Volume 53, Issue 1, Pages 151-165 (January 2009)

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Obesity Management in Adults With CKD

Index Words: Obesity, chronic kidney disease, end-stage renal disease, weight loss, bariatric surgery

Article Outline

• Case Presentation

• Introduction

• Overview of BMI and Mortality in the General Population

• Waist Circumference as a Predictor of Mortality in the General Population

• Adiposity Measures and Mortality

• Adults With Stages 1 to 4 CKD

• Patients Treated by Dialysis

• Identification of Adults with CKD who will Benefit from Weight Loss

• CKD Stages 1 to 4

• Patients on Dialysis Therapy

• Dietary Interventions

• CKD Stages 1 to 4

• Patients Receiving Dialysis

• Pharmacological Treatment of Obesity

• Bariatric Surgery

• Psychosocial Aspects of Obesity

• Summary

• Acknowledgment

• References

• Copyright

Case Presentation

A 22-year-old African American woman who has been dialysis dependent for 4 months because of hypertensive kidney disease is referred for kidney transplantation evaluation. Because of the recent occlusion of her left forearm arteriovenous graft, she currently is being dialyzed through a right internal jugular tunneled catheter. Her medications include methyldopa, 250 mg twice daily; calcium carbonate, 1,000 mg with each meal; and erythropoietin with dialysis. She is single without children, unemployed, and lives with her 38-year-old mother. She does not smoke or drink. Systems review findings are unremarkable. On physical examination, weight is 284 pounds (129 kg), height is 5 feet 2 inches (1.58 m), and body mass index (BMI) is 51.9 kg/m2. Blood pressure is 130/80 mm Hg, and cardiac and pulmonary examination findings are unremarkable. The surgeon believes she is a good candidate for transplantation, except she must lose weight before being listed. What advice should she be given regarding weight loss?

Introduction

This review addresses the identification and management of patients with chronic kidney disease (CKD) who may benefit from weight loss with lifestyle, pharmacological, and surgical therapies. Because of the existing controversy regarding obesity and mortality in this population, we have provided an overview of the definition of overweight and obesity in the general population and a discussion of the potential analytic problems in observational studies that try to determine BMI thresholds for mortality in populations with CKD. All adults will benefit from a healthy lifestyle regardless of kidney disease. Data also suggest that obese (BMI > 30 kg/m2 or waist circumference > 102 cm in men and > 88 cm in women) adults with CKD who are not being treated by dialysis will benefit from weight loss. For stable dependent dialysis patients, weight loss should be prescribed for persons who would be eligible for transplantation except for their degree of obesity. Otherwise, a more individualized approach is needed, and clinicians should evaluate nutritional needs along with comorbid conditions to determine the potential benefits. Multidisciplinary approaches are most effective for weight loss in any patient. However, if medical and nutritional interventions fail, bariatric surgery performed by an experienced surgeon at a certified center may be considered for a morbidly obese adult. Studies are urgently needed to determine safe approaches for effective and sustained weight loss in adults with CKD.

Overview of BMI and Mortality in the General Population

In the United States and most developed countries, the obesity epidemic substantially threatens the progress in health outcomes made during the past several decades1 and likely will lead to growth in the number of adults with CKD. Compared with adults with BMI of 18.5 to 24.9 kg/m2, adults with BMI greater than 35 kg/m2 have a 7-fold increased odds of being given a diagnosis of diabetes and 6-fold increased odds of being hypertensive,2 the 2 most common risk factors for CKD. A recent meta-analysis of observational studies reported that 24.2% and 33.9% of kidney disease in men and women may be attributed to overweight and obesity in the United States, respectively.3 Although these effects are mediated largely by the development of diabetes and hypertension, increased fat mass itself may have independent effects on CKD incidence and progression.4

