Chronic Kidney Disease As a Metabolic Syndrome with Malnutrition—Need for Strict Control of Risk Factors

□ REVIEW ARTICLE □

Chronic Kidney Disease as a Metabolic Syndrome with Malnutrition—Need for Strict Control of Risk Factors

Tetsuo SHOJI and Yoshiki NISHIZAWA

Abstract disease, congestive heart failure, and sudden death. The relative risk of CVD death in hemodialysis patients is in the Patients with chronic kidney disease (CKD) have an range of 10–30 (1–3). The aim of this review is to determine increased risk for death from cardiovascular disease the basic strategies to prevent CVD and to improve the out- (CVD). They have multiple metabolic abnormalities that come of patients with chronic kidney disease (CKD) by man- may accelerate atherosclerosis, such as hypertension, insu- aging metabolic alterations. lin resistance, and dyslipidemia, along with other CKD- One of the major causes for the increased risk of CVD related risk factors. In addition, a considerable propor- death is advanced arterial changes. Patients treated by tion of patients with advanced stages of CKD are mal- hemodialysis have increased arterial wall thickness, meas- nourished, presenting “metabolic syndrome with malnu- ured as intima-media thickness of the carotid artery (CA- trition”. The presence of malnutrition/inflammation dra- IMT) (4–7). They also have increased arterial wall stiffness, matically changes the apparent relationship between measured as aortic pulse wave velocity (PWV) (8–10). Both CVD death risk and some risk factors. For example, in of the morphological (11–13) and the functional changes (14, stage 5 CKD patients on hemodialysis, a higher body 15) of the large arteries are shown to be significant predic- mass index and a higher plasma cholesterol are predictors of CVD death in hemodialysis patients. Although tors of better survival. To understand the paradoxic Lindner et al (1) previously speculated that chronic hemo- epidemiology, we should recognize risk factors for occur- dialysis treatment may accelerate atherosclerosis, predialysis rence of CVD events and risk factors of fatality after an patients with chronic renal failure have increased CA-IMT event. In this article, we review the unique situation of (6) and aortic PWV (10) to a degree comparable with those CKD, emphasizing the need of more strict control of both on maintenance hemodialysis. The existence of renal failure, types of risk factors to improve survival of CKD patients. rather than the hemodialysis procedure, was a significant risk (Internal Medicine 44: 179–187, 2005) factor for these arterial wall changes independent of other traditional risk factors. Interestingly, being treated by Key words: atherosclerosis, cardiovascular disease (CVD), hemodialysis was not a significant factor associated with risk factors, chronic kidney disease (CKD), mal- CA-IMT (6). Based on these recent findings, we should con- nutrition sider renal failure as an important and independent risk factor for morphological and functional changes of large arteries that are present before starting renal replacement therapy. Elevated Risk of Cardiovascular Disease in Chronic Renal Failure Concept of Chronic Kidney Disease (CKD)

According to the latest statistics, there are more than Arterial wall changes are present in patients with earlier 230,000 patients receiving dialysis therapy in Japan. As stages of renal disease. Aortic PWV is inversely correlated compared with the general population, hemodialysis patients wtih the glomerular filtration rate (GFR) in hypertensive pa- are at an increased risk of death, and cardiovascular disease tients with moderate renal insufficiency (16). As compared (CVD) is the leading cause of death in the dialysis popula- to those with a normal urinary albumin excretion rate, in- tion. More than one half of these patients die from CVD increased aortic PWV, CA-IMT, and impaired endothelial cluding ischemic heart disease, stroke, peripheral arterial function are documented in subjects with microalbuminuria

From Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka Reprint requests should be addressed to Dr. Tetsuo Shoji, Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585

