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Although traditional risk factors for cardiovascular disease are common in dialysis patients, they alone cannot explain the unacceptably high prevalence of vascular disease in this patient group. Much recent interest has therefore focused on the role of various nontraditional cardiovascular risk factors, such as inflammation, wasting, obesity, vascular calcification, and oxidative stress. In addition, genetic factors such as single nucleotide polymorphisms (SNPs) may significantly influence the immune response, the levels of inflammatory markers and body composition, as well as the prevalence of vascular calcification in this patient group. While genetic variations in the tumor necrosis factor (TNF)-alpha-308 and interleukin (IL)-10 -1082 SNPs seem to be consistently associated with adverse clinical outcome in end-stage renal disease (ESRD) patients, the results regarding genetic variations in the IL-6 gene have been conflicting. To elucidate the respective role of DNA polymorphisms in the IL-6 and C-reactive protein (CRP) genes, as well as genes that encode vascular calcification inhibitors (such as fetuin-A, matrix Gla protein, and osteoprotegerin), sufficiently powered studies are needed in which both the protein product and the specific phenotype are determined. In addition, polymorphisms in genes related to body composition may be excellent candidates for analysis in the ESRD population, since nutritional parameters are strongly associated with adverse events in these patients. It seems conceivable that in the future, prognostic or predictive multigene DNA assays (which allow a simultaneous and rapid assessment of multiple genetic variants) will provide nephrologists with a more precise approach for the identification of "high-risk" ESRD patients and the development of accurate individualized treatment strategies.
Semin Dial
PMID:Gene polymorphism association studies in dialysis: the nutrition-inflammation axis. 1607 56

Several recent clinical trials using single modalities to correct the conventional cardiovascular risk factors in patients with chronic kidney disease (CKD) or to improve dialysis dose and techniques in maintenance dialysis patients have failed despite the high rate of cardiovascular mortality in these individuals. Protein-energy malnutrition and inflammation, two relatively common and concurrent conditions in CKD patients, have been implicated as the main cause of poor short-term survival in this population. The "malnutrition-inflammation-cachexia syndrome" (MICS) appears to be the main cause of worsening atherosclerotic cardiovascular disease in the CKD population. The MICS is associated with low serum cholesterol and homocysteine levels and leads to "cachexia in slow motion." Hence a reverse epidemiology of cardiovascular risk factors is observed in dialysis patients with a paradoxical association of obesity, hypercholesterolemia, and hyperhomocysteinemia with better survival. Correction of MICS can potentially ameliorate the cardiovascular epidemic in CKD patients. Because MICS is multifactorial, its correction will require an integral approach rather than a single intervention. The ongoing obsession with conventional cardiovascular risk factors largely reflecting overnutrition in a population that suffers from the short-term consequences of undernutrition and excessive inflammation may well be fruitless. Clinical trials focusing on the causes and consequences of MICS and its modulation using nutritional interventions may be the key to improving survival in these individuals.
Semin Dial
PMID:Recent advances in understanding the malnutrition-inflammation-cachexia syndrome in chronic kidney disease patients: What is next? 1619 Nov 72

There exists in the general population a complex and mostly positive relationship between adiposity and mortality risk. Because the dialysis population has a high prevalence of excess adiposity, in addition to a strikingly elevated mortality rate, the effects of obesity are of potential clinical importance. In contrast to the general population, the preponderance of data in dialysis, particularly hemodialysis patients, suggest that adiposity has a neutral or even protective association with mortality. Although methodological concerns exist with regards to confounding and survival bias, among others, the major limitation of this body of literature is its inability to establish causality. Thus, although obese dialysis patients, with certain exceptions, appear to live longer, there is no evidence to suggest that intentional weight loss adversely affects patient outcomes. In light of these limitations and the substantial body of literature implicating obesity as a pathophysiological state, it is currently premature to advocate for excess adiposity as being beneficial or intentional weight loss as dangerous. Decisions regarding optimal weight should be made by clinicians on an individual basis and with close supervision and follow-up. Efforts should be made to preserve lean mass during weight loss regimens by encouraging exercise and recommending sufficient protein consumption. Future research efforts in this area should focus on interventional trials designed to manipulate weight and measure outcomes, identifying potentially beneficial secretory products of adipose tissue, and documenting obesity's effects on quality of life and resource utilization in the dialysis setting.
Semin Dial
PMID:Adiposity in dialysis: good or bad? 1655 Dec 91

