Proceedings of the ISPD 2006 — The 11th Congress of the ISPD August 25 – 29, 2006, Hong Kong Peritoneal Dialysis International, Vol. 27 (2007), Supplement 2 0896-8608/07 $3.00 + .00 Copyright © 2007 International Society for Peritoneal Dialysis Printed in Canada. All rights reserved. WHAT IS THE OPTIMAL FAT MASS IN PERITONEAL DIALYSIS PATIENTS? David W. Johnson Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia Perit Dial Int 2007; 27(S2):S250–S254 www.PDIConnect.com KEY WORDS: Body mass index; chronic kidney failure therapy; nutrition status; peritonitis; risk factors; survival rate. Correspondence to: D.W. Johnson, Department of Renal Medicine, Level 2, Ambulatory Renal and Transplant Services Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane Queensland 4102 Australia. david_johnson@health.qld.gov.au S250 T he mean body mass index (BMI) of incident end-stage renal failure (ESRF) patients has risen progressively since the mid-1980s. In Australia and New Zealand, the mean BMI of patients commencing renal replacement therapy increased to 26 kg/m2 in 2004 from 22.1 kg/m2 in 1982 (1). A similar study in the U.S. ESRF population reported an increase in mean BMI to 27.5 kg/m2 in 2002 from 25.7 kg/m2 in 1995 (2). During this 7-year period, the prevalence of total obesity and stage 2 obesity increased by 33% and 63% respectively. Moreover, for all age groups, the BMI slope was approximately twice as high in the incident ESRF population as in the U.S. general population. This alarming increase in the prevalence of obesity in the dialysis population can likely be attributed to several reasons, including the increased prevalence of obesity in the general population (3,4), the accentuated risk of progression of chronic kidney disease to ESRF in obese subjects (4–9), the reduced probability of listing obese dialysis patients for renal transplantation (10), and a paradoxical enhancement of survival in at least some obese populations on dialysis as compared with nonobese ESRF patients (10–17). Moreover, obesity has been suggested to possibly be more prevalent in peritoneal dialysis (PD) patients than in hemodialysis (HD) patients because of excessive peritoneal glucose absorption (18), although this suggestion has been refuted by other studies (19–21). The purpose of the present paper is to review the studies examining the relationship between obesity and outcomes in PD patients and to determine whether interventions targeting obesity in PD patients are efficacious and justified. THE IMPACT OF OBESITY ON PD OUTCOME Although obesity is widely recognized to be a risk factor for morbidity and mortality in the general population, a higher BMI has consistently been shown to be Downloaded from http://www.pdiconnect.com/ by guest on September 30, 2014 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. PDI JUNE 2007 – VOL. 27, SUPPL 2 JOHNSON als in a prevalent cohort of 208 PD patients. Similarly, in a randomized controlled trial of two different PD doses in 965 CAPD patients (ADEMEX study), Paniagua et al. (29) stratified patient outcomes according to tertiles of three different indices of body size (body surface area, calculated total body water, and BMI). They found no significant differences in survival between these strata, but subjects were followed for only just over 2 years. A retrospective cohort study of 1675 HD and 1662 PD patients enrolled in the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Wave II Study (30) observed that obesity (BMI > 30 kg/m2) was associated with improved survival in HD patients (adjusted HR: 0.89; 95% CI: 0.81 to 0.99; p = 0.04), but not in PD patients (adjusted HR: 0.99; 95% CI: 0.86 to 1.15; p = 0.89). Similar results were reported by Stack et al. (32) in 134,728 new ESRF patients recorded on the USRDS Registry. Many of the above studies may potentially have suffered from informative censoring bias as a result of evaluating prevalent rather than incident patients (33). Moreover, most of the investigations were based on U.S. populations, where the uptake of PD is very low, raising the possibility of selection bias. In an attempt to better define the relationship between obesity and outcome in a larger cohort of incident PD patients where the selection of PD versus HD is more equal, my group performed a retrospective analysis of data from the Australia and New Zealand Dialysis and Transplantation Association (ANZDATA) registry on 19,635 patients who commenced renal replacement therapy in Australia or New Zealand between 1991 and 2002, and who received PD treatment at some stage during their dialysis career (31). Obesity, defined as a BMI greater than 30 kg/m2, was independently associated with death during PD treatment (HR: 1.36; 95% CI: 1.14 to 1.54; p < 0.05) and technique failure (HR: 1.17; 95% CI: 1.07 to 1.26; p < 0.01). When BMI was analyzed as a continuous variable, a J-shaped curve was observed, with the greatest survival occurring in patients