During the early part of the last century, life insurance companies were astute to the fact that obesity increases mortality. Until recently, the current standards used to classify “normal” or ideal weight, overweight, and obesity were based largely on the Metropolitan Life Insurance Company weight-for-height tables created from demographic data from adults who purchased life insurance from 1935 to 1954.5 Groups of individuals not likely to purchase life insurance during this period were not well represented, including nonwhite adults and those with chronic medical conditions precluding life insurance eligibility.6 Starting in 1995, the US Department of Agriculture and the US Department of Health and Human Services dietary guidelines suggested a BMI cutoff value of 25 kg/m2 or greater for defining overweight for men and women, but conceded the lack of credible evidence for a precise threshold and wide confidence intervals (CIs) for increased mortality.5, 7 These thresholds have largely been replaced by criteria published by the World Health Organization in 1997 that defined overweight as BMI of 25 kg/m2 or greater and included criteria for obesity stages I (BMI, 30 to 34.9 kg/m2), II (BMI, 35 to 39.9 kg/m2), and III (BMI ≥ 40 kg/m2)8 (Table 1).

Table 1.

Classification Scheme of Adult Underweight, Overweight, and Obesity Using Body Mass Index


	Classification	Body Mass Index (kg/m2)
	Underweight	<18.5
	Ideal weight	18.5-24.9
	Overweight	25.0-29.9
	Obese	≥30.0
	Class I	30.0-34.9
	Class II	35.0-39.9
	Class III	≥40

Adapted from World Health Organization 1998 guidelines for obesity classification.8

Although a particular BMI threshold currently is used to define overweight and obesity for all individuals,5 it remains a disputatious issue whether specific BMI cutoff values are appropriate for assessing cardiovascular and mortality risk for all age9, 10 and racial/ethnic groups.11, 12, 13, 14 Studies consistently have shown that obesity at a young age or during midlife decreases life expectancy.15, 16, 17 However, the association between BMI and mortality in older adults may not mirror the associations in middle-aged or young adults.13 A meta-analysis of studies limited to adults 65 years or older concluded that a wide range of BMI levels show no association with mortality in this group. Mortality risk does not appear to increase significantly until BMI exceeds 31 kg/m2.18 In addition to age, the association between mortality and BMI also appears to be modified by race/ethnicity.9, 16, 19, 20

Waist Circumference as a Predictor of Mortality in the General Population

Use of BMI as a proxy for degree of adiposity has become a routine part of clinical care. However, BMI reflects both fat-free mass and fat mass and does not provide information about body composition. Figure 1 shows how body fat may be preferentially distributed around the abdominal or hip area while some adults have an ideal BMI in the setting of abdominal obesity. Abdominal fat remains a strong predictor of mortality after adjustment for total body fat.21 Thus, the adverse effects of abdominal fat largely mediate the increased cardiovascular risk associated with obesity. Although abdominal fat can be measured directly by using dual-energy X-ray absorptiometry, computed tomography, or magnetic resonance imaging, waist circumference can be measured reliably without cost and correlates highly with abdominal fat.22, 23, 24 In the general population, adults with abdominal obesity, defined as waist circumference greater than 102 cm in men and greater than 88 cm in women, are more likely to have hypertension, diabetes, and increased cholesterol levels compared with those with a waist circumference less than these thresholds regardless of the presence of normal weight, overweight, or class I obesity.25, 26 These waist circumference cutoff values were selected from reference values associated with a BMI of 30 kg/m2 or greater in adults living in Scotland.27 Although smaller waist circumference thresholds may be appropriate for certain racial/ethnic groups, such as Chinese or Japanese adults,28 abdominal obesity, defined by increased waist circumference, increases the risk of cardiovascular disease and mortality regardless of BMI, age group, and race/ethnicity.26, 29, 30

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Figure 1. Adipose tissue may be distributed preferentially in the (A) abdomen or (B) hip and buttock area. (C) Some adults may have normal body mass index in the setting of abdominal obesity.

