, and decreased muscle mass. Many clinical studies showed that these patients run a higher risk of protein-energy malnutrition, which is responsible for their increased mortality rate, and that between 23% and 76% of patients on HD show elements of malnutrition. Because malnutrition can be a marker of associated diseases, the influence on mortality is not always a direct consequence of malnutrition.5 The aim of this study was to examine the influence of metabolic syndrome and malnutrition on mortality in patients on chronic HD.
Subjects and Methods In a follow-up study, we analyzed the outcome of clinical treatment of 284 HD patients, 122 (43%) female and 162 (57%) male, hospitalized for different reasons from 2004 to 2007 inclusive at the Center of Nephrology and Dialysis, Urology and Nephrology Clinic, Clinical Center Kragujevac (Krangujevac, Sebia). Even a single night’s hospital admission for any reason was considered hospitalization. These patients had been on a chronic program for at least 3 months. Most patients received HD thrice a week for 3.5 to 4 hours, using commercially available dialyzers (F6HPS, F7HPS, Fx 80-Fresenius [Fresenius Medical Care Srbija d.o.o.]; 14L, 17L-Gambro [Gambro-Medicon, Belgrade, Sebia]). The range of the blood pump during dialysis was 250 to 320 mL/min, whereas the flow of dialysis fluid was 500 mL/min. Metabolic syndrome was established according to at least 3 criteria, as suggested by the National Cholesterol Education Programs,2 whereas malnutrition was diagnosed according to the concentration of total proteins, albumin, and cholesterol and the body mass index (BMI), calculated using the quotient of body weight (kg) and body height squared (m2).5 According to the metabolic abnormalities found, patients were separated into 3 groups: 1. Patients without metabolic abnormalities; 2. Patients with metabolic syndrome; and 3. Patients with malnutrition. A blood sample for laboratory analyses was taken from each individual in the middle of the week,
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before hemodialysis. Hematological analyses were performed using a Coulter device (Coulter, Hialeah, FL) and the flow cytometric method. Other biochemical tests were performed spectrophotometrically on an Ilab-600 device (SHIMADZU Co., Japan). Statistical analysis included analysis of variance and the c2 test, using the Instat program (GraphPad Software, Inc., San Diego, CA). Analysis of survival and the Cox regression model were used to correlate survival with metabolic syndrome and malnutrition. Statistical hypotheses were tested at a level of significance of P , .05.
Results The demographic and clinical characteristics of our patients are shown in Table 1. Among 284 patients examined, 118 (41.6%) were without metabolic abnormalities, including 76 (64.4%) men and 42 (35.6%) women. Elements of metabolic syndrome were confirmed in 90 (31.7%) patients, of whom 58 (64.5%) were male and 32 (35.5%) were female, whereas malnutrition was found in 76 (26.7%) patients, of whom 48 (63%) were male and 28 (37%) were female. There were more male patients in all groups, but without statistically significant differences among groups regarding age and sex. Patients with malnutrition had a significantly lower mean BMI compared with patients with metabolic syndrome and those without metabolic abnormalities (P ,.0001). Patients with elements of malnutrition spent an average of 9 more months on dialysis than those with metabolic syndrome, and almost 4 months more than patients without metabolic imbalances, but this difference was not statistically significant (Table 1). In the group of patients without metabolic changes, only 3.4% of hospitalized patients died, whereas 20% had a lethal outcome in the group of patients with metabolic syndrome, and 65.8% of patients in the group with malnutrition died. The frequency of lethal outcomes was significantly higher in patients with malnutrition (P ,.001). An analysis of the reasons for hospitalization indicated that the high morbidity rate of 46% was caused by problems with vascular access in patients with malnutrition, and the difference between the examined groups was highly significant (P , .001). In patients with metabolic syndrome, the reason for 50% of hospitalizations was cardiovascular disease, and a significant difference was found (P , .001).