Internal Medicine Vol. 44, No. 3 (March 2005) 179 SHOJI and NISHIZAWA

(17), one of the earliest signs of kidney damage. In addition, impaired enzymatic activities of LPL, HL, and lecithin- the presence of microalbuminuria (18, 19) and reduced GFR cholesterol acyltransferase (LCAT) (37) are factors responsi- (20) are both significant predictors of CVD. Thus, not only ble for the lowered HDL-cholesterol and abnormal HDL patients with end-stage renal disease (ESRD), but also those subfraction distribution (30). Although the precise mecha- with very early signs of renal damage have arterial wall nisms are unknown for the altered enzyme levels, some of changes and the increased risk of CVD. the enzymatic changes are shown to be associated with al- Chronic kidney disease (CKD) is a concept covering tered calcium homeostasis (30). broad spectrum of kidney dysfunction from microalbumi- Arterial wall changes are associated with some of these nuria or other evidence of kidney damage to ESRD proposed lipoprotein abnormalities in CKD. In our previous analysis by the National Kidney Foundation (NKF) in 2002 (21). of hemodialysis patients, aortic PWV was found to be sig- Stages of CKD are defined primarily by GFR standardized nificantly correlated with VLDL-, IDL-, and LDL-choleste- by body surface area (ml/min/1.73 m2) into Stage 1 (90 or rol levels, independent of age, gender, blood pressure, and higher), Stage 2 (60–89), Stage 3 (30–5), Stage 4 (15–29), dialysis duration (9). Therefore, the sum of cholesterol of and Stage 5 (<15 or dialysis). This new staging system can these non-HDL lipoproteins, namely non-HDL-cholesterol, be applied to a wide range of renal damage caused by any serves as an integrated marker of atherogenic lipoproteins kind of underlying renal disease such as chronic glomerulo- (38). Non-HDL-cholesterol is also positively correlated with nephritis, hypertensive nephrosclerosis and diabetic nephro- CA-IMT in predialysis (6) and maintenance hemodialysis pathy. NKF has proposed the NKF K/DOQI guidelines for patients (5). Increased anti-oxidized LDL antibody titer is in- managing dyslipidemias (22), hypertension (23), and other versely correlated with IMT in hemodialysis patients (39), as complications (24) in CKD patients. Following these activi- well as in the general population (40). Thus, the direction of ties by nephrologists, the American Heart Association correlation between plasma lipids and arterial wall changes (AHA) has published the scientific statement that CKD is a in renal failure patients is the same as that of the general significant risk factor of CVD (25). Clearly, CVD in CKD population. has gained the attention of not only nephrologists but also CVD events in hemodialysis patients are also associated cardiologists and physicians in other fields of medicine. with plasma lipids and lipoprotein parameters. Koch et al (41) reported that a history of myocardial infarction is asso- Dyslipidemas in Patients with CKD ciated with higher levels of total cholesterol, LDL-cholesterol, apolipoprotein B, and low molecular weight isoforms of Patients with advanced stages of CKD often have hyper- apolipoprotein (a) compared to those without myocardial in- triglyceridemia and a lowered high-density lipoprotein farction. According to a report of the Japanese Society for (HDL) cholesterol level. Low-density lipoprotein (LDL) Dialysis Therapy (42), the risk of new myocardial infarction cholesterol is usually within the normal range (26). Elevated in one year is higher in those with higher plasma cholesterol serum triglycerides (TG) reflect the accumulation of TG-rich levels regardless of the presence of diabetes mellitus. These lipoproteins such as very-low-density lipoprotein (VLDL) data indicate that the atherogenic lipoprotein changes known and intermediate-density lipoprotein (IDL). The mean level for the general population also increase the risk of CVD of IDL-cholesterol is 2–3 times higher in non-diabetic events in the hemodialysis population. hemodialysis patients than the healthy subjects (27), and the The relationship between plasma lipids and mortality risk level is further elevated in hemodialysis patients with diabe- in observational cohort studies among CKD patients on di- tes mellitus (28). The increased levels of TG-rich lipopro- alysis is confusing. Previous studies in hemodialysis patients teins are explained by catabolic defects caused by suppressed (43) have shown that those with a higher plasma total choles- activity of hepatic triglyceride lipase (HTGL, HL). Post- terol had a lower risk of overall mortality. This was true for heparin plasma lipoprotein lipase (LPL) levels are reported deaths from cardiovascular diseases (43). Iseki et al (44) to be normal (29, 30) or decreased (31), but the decrease in confirmed the inverse correlation between cholesterol and the apolipoprotein C-II/C-III ratio (32) may contribute to the mortality risk in Japanese hemodialysis patients, but they impaired co-activator function for LPL, making uremic carefully found that an adverse impact of hypercholesterol- VLDL resistant to LPL. LDL size is smaller in diabetic emia was present in a subset of hemodialysis patients having nephropathy (33), but the LDL size returns to normal in pa- serum albumin of 4.5 g/dl or higher. A recent study by Liu tients on maintenance hemodialysis (34), presumably be- et al (45) showed that mortality risk was inversely related to cause the reduced HL activity in dialysis patients fails to plasma cholesterol in the total cohort of their hemodialysis convert large LDL into small dense LDL. patients, as previously shown in other studies. When the sub- Patients with stage 5 CKD on hemodialysis or peritoneal jects were divided into two subgroups based on the presence dialysis have markedly lowered HDL-cholesterol (35), par- and absence of inflammation/malnutrition status, the associa- ticularly cholesterol of the HDL2 subfraction. An in vivo ki- tion between mortality risk and cholesterol remained signifi- netics study (36) of apolipoprotein A-I, the major protein of cant and negative in the subgroup with inflammation/mal- HDL, revealed that the apolipoprotein A-I catabolic rate is nutrition. However, the relationship between cholesterol and increased in hemodialysis patients. Hypertriglyceridemia and mortality risk was significant and positive in those without