Uremic wasting is strongly associated with increased risk of death and hospitalization events in patients with advanced chronic kidney disease (CKD). Recent evidence indicates that patients with advanced chronic kidney disease are prone to uremic wasting due to several factors, which include the dialysis procedure and certain comorbid conditions, especially chronic inflammation and insulin resistance or deficiency. While the catabolic effects of dialysis can be readily avoided with intradialytic nutritional supplementation, there are no established alternative strategies to avoid the catabolic consequences of comorbid conditions other than treatment of their primary etiology. To this end, there is no indication that simply increasing dietary protein and energy intake above the required levels based on level of kidney disease is beneficial in patients with advanced chronic kidney disease. However, aside from the potential adverse effects such as uremic toxin production, dietary protein and energy intake in excess of actual needs might be beneficial in maintenance dialysis patients as it may lead to weight gain over time. Clearly, the role of obesity in advanced uremia needs to be examined in detail prior to making any clinically applicable recommendations, both in terms of ''low'' and ''high'' dietary protein and energy intake.
Semin Dial
PMID:Protein and energy intake in advanced chronic kidney disease: how much is too much? 1724 11

Peritoneal dialysis (PD) patients present an extremely high mortality rate, but the mechanisms mediating the increased risk of mortality observed in this group of patients are still largely unknown, which limits the perspective of effective therapeutic strategies. The leading hypothesis that tries to explain this high mortality risk is that PD patients are exposed to a number of traditional risk factors for cardiovascular disease (CVD) already at the onset of their chronic kidney disease (CKD), since many of these risk factors are common to both CVD and CKD. Of particular importance, chronic inflammation recently emerged as an important novel risk factor related to multiple complications of CKD. There are many stimuli of the inflammatory response in CKD patients, such as fluid overload, decreased cytokine clearance, presence of uremia-modified proteins, presence of chronic infections, metabolic disturbances (including hyperglycemia), obesity. Many of these factors are related to PD. Latin America has made some progress in economic issues; however, a large portion of the population is still living in poverty, in poor sanitary conditions, and with many health-related issues, such as an increasing elderly population, low birth weights, and increasingly high energy intake in the adult population, which, in combination with changes in lifestyle, has provoked an increase in the prevalence of obesity, diabetes, and CVD. Therefore, in Latin America, there seems to be a peculiar situation combining high prevalence of low education level, poor sanitary conditions, and poverty with increases in obesity, diabetes, and sedentary lifestyle. Since inflammation and mortality risk are intimately related to both sides of those health issues, in this review we aim to analyze the peculiarities of inflammation and mortality risk in the Latin-American PD population.
Perit Dial Int
PMID:Inflammation in peritoneal dialysis: a Latin-American perspective. 1746 89

The prevalence of obesity in peritoneal dialysis (PD) populations has risen dramatically since the mid-1980s. This epidemic has been driven by the increased prevalence of obesity in the general population, the increased risk of progression of chronic kidney disease to end-stage renal failure (ESRF) in obese subjects, the reduced probability of listing obese dialysis patients for renal transplantation, a paradoxical enhanced survival in at least some obese populations on dialysis as compared with non-obese ESRF patients, and a possible adipogenic effect of excessive peritoneal glucose absorption in PD. Although obesity has consistently been associated with improved outcomes in hemodialysis, conflicting results have been seen in PD. In general, an elevated body mass index (BMI) has been associated with a neutral or deleterious impact on PD outcomes, and the relationship appears to be explained predominantly by fat mass. Risk is also elevated in patients with a low BMI, such that the "optimal BMI" appears to lie between 20 kg/m2 and 25 kg/m2. The mechanisms underpinning the harmful effect of obesity appear to include increased peritonitis rate, proinflammatory effects, and a more rapid decline of residual renal function in obese patients. No proof exists that weight reduction engenders an improvement in outcome in PD patients, but the available studies suggest that cautious weight reduction is advisable. A few studies have demonstrated that clinically important and sustained weight reduction can be successfully achieved through a combination of individual meal plans, regular exercise, and substitution of icodextrin for dextrose in the once-daily long dwell.
Perit Dial Int 2007 Jun
PMID:What is the optimal fat mass in peritoneal dialysis patients? 1755 14