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STOLIC ET AL
Table 1. Demographic and Clinical Characteristics of the Examined Patients
Parameters Age (y) Sex (M/F) BMI (kg/m2) Time on dialysis (months) Lethal outcome (%) Vascular access Reasons for Surgical diseases hospitalization (%) Cardiovascular disease
Patients Without Metabolic Abnormalities (n 5 118)
Patients With Parameters of Metabolic Syndrome (n 5 90)
Patients With Parameters of Malnutrition (n 5 76)
P
58.1 6 13.4 76/42 20 6 3.75 56 6 6.92 3.4 21.1 33 20
56.2 6 12.8 58/32 23.6 6 2.34 50.9 6 6.04 20 32.9 36 50
56.4 6 13.5 48/28 17.3 6 0.92 59.8 6 8.4 65.8 46 31 30
ns ns ,.0001* ns ,.001* ,.001* ns ,.001*
ns, no significance. *Statistically significant difference.
Disorders requiring surgical intervention were equally present in all groups of patients (Table 1). Table 2 shows that the mean number of erythrocytes, hemoglobin concentration, total proteins, albumin, and low-density lipoprotein (LDL) cholesterol had significantly lower values in malnourished patients compared with the group of patients without metabolic disturbances. Patients with metabolic syndrome exhibited higher levels of glycemia, but total cholesterol was similar to the value for the group without metabolic disturbances. As an indicator of inflammable reaction, the mean C-reactive protein (CRP) concentration
was higher in patients with malnutrition (P 5.0035), whereas patients with metabolic syndrome had the highest mean fibrinogen concentration (P 5.0013; Table 2). Mean survival for patients with metabolic syndrome was 24 months, and for those showing malnutrition, it was 17.5 months. There was no correlation between the examined patients with metabolic syndrome and those with malnutrition regarding survival, which was significantly shorter in malnourished patients (P , .001; Fig. 1). No parameter in the patients with metabolic syndrome or elements of malnutrition
Table 2. Hematologic and Biochemical Characteristics of the Examined Patients
Parameters Erythrocytes 3 1012/L Leukocytes 3 109/L Hemoglobin (g/L) Glycemia (mmol/L) Urea (mmol/L) Creatinin (mmol/L) Total proteins (g/L) Albumins (g/L) Uric acid (mmol/L) Triglycerides (mmol/L) Cholesterol (mmol/L) HDL cholesterol (mmol/L) LDL cholesterol (mmol/L) CRP (mg/L) Fibrinogen (mmol/L) Parathormon (mg/L) ns, no significance. *Statistically significant result.
Patients Without Metabolic Abnormalities (n 5 118)
Patients With Parameters of Metabolic Syndrome (n 5 90)
Patients With Parameters of Malnutrition (n 5 76)
P
3.23 6 0.51 6.36 6 1.65 102 6 15.84 6.1 6 1.5 25.1 6 6.1 998 6 240 69.6 6 4.52 38.5 6 4.43 418 6 71.7 1.91 6 2.18 4.4 6 1.24 1.09 6 0.22 2.32 6 0.62 4.49 6 5.07 4.2 6 4.38 326 6 374.9
3.28 6 0.44 6.18 6 1.8 102 6 16.53 11.8 6 10.8 24.6 6 5.3 1009.7 6 272 67.2 6 4.89 36.3 6 6.34 448 6 97.1 2.5 6 1.34 4.6 6 1.46 0.92 6 0.27 2.56 6 0.9 4.43 6 3.2 6.5 6 3.9 273 6 349.6
2.91 6 0.75 6.43 6 2.32 87 6 15.9 6.4 6 1.53 24.05 6 5.4 907.6 6 232 66.2 6 5.45 29.5 6 3.77 421.6 6 77.6 2.7 6 2.41 3.2 6 1.2 1.22 6 0.71 1.78 6 1.13 7.09 6 3.04 5.54 6 1.8 256.2 6 444.2
.012* ns ,.0001* .032* ns ns .005* ,.0001* ns ns ,.0001* ns .037* .0035* .0013* ns
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31.7% of hospitalized patients at a similar mean age had elements of this abnormality, with a prevalent male population. We found no valid data in the literature about the demographic characteristics of patients with malnutrition, and our findings indicate that the profile of a malnourished patient is partly represented by a man aged 56 years. Malnutrition has often been associated with increased mortality in patients on HD, and possible contributing factors include chronic inflammatory conditions, physical inactivity, and catabolic processes.9,11 Between 20% to 36% of patients on long-term HD (mean, 51 months) showed signs of malnutrition,5 as confirmed here (with 26.7% of patients) after 56.4 months. A strong predictive influence of the duration of HD on malnutrition is accepted. The overall mean BMI in our patients was 19.95 kg/m2, indicating that all of them were malnourished. However, BMI