Our current knowledge about the risk factors that are instrumental in the initiation and propagation of atherosclerotic cardiovascular disease (ASCVD) was originally established by the Framingham Heart Study and later corroborated by numerous other observational studies and clinical trials in the general population.
In a seemingly paradoxical manner, observational studies examining outcomes in patients suffering from CKD have found significantly altered risk-factor patterns such that conventional mortality risk factors have been associated with better survival; this phenomenon was termed “reverse epidemiology” or “risk factor paradox.”
Perhaps the most striking reversal of risk-factor pattern in patients with CKD involves obesity.
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The dark side
Obesity has reached epidemic proportions in the developed world and has been widely accepted as a risk factor for the development of multiple chronic conditions, such as diabetes mellitus, ASCVD, and cancer. In addition, obesity has been linked to a greater risk for the development of decreased glomerular filtration rate and a higher incidence of end-stage renal disease.
Some authorities have suggested that this negative impact of obesity on kidney function is a result of the combined effects of metabolic syndrome/insulin resistance, diabetes mellitus, hypertension, and hemodynamic changes that are induced or worsened by obesity and ultimately lead to a state of glomerular hyperfiltration.
Indeed, characteristic features of metabolic syndrome are associated with obesity in patients with established CKD, suggesting that these deleterious effects are not limited to the general population. It would thus be logical to assume that the impact of obesity on survival in patients with established CKD (including dialysis-dependent and non-dialysis-dependent patients) should be similar to what we have been accustomed to seeing in the general population. How wrong we would be?
Altered risk factor pattern
In a seemingly paradoxical manner, obesity has been associated with better survival in chronic disease states, such as congestive heart failure, chronic obstructive pulmonary disease, and rheumatoid arthritis. Perhaps the most prominent example for such a paradoxical association occurs in patients with stage 5 CKD requiring maintenance hemodialysis treatment.
In this population, higher BMI has been repeatedly associated with better survival (e.g., Am J Clin Nutr. 2006;83:202-210; Am J Kidney Dis. 2005;46:489-500), with the benefit of greater body size extending linearly into the range of morbid obesity (BMI greater than 35 kg/m2). Some studies in patients receiving peritoneal dialysis have described a similar association (e.g., Kidney Int. 2003;64:1838-1844; Perit Dial Int. 2000;20:19-26), but others have not (e.g., Kidney Int. 2004;65:597-605; J Am Soc Nephrol. 2003;14:2894-2901).
The same altered risk-factor pattern has been observed in the much larger group of patients with non-dialysis-dependent CKD (Am J Kidney Dis. 2005;46:863-870; Am J Kidney Dis. 2007;49:581-591).