180 Internal Medicine Vol. 44, No. 3 (March 2005) CKD as a Metabolic Syndrome signs of inflammation/malnutrition. The risk of cardiovascu- hemodialysis-associated hypotension was shown to be an in- lar death was surprisingly low in hemodialysis patients with dependent predictor of 2-year mortality in hemodialysis pa- low plasma cholesterol levels in the subgroup without in- tients. It is conceivable that hypertension is bad for athero- flammation/malnutrition. sclerosis and heart failure, but once cardiac function is These studies indicate that dyslipidemia is bad for the impaired, low blood pressure is a sign of poor outcome. morphologic and functional properties of large arteries, and Hyperhomocysteinemia is associated with atherosclerotic increases the risk of CVD events in dialysis patients. The ad- arterial wall changes (13) and an increased risk of CVD verse effect of dyslipidemia on mortality is also significant in events (58), whereas it is associated with a reduced risk for hemodialysis patients without inflammation/malnutrition. mortality in hemodialysis patients (59), presenting another However, the relationship between plasma cholesterol and example of the risk factor paradox. This can also be ex- mortality risk is strongly modified by the presence of inflam- plained by the close interaction between malnutrition and a mation/malnutrition status, presumably through interaction lowered homocysteine concentration (59). between inflammation/malnutrition and plasma lipids (re- C-reactive protein (CRP) is positively associated with duced lipid levels in ill conditions). CA-IMT (6). CVD mortality is predicted by increased CRP (60) and elevated interleukin-6 (61), one of the pro-inflam- Underweight Rather Than Overweight matory cytokines. There is an inverse correlation between as a Risk Factor of Death creatinine clearance and the plasma levels of CRP and interleukin-6 (62). Since at least some pro-inflammatory cyto- Although racial difference is known for the BMI-survival kines are excreted through the kidneys, CKD may directly relationship among dialysis patients (46, 47), underweight increase plasma cytokines and induce inflammation. Also, has been recognized as an important predictor of poor sur- the genotype of interleukin-10, an anti-inflammatory cyto- vival in hemodialysis patients. This is in sharp contrast to the kine, is a predictor of cardiovascular events; The -1082A* situation in the general population where overweight or obe- allele of interleukin-10 gene, which is associated with a low sity is an established risk factor of CVD. In hemodialysis pa- production of interleukin-10 and elevated inflammation tients, a higher BMI is associated with a lower risk of death markers such as CRP, was predictive for a higher cardiovas- from all causes (43, 48, 49), CVD (43) and other causes (43). cular morbidity compared to the –1082G* genotype (63). This is true in a wide range of BMI in a recent cohort study Insulin resistance develops in uremic patients as evi- (47) including more than 418,000 patients starting hemo- denced by decreased glucose disposal in response to insulin dialysis. Because high BMI remained a significant and inde- infusion during glucose clamp test (64). The insulin resis- pendent predictor of better survival even after adjustment for tance index derived from homeostasis model assessment other nutritional parameters (50), the survival advantage as- (HOMA-IR) correlates well with the result of glucose clamp sociated with high BMI suggests some undefined mecha- test in patients with and without renal failure (65). High nisms other than better nutrition. HOMA-IR (insulin resistance) was an independent predictor In addition to dialysis patients, high BMI is associated of death from CVD in non-diabetic hemodialysis patients with better survival in elderly individuals (51–54). Also, in (66). In diabetic patients starting hemodialysis, a high level patients with congestive heart failure, better survival was of glycohemoglobin (HbA1c) is a predictor of poor survival predicted by high BMI and high cholesterol (55). Based on (67). these observational studies, it may be that increased body fat Oxidative stress and lipoprotein oxidation are believed to and/or muscle mass have protective effects on survival when exert important roles in atherosclerosis and CVD. In dialysis the subjects are ill. Further data on the relative importance of patients, the lag phase during in vitro oxidation of plasma body fat and lean mass on outcome is necessary. LDL is reported to be shorter than normal (68), suggesting that the oxidizability of uremic LDL is increased. A high Other Risk Factors titer of serum anti-oxidized LDL antibody (69) may be another indirect support for elevated oxidized LDL levels in Other risk factors for CVD include blood pressure, homo- these patients. Direct measurement of plasma oxidized LDL cysteine, inflammation markers, pro-inflammatory cytokines, is needed to conclude whether or not oxidized LDL is in- insulin resistance, glycemic control in diabetics, adiponectin, creased in CKD. An increased serum titer of anti-oxidized oxidized LDL, and other CKD-related risk factors. LDL antibody inversely correlated with arterial wall thick- Blood pressure has a positive correlation with arterial wall ness (IMT) among hemodialysis patients (39), as well as in thickness and stiffness in hemodialysis and predialysis pa- the general population (40). Also, an increased serum anti- tients with renal failure. However, blood pressure-mortality oxidized LDL antibody is an independent predictor of the re- curves show a U-shaped relationship in dialysis patients (56). duced risk of CVD mortality (70). These studies indirectly Increased mortality risk at low blood pressure may indicate indicate that oxidized LDL is involved in atherosclerosis and pre-existence of impaired cardiac function. In fact, among CVD of CKD patients. patients with congestive heart failure, high blood pressure is There are CKD-related risk factors for mortality, such as a predictor of better survival (55). In a recent study (57), underlying renal disease, renal anemia (71), delivered dose