The increasing rates in incidence and prevalence of chronic kidney disease (CKD) are important challenges for health systems around the world, and are even more significant for undeveloped countries. In Mexico the prevalence of CKD seems to be similar to that in highly developed nations, with diabetes as the leading cause of CKD; however, human and economic resources seem to be insufficient for treatment needs. This is reflected in the unacceptably high mortality rates and in noncompliance with established standards and guidelines. Several measures need to be taken to improve this picture, such as more efficient programs for the prevention of obesity, diabetes, and hypertension. Organizing a national registry of patients with CKD is now a pressing need, as is a continuous search for additional funding and budgets to increase the number of qualified nephrologists and specialized nurses and to continue the much-needed research on CKD.
Perit Dial Int
PMID:Chronic kidney disease and dialysis in Mexico. 1760 47

Since the original description of the obesity-survival paradox in 1999, which suggested a survival advantage for overweight and obese patients undergoing hemodialysis, a large body of evidence supporting the paradox has accumulated. The reason for the paradox has yet to be defined. Better nutrition may be a partial explanation, or it may be that in uremic milieu, excessive fat and surplus calories might confer some survival advantage. The "surplus calorie theory" as a potential mechanism for the paradox is of great interest. If proven to be correct, it might explain why peritoneal dialysis patients who receive excessive calories through dialysis do not exhibit the paradox and, secondly and more importantly, therapy could be directed to enhance a greater caloric intake by renal failure patients to engender a better survival outcome. Finally, other clinical settings, for example, congestive heart failure, have their own obesity-survival paradox. Thus, the paradox appears to be a wider phenomenon and might merely be the external expression of a larger principle yet to be uncovered.
Semin Dial
PMID:Obesity-survival paradox-still a controversy? 1799 Nov 92

In contrast to the associations of high body mass index (BMI) with increased mortality in the general population, high BMI is associated with better survival in dialysis patients. Nonetheless, high BMI/adiposity in chronic kidney disease (CKD)/dialysis patients is associated with insulin resistance, inflammation, dyslipidemia, atherosclerosis and coronary calcification as described in the general population. These apparently perplexing associations might be explained if (1) adiposity has dual competing effects on survival; a protective nutritional effect and a deleterious metabolic effect resulting in insulin resistance, dyslipidemia, hypertension and inflammation and (2) the level of kidney function modifies the relative importance of these effects. In this paradigm, the deleterious metabolic effects of obesity outweigh its protective nutritional effects in the non-CKD population, the deleterious metabolic effects of obesity are neutralized by its protective nutritional effects in the moderate CKD population and the deleterious metabolic effects of obesity are outweighed by its protective nutritional effects in stage V CKD on dialysis. In other words, the over-all effects of obesity on survival vary according to the level of kidney function and there is an interaction of body size and presence or absence of CKD on survival even though the metabolic effects of adiposity are not modified by the level of kidney function. Therefore, we propose that despite an association of adiposity with better survival, there is no reverse epidemiology of the associations traditional and nontraditional cardiovascular risk factors and disease with adiposity in dialysis patients.
Semin Dial
PMID:A story half untold: adiposity, adipokines and outcomes in dialysis population. 1799 Nov 93

"Reverse epidemiology" refers to paradoxical and counterintuitive epidemiologic associations between survival outcomes and traditional cardiovascular risk factors such as obesity, high blood pressure, and high cholesterol. Reverse epidemiology has been well described in end stage renal disease, but also has been observed in chronic disease states, including chronic heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease, and Acquired Immune Deficiency Syndrome, and in elderly populations. This review will highlight the recent medical literature on reverse epidemiology in these populations. Common pathophysiologic underpinnings in these chronic disease states may help explain the reversal of risk factors observed in these diverse populations. Furthermore, guidelines for the general population for optimal goals of weight, cholesterol levels, and blood pressure may not apply to special populations, including patients with chronic diseases or elderly persons.
Semin Dial
PMID:Reverse epidemiology beyond dialysis patients: chronic heart failure, geriatrics, rheumatoid arthritis, COPD, and AIDS. 1799 Dec 3


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