An Alternative Hypothesis

The reduced survival in MHD patients with a low BMI has recently been explained by a novel hypothesis [7]. Briefly, both in healthy and MHD subjects, visceral organ mass (i.e. high metabolic rate compartment, HMRC) relative to whole body mass (HMRC%BW) is inversely related to weight and urea distribution volume (V). V, as determined by urea kinetic modeling, is closely related to MM (fig. 1), whereas fat mass contributes only marginally. Viscera are the most likely source of uremic toxins, and their mass and metabolic activity may be related to uremic toxin generation. According to this hypothesis the concentration of uremic toxins in V is higher in subjects with a low V (and thus low MM and low BMI), resulting in an under-dialysis in low BMI patients when dosed by Kt/V. Dialysis dose is currently pre-

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Uremic toxins from viscera

Fig. 1. Muscle mass (estimated by whole body MRI) is positively correlated with urea distribution volume derived from urea kinetic modeling (for details of the methods applied see [17].

Fig. 2. Uremic toxin generation in the visceral organs and their mass relative to body weight is highest in small people. Consequently, the rate of uremic toxin generation per unit of weight (or BMI) is highest in patients with low body weight (or BMI). Body water, the volume of which is mainly determined by the muscle mass, serves as the dilution compartment of uremic toxins. In addition, uremic toxins (lipophilic » hydrophilic) are taken up by adipose and muscle tissues and subsequently metabolized and stored. Thus, the larger the ratio of fat and muscle mass to visceral mass, the lower the concentration of uremic toxins.

scribed based on V with the basic assumption that body composition variability is not relevant and the only differences between individuals having different values for V is quantitative and not qualitative. This hypothesis is difficult to test, since visceral mass cannot easily be assessed in a large cohort of MHD patients. Currently with novel high-resolution MRI data becoming available, it will be possible to develop models for the estimation of visceral mass.

In addition to the dilution of uremic toxins in a larger volume in patients with larger body mass (and thus larger V), uremic toxins may be metabolized, detoxificated, and stored in adipose tissues and skeletal muscle. This may be particularly relevant for lipophilic uremic toxins such as p-cresol and pentosidine, which can penetrate the lipid bilayer of cell membranes easily but are poorly removed by hemodialysis [18]. It has recently been shown that the concentration of pentosidine, a lipophilic uremic toxin, is indeed higher in MHD patients with a lower BMI [19]. This concept is summarized in figure 2.

I n order to test this hypothesis, detailed studies on uremic toxin kinetics (both hydrophilic and lipophilic)

in relation to body composition and dialysis vintage are needed. In these studies, the mass of specific organs (especially liver and gut), subcutaneous and visceral fat and MM have to be measured accurately (e.g. by whole-body MRI). Results from such studies may provide valuable information for tailoring the dialysis dose to the individual patients' needs.

References

1 Degoulet P, Legrain M, Reach I, Aime F, Devries C, Rojas P, Jacobs C: Mortality risk factors in patients treated by chronic hemo-dialysis. Report of the Diaphane collaborative study. Nephron 1982;31:103-110.

2 Leavey SF, Strawderman RL, Jones CA, Port FK, Held PJ: Simple nutritional indicators as independent predictors of mortality in he-modialysis patients. Am J Kidney Dis 1998; 31:997-1006.

3 Port FK, Ashby VB, Dhingra RK, Roys EC, Wolfe RA: Dialysis dose and body mass index are strongly associated with survival in hemodialysis patients. J Am Soc Nephrol 2002; 13: 1061-1066.

4 Leavey SF, McCullough K, Hecking E, Good-kin D, Port FK, Young EW: Body mass index and mortality in 'healthier' as compared with 'sicker' haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2001;16:2386-2394.

5 Kaizu Y, Tsunega Y, Yoneyama T, Sakao T, Hibi I, Miyaji K, Kumagai H: Overweight as another nutritional risk factor for the long-term survival of non-diabetic hemo-dialysis patients. Clin Nephrol 1998; 50: 44-50.

6 Kalantar-Zadeh K, Kuwae N, Wu DY, Shan-touf RS, Fouque D, Anker SD, Block G, Kopple JD: Associations of body fat and its changes over time with quality of life and prospective mortality in hemodialysis patients. Am J Clin Nutr 2006;83:202-210.

7 Axelsson J, Rashid Qureshi A, Suliman ME, Honda H, Pecoits-Filho R, Heimburger O, Lindholm B, Cederholm T, Stenvinkel P: Truncal fat mass as a contributor to inflammation in end-stage renal disease. Am J Clin Nutr 2004;80:1222-1229.

8 Yamauchi T, Kuno T, Takada H, Nagura Y, Kanmatsuse K, Takahashi S: The impact of visceral fat on multiple risk factors and carotid atherosclerosis in chronic haemodialy-sis patients. Nephrol Dial Transplant 2003; 18:1842-1847.

9 Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21: 697-738.

10 Hauner H: Secretory factors from human adipose tissue and their functional role. Proc Nutr Soc 2005;64:163-169.

11 Otero M, Lago R, Lago F, Casanueva FF, Die-guez C, Gomez-Reino JJ, Gualillo O: Leptin, from fat to inflammation: old questions and new insights. FEBS Lett 2005;579:295-301.

12 Beddhu S, Pappas LM, Ramkumar N, Samo-re M: Effects of body size and body composition on survival in hemodialysis patients. J Am Soc Nephrol 2003; 14:2366-2372.

13 Kalantar-Zadeh K, Abbott KC, Salahudeen AK, Kilpatrick RD, Horwich TB: Survival advantages of obesity in dialysis patients. Am J Clin Nutr 2005;81:543-554.

14 Kalantar-Zadeh K, Kilpatrick RD, Kuwae N, Wu DY: Reverse epidemiology: a spurious hypothesis or a hardcore reality? Blood Pu-rif 2005;23:57-63.

15 Salahudeen AK: Is it really good to be fat on dialysis? Nephrol Dial Transplant 2003; 18: 1248-1252.

16 Salahudeen AK: Obesity and survival on dialysis. Am J Kidney Dis 2003;41:925-932.

17 Sarkar SR, Kuhlmann MK, Kotanko P, Zhu F, Heymsfield SB, Wang J, Meisels IS, Gotch FA, Kaysen GA, Levin NW: Metabolic consequences of body size and body composition in hemodialysis patients. Kidney Int 2006;70:1832-1839.

18 Martinez AW, Recht NS, Hostetter TH, Meyer TW: Removal of P-cresol sulfate by hemo-dialysis. J Am Soc Nephrol 2005; 16: 34303436.

19 Slowick-Zylka D, Safranow K, Dziedziejko V, Dutkiewicz G, Ciechanowski K, Chlubek D: The influence of gender, weight, height and BMI on pentosidine concentrations in plasma of hemodialyzed patients. J Nephrol 2006;19:65-69.

Blood Purif 2007;25:31-35 DOI: 10.1159/000096394

Published online: December 14, 2006

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