Internal Medicine Vol. 44, No. 3 (March 2005) 181 SHOJI and NISHIZAWA of dialysis (Kt/V) (72), increased serum phosphate (73), high CVD event occurrence, and others may increase the risk of and low levels of parathyroid hormone (PTH) (74, 75), and fatality following the event. Probably, some risk factors are presumably vitamin D deficiency (76, 77). The repeat dialy- acting both ways. For example, diabetes mellitus is a predic- sis procedure itself may have some impact on inflammation tor of CVD event occurrence (82), and also a predictor of and outcome. Arterial calcification is also a predictor of poor survival after ischemic heart attack and congestive heart CVD mortality in hemodialysis patients (78). These CKD- failure (82). To reduce the risk of death from CVD, we related risk factors, combined with the deterioration of the should aim at the prevention of CVD events, and also the re- common risk factors, are presumably responsible for the ele- duction of fatality risk. vated risk of death in CKD patients. Lipid reduction without worsening nutritional state will decrease the risk of CVD event occurrence. In a primary pre- Understanding of Reverse Epidemiology vention trial with pravastatin in the general population (WOSCOPS) (83), the treatment reduced the occurrence of Theoretically, mortality risk is the product of the risk of myocardial infarction by 31%, and the death due to myocar- event occurrence and the risk of fatality (79). Some patients dial infarction by 28%, suggesting that fatality risk was not who have had a heart attack may die due to the event, but changed by this treatment. High cholesterol level was associ- others may survive despite the dangerous event. Therefore, ated with increased risk of CVD death in dialysis patients some risk factors for mortality may increase the risk of event without malnutrition (45). Malnutrition presumably is a key occurrence, whereas others may raise the risk of fatality. As factor for increased fatality and low cholesterol. If so, it discussed above, reverse epidemiology is known for BMI in would be a logical conclusion that dyslipidemia and other dialysis patients, elderly people, and patients with congestive risk factors for event occurrence should be controlled in heart failure. Based on these findings, increased BMI may be CKD patients as in the general population, but that nutri- protective when the patients are ill. In other words, low BMI tional condition and body weight should be kept or rather in- or poor nutritional status could fall into the latter category of creased in this unique patient group presenting “metabolic risk factors influencing the fatality risk after having a serious syndrome with malnutrition”. event, although direct evidence is needed. Although the The NKF K/DOQI has published the Clinical Practice mechanism for the protective effect of increased BMI is un- Guidelines for Managing Dyslipidemias in Chronic Kidney known at present, it may be a low likelihood of energy de- Disease in 2003 (22). Based on the National Cholesterol pletion in obese patients. Following an event, they could Education Program Expert Panel on Detection, Evaluation, survive for a certain period of time that is needed to recover and Treatment of High Blood Cholesterol in Adults, Adult from the event, without food intake or instead of increased Panel III (ATP III) (84) and the fact that CKD patients are at energy requirement. Otherwise, muscle and/or other protein the highest risk for CVD, the K/DOQI guidelines recom- storage may be used for gluconeogenesis for survival. mend the target LDL cholesterol level <100 mg/dl (Table 1). Another possibility is that adipocyte function is altered in ill In patients with increased fasting triglycerides= >200 mg/dl, conditions. We recently found that the negative effects of non-HDL cholesterol <130 mg/dl is another target for pre- male gender and increased body fat mass on adiponectin, an vention of CVD. Also, very high fasting triglycerides= >500 anti-atherogenic adipocytokine (80), were insignificant in mg/dl should be reduced to avoid pancreatitis. To achieve hemodialysis patients (81). This suggests that the adverse these targets, the guidelines recommend therapeutic lifestyle impact of fat mass is severely attenuated and the protective changes (TLC) and drug therapies using a statin, bile acid effect of fat mass becomes dominant in this condition. sequestrant, fibrate, or niacin. The reverse epidemiology for plasma cholesterol may be Although a fibrate is an appropriate choice to normalize explained by the interaction between malnutrition and triglyceride-rich lipoprotein metabolism (85), most of the plasma lipids at the level of fatality risk. As reviewed above, drugs in this class are not recommended for use in patients dyslipidemia is associated with advanced arterial wall with renal failure, because of the renal excretion of these changes and an increased risk of CVD event in dialysis pa- fibrates. Drug accumulation in plasma would increase the tients. Adverse effect of dyslipidemia on mortality is also risk of rhabdomyolysis. However, only a few fibrate drugs significant in dialysis patients without inflammation/malnu- may be used safely in patients with CKD. Clinofibrate (32) trition. However, the relationship between plasma choles- is excreted by the liver in experimental animals and human terol and mortality risk is reversed in the presence of subjects, and was well tolerated by renal failure patients inflammation/malnutrition. We speculate that dyslipidemia treated by peritoneal- or hemodialysis. To date, no outcome itself increases the risk of CVD event occurrence, whereas study with this fibric acid derivative has been reported for malnutrition raises the risk of fatality. CKD patients or other patient groups. Recently, Tonelli et al (86) reported the subanalysis of the Veterans’ Affaires High- Lipid Reduction to Prevent CVD Events Density Lipoprotein Intervention Trial (VA-HIT) study, a secondary intervention trial with gemfibrozil, that originally CKD patients have multiple risk factors for CVD and excluded subjects with increased serum creatinine (>2.0 malnutrition. Some risk factors may increase the risk of mg/dl). Among the 2,531 original male subjects with