was only 17.3 kg/ m2 in the group with malnutrition, compared with 23.6 kg/m2 for patients with metabolic syndrome, and 20 kg/m2 for those without symptoms. It is clear that norms for the anthropometric estimation of the nutritive status of patients with terminal renal insufficiency are, generally speaking, discussable, considering those different evaluations of criteria for the estimation of protein-energy malnutrition. For example, Hecking et al.12 used the recommended standards, i.e., that patients with a BMI of less than 20 kg/m2 are malnourished, and those with a BMI greater than 30 kg/m2 are overweight. The World Health Organization considers BMI values from 18 to 25 kg/m2 to be normal for the general population. Nevertheless, many studies confirm a positive relationship between BMI and mortality rate in patients on HD.9 Therefore, in the Dialysis Outcomes and Practice Patterns Study, the influence of BMI on mortality of patients on HD was evaluated, and a clear recommendation was presented concerning all technical details for the analysis of dietetic markers.13 The adequacy of BMI could be discussed in severe hypervolemia, which occurs very often in patients with terminal-stage renal insufficiency, congestive heart decompensation, and liver insufficiency.9 In our study, BMI was also an important parameter of general protein-energy imbalance. Thus, 31.7% of patients exhibited elements of metabolic syndrome, and 26.7% exhibited clinical-biochemical parameters of malnutrition. Moreover, patients with malnutrition had a lower survival rate compared with patients with metabolic syndrome, i.e.,
two thirds of hospitalized patients with malnutrition died during the examination period. Such a high mortality rate strongly confirms earlier results showing that malnutrition is associated with increased mortality. However, BMI is not an exact parameter of dietetic status, especially in situations of water imbalance in cardiac decompensation or liver and renal insufficiency. Hence Stenvinkel et al.13 considered the measurement of waist size more suitable than BMI. Protein-energy malnutrition is an independent factor of cardiovascular mortality in the dialysis population, particularly if it is associated with an infection. An elevated concentration of CRP as a marker of inflammation is associated with a mortality rate 3 to 5 times higher in patients on HD.14 By numerous mechanisms, protein-energy malnutrition can initiate the synthesis of inflammatory markers, creating the possibility of atherogenesis and increasing the mortality risk in patients on dialysis.13 The significantly higher concentration of CRP in our patient group with malnutrition confirms these conclusions. Qureshi et al.15 established that age, gender, cardiovascular disease, nutritive status, and CRP were independent factors of mortality, in contrast to serum albumin concentrations which, for a long time, were regarded as an indicator of reduced survival in patients on HD.15,16 Moreover, among laboratory parameters of dietetic status, serum proteins are considered suitable markers of nutritive status and significant predictors of morbidity and mortality in patients on HD.15 Low concentrations of total protein and albumin in our study were characteristic of patients with elements of malnutrition, with statistically significant differences among groups. Cox regression analysis of the expected parameters of survival showed no predictive importance of the estimated variables, without excluding the possibility of a significant influence of soft-tissue calcifications as a mortality risk factor. A small number of samples, especially in epidemiological studies, can have a negative impact on displaying real differences, which is usually explained by statistical errors, particularly in parameters supposed to have an influence on heightened mortality rates. There are many questions, dilemmas, and illogicalities regarding the predictive values of particular dietetic factors. The most important predictor of mortality in our study is itself belonging to the group of patients with metabolic syndrome or malnutrition.