Adiposity Measures and Mortality

Adults With Stages 1 to 4 CKD

Obesity and abdominal obesity are common in adults with CKD and likely have a causal role for kidney disease incidence and progression.31, 32, 33, 34, 35 However, it is unclear whether greater BMI increases mortality risk in this population. In adults with CKD, waist circumference correlates highly with abdominal fat36 and may outperform BMI for prediction of future cardiovascular events and mortality. Elsayed et al37 pooled data from the Atherosclerosis in Communities (ARIC) Study and the Cardiovascular Health Study (CHS) to examine the association between adiposity measures (BMI and waist-to-hip ratio) and mortality in adults with CKD. CHS participants were 65 years and older at the baseline visit, whereas the ARIC Study recruited adults aged 45 to 64 years. A total of 1,669 participants with CKD, defined as an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m2, were included in the analysis, and the primary outcome was myocardial infarction or cardiovascular death. After a mean follow-up of 9.3 years, no significant association was noted between overweight or obesity and cardiac events compared with an ideal BMI (20 to 24.9 kg/m2). Conversely, the highest waist-to-hip ratio (≥1.02 and ≥0.96 in men and women, respectively) had a 36% greater relative risk of cardiac events (95% CI, 1.02 to 1.85) compared with the group with the lowest waist-to-hip ratio (≤0.95 and 0.87 in men and women, respectively).37 An additional analysis limited to ARIC Study participants with CKD showed that greater BMI in individuals with BMI in the normal range was associated with lower risk of mortality.38 In contrast, no association was noted between BMI and mortality in participants with CKD and BMI of 25 kg/m2 or greater.38 Madero et al39 reported no association between sex-specific BMI quartiles and all-cause or cardiovascular mortality after a median follow-up of 10 years in 1,759 participants in the Modification of Diet in Renal Disease (MDRD) Study. Mean age of these adults with CKD was 51 years, and mean glomerular filtration rate was 39 ± 21 mL/min/1.73 m2.

Patients Treated by Dialysis

The issue of obesity in patients treated by dialysis presents a difficult dilemma. Although obese dialysis dependent patients face obstacles for transplantation, observational studies suggest that greater BMI is associated with improved survival in this population.40, 41, 42, 43, 44 One of the largest studies, which included more than 400,000 dialysis dependent patients who initiated dialysis therapy from 1995 to 2000, noted substantial and significant differences in overall survival by BMI groups after a median follow-up of 2 years. The unadjusted annual cardiovascular mortality rate was approximately 2-fold greater in patients with BMI less than 22 kg/m2 compared with those with BMI of 37 kg/m2 or greater, and the all-cause mortality rate was more than 2-fold greater in patients with BMI less than 19 kg/m2 versus 37 kg/m2 or greater.42 The prevalence of reported congestive heart failure was similar across BMI groups, but ischemic heart disease, myocardial infarction, peripheral vascular disease, previous stroke, and tobacco use were all lowest in the group with BMI of 37 kg/m2 or greater. After adjustment for these factors, BMI categories starting at BMI of 25 kg/m2 or greater, including the highest BMI category (≥37 kg/m2), were associated with decreased mortality compared with BMI of 22 to less than 25 kg/m2. Conversely, BMI less than 22 kg/m2 was associated with the greatest mortality risk.42 When the investigators limited the analysis to incident dialysis dependent patients who had previously received a transplant, a potentially healthier group compared with the entire dialysis population, increased mortality was noted in those with BMI less than 22 kg/m2 and those with BMI of 37 kg/m2 or greater compared with the BMI group of 22 to less than 25 kg/m2.42 Thus, morbid obesity did not appear to be protective in “healthier” patients receiving dialysis.

Beddhu et al45 explored the potential confounding effects of muscle mass on the association between BMI and mortality in the dialysis population. A total of 70,028 patients who initiated dialysis therapy between 1995 and 1999 were stratified by level of urine creatinine excretion (>0.55 g/d [upper 25th percentile] versus ≤0.55 g/d) as reported on the US Renal Data System 2728 Form. Compared with the ideal-BMI group (18.5 to 24.9 kg/m2) with greater than 0.55 g/d of urine creatinine excretion, adults with BMI of 25 kg/m2 or greater and urine creatinine excretion of 0.55 g/d or less had a 14% increased risk of death (95% CI, 1.10 to 1.18), whereas those with BMI of 25 kg/m2 or greater and urine creatinine excretion greater than 0.55 g/d had 15% increased survival (95% CI, 0.83 to 0.87).45 This analysis was criticized for potential confounding by differences in residual renal function.44 However, regardless of BMI, those with high muscle mass had better survival than those with low muscle mass. This suggests that increasing muscle mass in hemodialysis dependent patients may improve survival.46, 47, 48