182 Internal Medicine Vol. 44, No. 3 (March 2005) CKD as a Metabolic Syndrome

Table 1. The Management of Dyslipidemias in Adults with Chronic Kidney Disease Proposed by the NKF K/DOQI Clinical Practice Guidelines (2003)

Dyslipidemia Goal Initiate Increase Alternative

TG >=500 mg/dl TG <500 mg/dl TLC TLC+Fibrate or Niacin Fibrate or Niacin LDL100–129 mg/dl LDL <100 mg/dl TLC TLC+low dose Statin Bile acid seq. or Niacin LDL= >130 mg/dl LDL <100 mg/dl TLC+low dose Statin TLC+max. dose Statin Bile acid seq. or Niacin TG= >200 mg/dl and Non-HDL <130 mg/dl TLC+low dose Statin TLC+max. dose Statin Fibrate or Niacin Non-HDL= >130mg/dl

TG: triglycerides, LDL: low-density lipoprotein cholesterol, TLC: therapeutic lifestyle changes.

established coronary artery disease having an HDL cholesterol level of 40 mg/dl or less, an LDL cholesterol level of 140 mg/dl or less, and a triglyceride level of 300 mg/dl or lower, 1,046 men had decreased creatinine clearance of 75 ml/min or less by the Cockcroft-Gault equation. Of the subjects, 638, 406, and 2 had creatinine clearance of 60–75 ml/ min, 30–59.9 ml/min, and <30 ml/min, respectively. During the median follow-up period of 5.3 years, the gemfibrozil recipients had a significantly lower risk of the primary outcome (coronary death or nonfatal myocardial infarction) with a hazards ratio of 0.73 (95% confidence interval 0.56–0.96, p=0.02). Although the overall incidence of adverse effects was similar between the gemfibrozil and placebo groups, the risk of sustained increase of serum creatinine was higher in individuals receiving gemfibrozil (5.9 vs 2.8%, p=0.02). It is unknown whether a fibrate drug can be safe and effective in reducing the risk of CVD in patients with more advanced stages of CKD. In an observational study by Seliger et al Figure 1. Prediction of CVD death by Non-HDL cholesterol in (87), the use of fibrate was not associated with better sur- a cohort of hemodialysis patients. Bar graphs indicate relative vival in patients starting dialysis. hazards of CVD mortality compared with the lowest tertile of non-HDL cholesterol. Serum lipid levels were measured in cas- Statins can be safely used in patients with CKD when ual blood samples taken before a dialysis session in 525 patients monitored carefully. All statins available today are excreted on maintenance hemodialysis. through bile. Effective and safe use in Japanese dialysis patients has been reported for pravastatin (88), simvastatin (89), fluvastatin (90), and atorvastatin (91). These statins reduce plasma LDL cholesterol by approximately 25–40%. standard fasting blood is quite difficult to obtain in CKD pa- According to Seliger et al (87), the use of statin was signifi- tients particularly those on hemodialysis in the afternoon or cantly associated with better survival in patients starting di- evening sessions. Because total and HDL cholesterol levels alysis, although this analysis was not controlled for plasma do not change following oral fat load, non-HDL cholesterol cholesterol level. Those on statin therapy were more likely to is not affected by eating. Because non-HDL cholesterol is have a high cholesterol level, a predictor of better survival. the sum of