**6. Treatment**

304 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

higher levels of mortality in HP. A more recent study reported on the cross-sectional association with MIC and the effects on cholesterol in HP (Bowden & Wilson, 2010). When comparing cholesterol levels, those classified as having hypoalbuminemia had a reverse epidemiological effect with LDL particle number. In the same study when HP were classified as having high inflammation, based on CRP, LDL, VLDL, and LDL particle number reported counter-intuitive findings. But, in patients classified as having both hypoalbuminemia and high inflammation, all lipid variables, with the exception of HDL, reported a reverse epidemiological effect. This suggests that though inflammation may play a more prominent role with reverse epidemiology, both inflammation and malnutrition can have a pronounced effect on lipids causing low cholesterol levels to be associated with more mortality. Additionally, other study authors have reported inverse associations with cholesterol and all-cause mortality, but also a U-shaped relationship with cholesterol in the presence of malnutrition and inflammation (Liu, et al., 2004). When malnutrition and inflammation were controlled for in the analysis, a strong, graded and positive association existed between high cholesterol levels and mortality further supporting the thought that reverse epidemiological associations with cholesterol in HP is associated with MIC. An additional review paper has suggested that previous studies that have controlled statistically for factors associated with MIC in HP, risk associated with cholesterol was the same as the general population and further speculates that cholesterol may be an additional marker of malnutrition (Chmielewski, et al., 2008). It should be noted that not all studies

Another theory behind why low cholesterol in HP patients can be associated with high mortality has been called survival selection. It is well-established that most chronic kidney disease patients will not survive to kidney failure and End-Stage Renal Disease. Presently, it is suggested that only 10% (Trivedi, et al., 2009) of patients will live long enough to initiate dialysis. Therefore, since so few survive it is thought that only those who have a strong genetic predisposition for survival may be more likely to live but may also have a poorer risk profile. Additionally, simply stated, HP may not live long enough to die of the consequences of traditional CVD risk factors. Though this theory is not very new, it has yet to be confirmed with well controlled studies that take into consideration the age of the patients. Kalantar-Zadeh et al. (2003) also suggests that reverse epidemiology may be normal and that over-nutrition is primarily a 20th and 21st century phenomenon and that our understanding of traditional Framingham risk factors may in fact be new and the exception. Though over-nutrition is a problem in many countries it has been associated with longer living populations in Western nations. As one would expect this idea is highly controversial

Additional study authors (Nanayakkara & Gaillard, 2010) have reported reverse epidemiology in HP concerning lipids could possibly be due oxidative stress. Reactive oxygen species (ROS) production that is not balanced by antioxidant control is associated with oxidative stress. Furthermore, oxidative injury has been reported to alter lipids in both the general population and HP and is involved in CVD acceleration (Diepeveen, et al., 2008). Though HP are normally supplemented with B vitamins and folic acid, many still have deficiencies in antioxidants with many patients shifting to a more pro-oxidative stress profile. High oxidized LDL is a well established comorbidity in both HP and CKD patients and is associated with small, dense LDL particles. Moreover, modification of LDL through oxidation is thought to be the first step in the development of CVD and specifically atherosclerosis. Oxidative stress occurs routinely in HP, especially in patients with a long-

agree with these findings.

among scientist and nephrologists.

Reverse epidemiology has been associated with cholesterol but also body mass index (BMI), systolic and diastolic blood pressure, homocysteine, and creatinine levels (Balakrishnan & Rao, 2007) in HP suggesting the need for novel treatments. Since the counter-intuitive findings are prevalent in HP additional approaches are necessary to help identify novel treatments and to discover if new therapies are warranted. Though counter-intuitive findings are present in HP as well as advanced age, congestive heart failure, malignancies, and AIDS little data exists to support changes in non-traditional risk factors as a means to control CVD. To help increase albumin levels it has been proposed to increase protein content in the diet. But levels of protein augmentation with HP patients on chronic hemodialysis has not been sufficiently elucidated simply because dietary protein can be a significant source of uremic toxins and increase phosphate levels which can have deleterious effects on the health of HP patients (Stolic, 2010). It should be noted that hypercaloric consumption may take several years and even decades for serious health effects to occur, yet hypocaloric consumption, measured by albumin levels in HP patients, normally causes a more rapid deterioration in health. Combined with high inflammation levels, a decreased appetite and hypocaloric levels may cause a significant decrease in cholesterol but accelerated risk for mortality (Kalantar-Zadeh, et al., 2001). This short-term effect of

Malnutrition, Inflammation and Reverse Epidemiology in Hemodialysis Patients 307

~ 2 years

~ 3 years

~ 3 years

~ 10 years

Table 1. Studies reporting a reverse epidemiology affect regarding cholesterol and HP (2002-

Balakrishnan, V. S., & Rao, M. (2007). Genetics and reverse epidemiology among patients on

Barreto, D. V., Barreto, F. C., Liabeuf, S., Temmar, M., Lemke, H. D., Tribouilloy, C., et al.

Bergstrom, J. (1996). Anorexia in dialysis patients. *Seminars in Nephrology, 16*(3), 222-229. Bolasco, P., Caria, S., Cupisti, A., Secci, R., & Saverio Dioguardi, F. (2011). A novel amino

(2009). Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease. *Kidney* 

acids oral supplementation in hemodialysis patients: a pilot study. *Renal Failure,* 

chronic hemodialysis. *Seminars in Dialysis, 20*(6), 570-576.

*International, 77*(6), 550-556.

*33*(1), 1-5.

2009 136 HP Prospective

2007 15,859 HP Prospective

Liu, et al 2004 823 HP Prospective

Iseki, et al 2002 1167 HP Prospective

Tsirpanlis, et al

Kilpatrick, et al

Present).

**8. References** 

adjusted relative risk equivalent to patients with high cholesterol and low inflammation in CVD death and all-cause mortality

Low cholesterol levels together with selected inflammatory markers predict CVD and all-cause mortality and morbidity

Inverse associations between hyperlipidemia and survival, however, black HP with high LDL show almost two-fold increase in cardiovascular

Inverse association of cholesterol levels with allcause mortality and a Ushaped relationship with CVD mortality in the

inflammation/malnutrition

Hypercholesterolemia was an independent predictor on survival but was only evident in a sub-group of patients whose serum albumin was more than 4.5

death risk

presence of

g/dl

malnutrition enhanced by inflammation may overcome the long-term impact of traditional risk factors for CVD and may cause the HP patients to not live long enough to develop elevated levels of cholesterol causing them die sooner than is expected. Also, evidence suggests that lipid levels become more elevated and more strongly associated with CVD the longer the HP receives dialysis and suggests that even though counter-intuitive cholesterol findings are evident in early dialysis traditional therapies such as statins, fibrates and niacin are necessary even with cholesterol levels are low (Chavalitdhamrong, et al., 2007). Therefore, treatment for HP patients with MIC needs to focus short-term on inflammation and malnutrition through dietary counseling and medication. Once MIC is controlled, a more long-term therapy may need to look at controlling lipids associated with CVD risk.