A major issue regarding studies examining the association between BMI and mortality in the dialysis population is the length of follow-up. Studies that show increased mortality in overweight and obese adults compared with normal BMI in the general population generally have follow-up durations that exceed 5 years.9, 12, 49, 50 Conversely, most studies examining BMI and mortality in dialysis dependent patients have average follow-up durations of 2 years or less.40, 41, 42, 43, 45 In the short term, the presence of preexisting disease in those with BMI in the low end of normal will lead to greater mortality, and there may be incomplete ascertainment of these comorbid conditions. One team of investigators examined the association between BMI and mortality in 2 groups of adults living in The Netherlands. Hemodialysis dependent patients (n = 722) with a mean age of 66 ± 7 years made-up the first group, and the second group included 2,436 adults with a mean age of 62 ± 7 years not on dialysis therapy who were participants in the Hoorn Study, a population-based cohort. After 7 years of follow-up, a baseline BMI of 30 kg/m2 or greater in the hemodialysis dependent patients was associated with a 20% (95% CI, 0.8 to 1.7) increased risk of mortality compared with patients with ideal BMI. Similar results were noted in the Hoorn Study group, in which a baseline BMI of 30 kg/m2 or greater increased mortality risk by 30% (95% CI, 0.9 to 2.0) compared with an ideal BMI. The CIs for both populations crossed 1.0, most likely because of inadequate power, but the magnitude and direction of the association between obesity and 7-year mortality in these 2 groups did not differ substantially.51

Identification of Adults with CKD who will Benefit from Weight Loss

CKD Stages 1 to 4

The management of obesity requires identification of individuals who will benefit from weight loss. Studies show that intentional weight loss improves glucose control and decreases blood pressure in the general population,52 2 important factors for CKD progression.53 Even moderate weight loss will reduce metabolic demands on the kidney54 and may delay the progression of CKD. Weight loss has been shown to reduce proteinuria in patients with both diabetic and nondiabetic kidney diseases.55 The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recently published clinical practice guidelines (for which evidence is strong) and clinical practice recommendations (for which evidence is limited) for diabetes and CKD.56 Weight goals are addressed in the clinical practice recommendations section because of the dearth of evidence for the diabetic CKD population. Although these recommendations suggest that patients with CKD should maintain BMI in the range of 18.5 to 24.9 kg/m2, this is based largely on extrapolation from other populations. As such, the clinical practice recommendations strongly encourage the development of data-driven optimal BMI targets for patients with CKD.56

Maintaining behavioral changes for weight loss in obese individuals is very challenging, and such common CKD comorbid conditions as decreased exercise capacity only compound this difficulty. Because obtaining an ideal BMI may be especially challenging for many obese patients with CKD, clinicians should emphasize benefits of even modest weight loss and an overall healthy lifestyle encompassing diet, exercise, smoking cessation, and moderation of alcohol intake. The American College of Physicians guidelines for obesity in primary care state that clinicians should counsel all patients with BMI of 30 kg/m2 or greater on lifestyle changes for weight loss, and weight loss goals should be individually determined.57 In adults with CKD, abdominal obesity, measured by waist circumference, should also be considered an indication for weight loss because of the strong association between abdominal obesity, metabolic syndrome, and CKD.31, 32, 58 Suggested recommendations for patients with CKD who should receive interventions for weight loss are listed in Table 2.

Table 2.

Identification of Adults Who May Benefit From Lifestyle Modifications and Weight Loss


	Lifestyle Modification⁎	Weight Loss	References
CKD stages 1-2 (kidney damage with GFR ≥ 60 mL/min/1.73 m2)	All	Presence of type 2 diabetes mellitus, BMI ≥ 30 kg/m2, or increased waist circumference†	56, 59, 63
CKD stages 3-5: nondialysis (GFR < 60 mL/min/1.73 m2)	All	Presence of type 2 diabetes mellitus, BMI ≥ 30 kg/m2, or increased waist circumference†	56, 59, 63
CKD stage 5: dialysis	All	Preclusion from transplantation because of obesity‡

Note: CKD stages defined by the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Clinical Practice Guidelines for Chronic Kidney Disease.64

Abbreviations: BMI, body mass index; CKD, chronic kidney disease; GFR, glomerular filtration rate.

⁎

Following a healthy diet and engaging in regular exercise.