IMPACT OF METABOLIC SYNDROME AND IN CHRONIC HD PATIENTS
Obesity is connected with an elevated synthesis of proinflammatory cytokines, in both the general population and the dialysis population. The protective mechanism of obesity in patients on HD is directly disproportionate to its well-known influence on cardiovascular disease, diabetes mellitus, and hypertension in the general population. For that reason, the so-called ‘‘paradox obesity’’ in HD, because of enlarged muscle mass, has a direct positive influence on increased survival rate. More and more doctors and scientists support this theory.16–18 In our follow-up study, metabolic syndrome was found in 31.7% of the examined patients, whereas parameters of malnutrition were evident in 26.7%. Patients with malnutrition had a lower survival rate than those with metabolic syndrome. Two thirds of our hospitalized patients with malnutrition died during the period of examination. Total mortality rate for the examined sample was 38%. The most important predictor of mortality in our study is itself belonging to the group of patients with metabolic syndrome or malnutrition.
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6. Bradbury BD, Fissell RB, Albert JM, et al: Predictors of early mortality among incident US hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Clin J Am Soc Nephrol 2:89-99, 2007 7. Seliger SL, Gillen DL, Tirschwell D, et al: Risk factors for incident stroke among patients with end-stage renal disease. J Am Soc Nephrol 14:2623-2631, 2003 8. Ikizler TA, Pupim LB, Brouillette JR, et al: Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation. Am J Physiol Endocrinol Metab 282:107-116, 2002 9. Pifer TB, Mccullough KP, Port FK, et al: Mortality risk in hemodialysis patients and changes in nutritional indicators: DOPPS. Kidney Int 62:2238-2245, 2002 10. Johansen KL, Kaysen GA, Young BS, et al: Longitudinal study of nutritional status, body composition, and physical function in hemodialysis patients. Am J Clin Nutr 4:842-846, 2003 11. Jager KJ, Merkus MP, Huisman RM, et al: Necosad Study Group. Nutritional status over time in hemodialysis and peritoneal dialysis. J Am Soc Nephrol 12:1272-1279, 2001 12. Hecking E, Bragg-Gresham JL, Rayner HC, et al: Haemodialysis prescription, adherence and nutritional indicators in five European countries: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 19: 100-107, 2004 13. Stenvinkel P, Heimbu¨rger O, Lindholm B: Wasting, but not malnutrition, predicts cardiovascular mortality in end-stage renal disease. Nephrol Dial Transplant 19:2181-2183, 2004 14. Johnson DW, Craven AM, Isbel NM: Modification of cardiovascular risk in hemodialysis patients: an evidence-based review. Hemodialysis Int 11:1-14, 2007 15. Qureshi AR, Alvestrand A, Divino-Filho JC, et al: Inflammation, malnutrition, and cardiac disease as predictors of mortality in hemodialysis patients. J Am Soc Nephrol 13:28-36, 2002 16. Beddhu S, Pappas LM, Ramkumar N, et al: Malnutrition and atherosclerosis in dialysis patients. J Am Soc Nephrol 15: 733-742, 2004 17. Spiegel DM, Raggi P, Smits G, et al: Factors associated with mortality in patients new to haemodialysis. Nephrol Dial Transplant 22:3568-3572, 2007 18. Kalantar-Zadeh K, Kuwae N, Wu DY, et al: Associations of body fat and its changes over time with quality of life and prospective mortality in hemodialysis patients. Am J Clin Nutr 83: 202-210, 2006