with a BMI of 20 kg/m2. Survival decreased progressively with BMI values above and below that level. POTENTIAL MECHANISMS UNDERLYING THE IMPACT OF BODY SIZE ON PD OUTCOME The apparently conflicting results regarding the effect of body size on PD outcome may relate in part to the inability of BMI to differentiate between muscle mass and fat tissue. Using 24-hour urinary creatinine excretion as a measure of muscle mass, Ramkumar et al. (34) examined the influence of body composition on survival in 10,140 incident PD patients. Patients with a high BMI and normal or high muscle mass had lower risks of all-cause mortality S251 Downloaded from http://www.pdiconnect.com/ by guest on September 30, 2014 associated with reduced mortality risk in patients undergoing HD (13,15,16,22–24). The role of body size in PD has been less well investigated than it has in HD, and studies have variously reported a propitious (10,17, 25,26), neutral (27–30), or deleterious effect of BMI on PD outcome (31,32). The first investigation of the impact of BMI on PD patient outcome was a 3-year observational cohort study of 43 prevalent PD patients at my center (17). Using multivariate Cox proportional hazards model analysis, a BMI greater than 27.5 kg/m2 was found to be a positive predictor of patient survival [adjusted hazard ratio (HR): 0.09; 95% confidence interval (CI): 0.01 to 0.85; p < 0.05], independent of other clinical, biochemical, nutritional, and echocardiographic parameters. Overweight patients also tended to experience fewer fatal myocardial infarctions (adjusted HR: 0.33; 95% CI: 0.07 to 1.48; p = 0.15), although this difference was not statistically significant. In contrast, Fried et al. (27) showed that survival in patients whose body weights were more than 1 standard deviation above the mean (82.7 kg) was not significantly different from that seen in the rest of the adult PD population. However, when the data were reanalyzed using body surface area, a significant positive correlation was found between that parameter and survival. A retrospective study of 242 incident CAPD patients (25) reported that individuals with a body weight greater than 80 kg spent significantly fewer days in hospital and had rates of peritonitis, technique survival, and death that were similar to those of patients weighing between 60 kg and 80 kg. Another retrospective study of 41,197 Medicare PD patients in the United States (10) similarly demonstrated that the overall survival rate was slightly higher in obese patients (BMI > 30 kg/m2) after 1 year (HR: 0.89), but was similar at 2 and 3 years (HR: 0.99 and 1.00 respectively). Johansen et al. (26) analyzed 418,055 patients starting dialysis in the United States between April 1995 and November 2000 (including 44,869 patients on PD) and observed increased survival and reduced hospitalization risk in the overall cohort, even at extremely high BMI. This positive association remained when alternative estimates of adiposity, including Benn index and estimated fat mass, were substituted for BMI. However, the beneficial effect was blunted in PD patients as compared with HD patients, such that enhanced survival could be demonstrated only in the BMI range between 25 kg/m2 and 31 kg/m2. Other published studies have generally found that obesity has a neutral effect on outcome in PD patients. For example, Aslam et al. (28) reported comparable 2-year survival rates in obese and non-obese individu- PROCEEDINGS OF THE 11TH CONGRESS OF THE ISPD OBESITY IN PD PROCEEDINGS OF THE 11TH CONGRESS OF THE ISPD JOHNSON S252 individuals is the observed proinflammatory effect of adipose tissue (41). IS THERE ANY EVIDENCE THAT WEIGHT REDUCTION IS ASSOCIATED WITH IMPROVED PD PATIENT OUTCOMES? The short answer to the question of whether weight reduction is associated with improved patient outcomes in PD is no. Nevertheless, based on the hypothesis-generating observations of a generally neutral or deleterious effect of obesity on PD outcomes, primarily associated with inferred high fat mass, it would appear reasonable to cautiously advise weight reduction in obese individuals receiving PD. To date, only one study has been published of a multidisciplinary (dietitian, nurse, physiotherapist) weight reduction program in PD patients. This program comprised a 12-month intervention with individual meal plans, a regular exercise program, augmentation of peritoneal small-solute clearance, and optimization of the PD prescription to reduce caloric load in 11 PD patients, each having a BMI exceeding 25 kg/m2 (42). Only 8 patients completed the study, of whom 7 experienced a sustained, significant weight loss (median weight change to 89.5 kg from 94.6 kg; p = 0.017). This weight loss was associated with a fall in resting and post-exercise heart rates, but no other changes in indices of cardiovascular fitness or quality-of-life scores were discernible. Substituting icodextrin for dextrose in PD solution may also reduce