†

Waist circumference of 102 cm or greater and 88 cm or greater in men and women, respectively. For Asian populations, waist circumference of 89 cm or greater and 79 cm or greater in men and women, respectively.

‡

Individual assessment for benefits of weight loss should be made in all dialysis dependent patients regardless of transplantation status.

Regardless of BMI and waist circumference, all individuals with diabetes should receive medical nutrition therapy according to the American Diabetes Association guidelines.59 Because many adults with CKD have diabetes, these recommendations apply to a large proportion of the CKD population and include reduced intake of total energy, saturated and trans fatty acids, cholesterol, and sodium and increased physical activity. Although BMI goals were not specified in these guidelines, they emphasize the likely benefits of a 5% to 10% weight loss, including improvements in blood pressure and cholesterol and glucose control.59 Nutritional restrictions are discouraged for older adults in long-term care facilities because of the high risk of malnutrition in these individuals.59

Patients on Dialysis Therapy

Similar to the general population, increased visceral fat is associated with greater fasting plasma insulin and triglyceride levels and greater prevalence of carotid atherosclerosis in dialysis dependent patients without diabetes mellitus.60, 61, 62 A small study of 197 adults with stage 5 CKD showed that presence of inflammation (C-reactive protein level ≥ 10 mg/L), regardless of nutritional status, was associated with significantly greater truncal body fat mass compared with no presence of inflammation.65 Because inflammation is strongly linked to mortality in patients treated by dialysis,66, 67 adiposity itself is unlikely to confer a survival advantage.68, 69 The strength of the reported association between morbid obesity and survival does not equal the marked increase in survival associated with transplantation. One of the largest studies of obesity and mortality in the dialysis population showed a 20% greater adjusted mortality risk for patients with BMI of 22 to less than 25 kg/m2 compared with those with BMI greater than 37 kg/m2.42 Conversely, dialysis dependent patients who receive a kidney transplant have adjusted total annual survival rates up to 200% greater than patients who remain on the transplant waiting list.70, 71

The safety of intentional weight loss in stable dialysis dependent patients has not been studied, but many medical centers preclude kidney transplantation for patients with BMI of 35 kg/m2 or greater because of greater rates of surgical wound infections and dehiscence, delayed graft function, and acute rejection compared with kidney transplant recipients who are not obese.72, 73, 74, 75 The average hospital stay after kidney transplantation consequently is longer for obese patients compared with patients with ideal BMI.72 The current reimbursement structure, which penalizes centers for performing transplantation on high-risk patients, along with other factors, may influence a center's decision to preclude transplantation for morbidly obese patients.76 Differences in long-term allograft and patient survival between obese and nonobese kidney transplant recipients may vary by center.74, 77 However, 2 large studies, which together included data from more than 70,000 kidney transplant recipients, reported significantly greater rates of graft failure in adults with BMI of 35 kg/m2 or greater compared with patients with ideal BMI.72, 73 In the most recent study reported by Gore et al,72 morbidly obese adults had a 22% (95% CI, 1.09 to 1.38) greater adjusted risk of graft failure compared with transplant recipients with ideal BMI. The magnitude of the association between morbid obesity and risk of graft failure was similar to the risk of graft failure associated with diabetes in this study population (hazard ratio, 1.28; 95% CI, 1.19 to 1.36).72 Graft survival time exceeded 80 months in approximately 50% of morbidly obese transplant recipients versus 70% of transplant recipients with ideal BMI.72 Thus, graft survival is negatively affected by the presence of morbid obesity. However, overall survival is substantially and significantly improved with kidney transplantation in obese dialysis dependent patients.78 Using data from the US Renal Data System, Glanton et al79 showed that cadaver and living donor transplantation reduced mortality incidence in obese adults by 61% and 77% compared with obese adults remaining on the transplant waiting list, respectively. Until transplant centers change their policy of using BMI thresholds for access to kidney transplantation, obesity in a patient who would otherwise be eligible for a kidney transplant must be viewed as the most important modifiable factor that can influence his or her overall survival. In stable dialysis dependent patients who are not eligible for transplantation for other reasons, benefits of weight loss need to be individually assessed based on the patient's comorbid conditions and nutritional status. Moreover, in the dialysis population, the focus should not simply be on weight loss, but on body composition, because interventions that increase muscle mass and improve overall fitness may improve survival.

