Sivakumar Sridharan, MBBS, MRCP (UK), PhD, (@sayitmyway) is currently a nephrology fellow at Lister Hospital in Stevenage, UK as part of the North London Nephrology Training Program. Dr. Sridharan received his MBBS from Madras Medical College in Chennai, India and his PhD from the University of Herfordshire, UK. He is interested in understanding the relationship between physical activity and CKD. He is also interested in energy expenditure, dialysis dosing and physical activity in ESRD.

As Obesity as a Survival Factor in ESRD made an early exit from this years NephMadness. Dr. Sridharan submitted his commentary to discuss why this concept deserved the win.

Obesity is one of the major risk factors for cardiovascular disease in the general population. Given the close association between end-stage renal disease (ESRD) and cardiovascular disease, one would expect a similar effect of obesity in ESRD too. Hence, it comes as a surprise that obesity confers a survival advantage to ESRD patients on haemodialysis (HD).

Since the publication of the HEMO Study in 2002, there has been increased scrutiny on survival differences in HD patients observed amongst different genders and in those with different body sizes. A number of retrospective and prospective studies have shown that high body mass index (BMI) is associated with lower short– and long-term mortality in HD patients. This interaction, termed ‘reverse epidemiology’, was observed even in patients with very high BMI (≥ 37) even after adjustment for serum creatinine and estimated lean body mass.

What could be the reason behind such an anomaly that challenges our understanding of basic physiology? The answer to this remains firmly elusive. A common notion is that lower BMI is a marker of poor nutrition which may contribute to excess mortality. However, this does not explain the increased mortality observed in those with normal BMI (and thereby, inferring adequate nutrition) compared to obese individuals. The answer to this, most probably, is hidden amongst the concoction of uremic toxins and in our own practice of how we achieve clearance of these toxins.

To tackle this problem of reverse epidemiology, we need to turn to the roots of our physiology. Uremic toxins are a result of metabolic activity and this activity occurs largely in the visceral organs and to a lesser extent, in the muscles. It has been suggested that muscles act as dilutional compartments for these toxins and hence, high BMI patients with relatively high muscle mass may have less exposure to circulating uraemic toxins. The disadvantage of using BMI as a body size measure is that it does not take into consideration the body composition. It has been shown that obese patients have relatively less visceral organ mass as a proportion of body weight compared to normal and low BMI patients. This implies that the uraemic toxin production, expressed as a proportion of body weight, is relatively less in obese individuals.

We then move onto our current practice of delivering dialysis based on total body water, which is a direct function of body weight. Due to this association between weight and total body water (V), relatively higher doses of dialysis are needed in obese individuals to achieve a target Kt/V. On the other hand, smaller patients will need lesser doses. Therein lies the discrepancy. Smaller patients will, if anything, need higher dialysis doses due to higher metabolic waste exposure relative to body weight. This practice of sub-optimal dialysis dosing based on body weight may contribute to excess mortality in smaller individuals. A number of alternate parameters – body surface area, metabolic rate, liver size and high metabolic rate organ mass – have been suggested for scaling dialysis dose. There is a strong argument that body surface area may be a better parameter than V from some observational studies but the usefulness of other parameters are yet to be explored.
So, which of these is the reason for the phenomenon of reverse epidemiology? – Poor nutrition, body composition differences or sub-optimal dialysis dosing in at-risk patients. The answer, perhaps, is all of the above. There is a pressing need for studies to explore the dynamics of various uremic toxins and ways to prescribe dialysis dose based on metabolic needs of the individual patient. Until such time comes, the cause of reverse epidemiology will remain a ‘known unknown’ in the field of nephrology.

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