caloric load, particularly in high transporters. A recent double-blind randomized controlled trial of icodextrin versus 2.5% dextrose solution for the once-daily long dwell in 175 PD patients reported weight stabilization in the icodextrin group (–0.3 kg) as compared with a significant increase in body weight in the control group (+2.33 kg) over a period of 1 year. However, a significant component of this difference in weight gain may have been attributable to differences in body fluid status, because significantly fewer patients reported edema in the icodextrin group (6.3% vs. 17.9%, p < 0.01). Pharmacotherapy has also been advocated for weight reduction, but most of the available agents (benzphetamine, phendimetrazine, diethylpropion, phentermine, sibutramine, orlistat, rimonabant) are considered contraindicated in the presence of severe chronic kidney disease. Laparoscopic banding may need to be considered for extreme obesity. CONCLUSIONS Obesity is an increasingly common problem in PD populations, with a rate of increase that is more than double that seen in the general population. This alarm- Downloaded from http://www.pdiconnect.com/ by guest on September 30, 2014 (HR: 0.90; 95% CI: 0.83 to 0.97) and cardiovascular mortality (HR: 0.88; 95% CI: 0.79 to 0.97) than did those with a normal BMI and normal or high muscle mass. Moreover, high-BMI patients with low muscle mass (and therefore an inferred high fat mass) had higher observed risks of all-cause mortality (HR: 1.29; 95% CI: 1.17 to 1.42) and cardiovascular mortality (HR: 1.21; 95% CI: 1.06 to 1.39). Thus, the harmful effects of high BMI in PD patients were limited to individuals with (inferred) high body fat; normal or high muscle mass conferred a protective effect. Part of the mechanism underlying a deleterious effect of obesity on PD outcome may be an increased risk of PD-related infection. Piraino et al. (35) observed a trend toward higher peritonitis rates in 228 incident PD patients as the ratio of actual to ideal body weight increased from less than 0.9 (underweight: 0.8 episodes per year) to between 0.9 and 1.1 (normal weight: 0.9 episodes per year) to greater than 1.1 (overweight: 1.0 episode per year). Moreover, these investigators observed that catheter losses from infection were significantly higher in overweight PD patients. A subsequent analysis of incident Australia and New Zealand PD patients demonstrated that obese individuals had a poorer peritonitis-free survival than did patients of lesser body weight (36). Every 5 kg/m2 increase in BMI was associated with a 7% increase in the risk of a first peritonitis episode. Similarly, the overall rate of peritonitis, when expressed as episodes per year of PD treatment, was higher in obese individuals. Every 5 kg/m2 increase in BMI was associated with a 14% increase in the risk of a first peritonitis episode. Thus, obese PD patients were more likely to experience infection, which in turn contributed to their poorer outcomes. An alternative possibility is that the more frequent occurrence of peritonitis and poorer overall outcomes in obese patients reflect a greater tendency for this group to be underdialyzed. Small-solute clearance in PD is less efficient than in HD, which may be particularly limiting in large patients (37). In the Australia and New Zealand study, technique failure in obese (as compared with other) patients was more likely to result from inadequate small-solute clearance (underweight 13%, normal weight 18%, overweight 20%, obese 23%; p < 0.01). Moreover, RRF, loss of which is strongly correlated with PD peritonitis (38), has recently been found to decline at a more rapid rate in obese patients than in normal or underweight PD patients (39). Interestingly, in a subsequent analysis of the Australia and New Zealand study, my group demonstrated that, after adjustment for RRF, obesity no longer predicted mortality in PD patients (40). A plausible, though unproven, hypothesis for the more rapid loss of RRF in obese JUNE 2007 – VOL. 27, SUPPL 2 PDI OBESITY IN PD PDI JUNE 2007 – VOL. 27, SUPPL 2 JOHNSON REFERENCES 1. Johnson DW, McDonald SP, Excell L, Livingston B, Shtangey V. Peritoneal dialysis. In: McDonald SP, Excell L, eds. ANZDATARegistry Report 2005. 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Influence of excess weight on mortality and hospital stay in 1346 hemodialysis patients. Kidney S253 Downloaded from http://www.pdiconnect.com/ by guest on September 30, 2014 ing increase in the prevalence of obesity in PD patients is being driven by an increased risk of progression of chronic kidney disease to ESRF in obese subjects, a reduced probability of listing obese dialysis patients for renal transplantation, paradoxically enhanced survival of 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 HD, the results in PD are conflicting, generally showing a neutral or deleterious effect of elevated BMI. 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