cholesterol of LDL, triglyceride-rich lipoproteins The 4D trial (Die Deutsche Diabetes Dialyse Studie) (92, 93) and remnant particles, it serves as an integrated marker of is a randomized, placebo-controlled trial with atorvastatin in atherogenic lipoproteins. We (38) showed that non-HDL approximately 1,200 dialysis patients with type 2 diabetes cholesterol by casual blood sampling was an independent mellitus. The final results are to be presented at the Ameri- predictor of CVD death in an observational cohort of can Society of Nephrology meeting in October, 2004. There hemodialysis patients (Fig. 1). Therefore, we propose that is another plan to conduct a randomized controlled interven- non-HDL cholesterol of <130 mg/dl in casual blood sample tion trial with rosuvastatin (the AURORA study) that will in- can be used as the target lipid level in hemodialysis patients clude close to 3,000 male and female patients on hemodialy- (stage 5 CKD) regardless of the fasting plasma triglyceride sis (94). level. With a statin that reduces non-HDL cholesterol by In our opinion, casual blood sampling may be useful 40%, we can achieve the target non-HDL cholesterol of enough to estimate the CVD risk, although the K/DOQI <130 mg/dl in patients with a pretreatment non-HDL choles- guidelines call for measurements after an overnight fast. The terol of <216 mg/dl. Therefore, we have sufficient tools to

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Figure 2. Distribution of Non-HDL cholesterol levels in hemodialysis patients. Serum lipid levels were measured in casual blood samples taken before a dialysis session in 525 patients on maintenance hemodialysis.

Figure 3. Chronic kidney disease (CKD) as a metabolic syndrome with malnutrition. CKD is a metabolic syndrome with malnutrition. To reduce the unacceptably high risk of CVD mortality in CKD, we should lower the incidence of CVD events, and also decrease the risk of fatality after an event. In this unique disease condition, nutritional improvement and maintenance of body mass appear to be of particular importance. Lipid- lowering medication with careful monitoring is justified when initiated with appropriate lifestyle changes. Treatment for the CKD-related risk factors may have additional benefit.

184 Internal Medicine Vol. 44, No. 3 (March 2005) CKD as a Metabolic Syndrome control non-HDL cholesterol for 98% of all hemodialysis pa- 4) Kawagishi T, Nishizawa Y, Konishi T, et al. High-resolution B-mode tients based on our patient data (Fig. 2). ultrasonography in evaluation of atherosclerosis in uremia. Kidney Int 48: 820–826, 1995. 5) Shoji T, Kawagishi T, Emoto M, et al. Additive impacts of diabetes and Control of Other Risk Factors renal failure on carotid atherosclerosis. Atherosclerosis 153: 257–258, 2000. The mechanisms for protein-energy malnutrition in CKD 6) Shoji T, Emoto M, Tabata T, et al. Advanced atherosclerosis in are not well understood. However, decreased intake and in- predialysis patients with chronic renal failure. Kidney Int 61: 2187– creased catabolism are both contributory. Decreased intake 2192, 2002. 7) Nakashima A, Yorioka N, Asakimori Y, et al. 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