Dietary Interventions

CKD Stages 1 to 4

The goal of a dietary intervention is to maximize sustained weight loss at an optimal level, yet long-term behavioral changes are the toughest obstacle for individuals trying to lose weight. Accordingly, 1 single dietary intervention cannot be broadly recommended. Instead, clinicians need to work with dieticians, nurses, psychologists, and social workers to determine the particular needs, motivations, and barriers for each patient. As food prices continue to increase, many patients may have difficulty affording healthy foods, an important consideration when determining a diet plan. Before recommending weight loss, the patient should be assessed for existing comorbid conditions caused by obesity, and medications that may contribute to weight gain should be delineated. A diet history should be obtained, and past experience with weight loss should be discussed.80 There are a wide variety of healthy diets that can be considered, and these have been previously summarized in an excellent review.81 A conservative approach is to restrict caloric intake by approximately 500 kcal/d, which in the absence of physical activity changes will lead to a weight loss of 1 lb/wk.80 More restrictive diets (<1,200 kcal/d) should be accompanied by intensive monitoring of the nutritional status and well-being of the patient. Increasing physical activity in the absence of diet may lead to modest weight loss and improvement in many obesity-related comorbid conditions,80 but may not be sufficient for the morbidly obese. Potential benefits of exercise to enhance weight loss and improve muscle mass in all adults with CKD, including persons who receive a kidney transplant, deserve further investigation.82 Because weight gain is so common after kidney transplantation, dietary counseling for healthy diets with portion control should be provided before transplantation, with intensive and frequent follow-up after transplantation. Studies have documented that such interventions can ameliorate weight gain after kidney transplantation.83, 84

The American Heart Association guidelines for a healthy lifestyle provide no specific recommendations for diet and state that the exact percentage of carbohydrates, protein, and fat within a given meal will not in itself influence weight management. Addressing portion size and reducing energy intake to less than energy expenditure is the only reliable method to facilitate weight loss.63 High-protein diets for weight loss are extremely popular, and they appear to be useful for short-term weight loss in some individuals, but their long-term safety is unknown.85 In adults with CKD, protein intake exceeding 20% of total calories is not recommended because of the potential detrimental effects on kidney damage and function.86, 87 The NKF–KDOQI guideline for nutritional management of patients with diabetes and CKD recommends that protein should meet, but not exceed, the Recommended Daily Allowance of 0.8 g/kg/d, with 50% to 75% of the protein derived from lean poultry, fish, and vegetables.56 Diets that emphasize the consumption of such whole foods as fresh fruits and vegetables and whole grains, as well as the avoidance of processed foods, will provide additional benefits beyond those associated with weight loss. However, additional information about effects of specific nutrients on CKD initiation and progression is needed to better define optimal diets.

Patients Receiving Dialysis

Current guidelines for nutritional management of dialysis dependent patients recommend protein intake of 1.2 g/kg/d and 30 to 35 kcal/kg/d for stable patients.88 However, obese dialysis dependent patients must reduce caloric consumption to levels less than energy expenditure to lose weight. Individualized treatment plans that encompass the nutritional requirements of the dialysis population are required to optimize patient outcomes. Consistent with behavioral interventions for any patient, dietary histories and food diaries are useful to determine sources of empty calories and areas in which behavioral modifications will be most helpful. Currently, evidence to support particular diets and interventions for weight loss in patients receiving dialysis is scant. A wide variety of methods may be used to create a caloric-restricted dietary plan to facilitate weight loss in this unique patient population. One conservative approach is to start with 25 kcal/kg/d based on the adjusted body weight (ideal body weight − [dry total body weight − ideal body weight]/4). This suggested caloric intake can be used as a starting point, but should be modified based on the patient's results with weight loss (personal communication, Judith Fitzhugh, Kovler Organ Transplant Center, Northwestern Memorial Hospital, August 17, 2008). Using the adjusted body weight is not as reliable as direct measures of resting energy expenditure.6 Hence, research is needed to determine the efficacy and safety of using adjusted body weight to guide caloric intake, along with other potential methods.

Pharmacological Treatment of Obesity

After 6 to 12 months, recidivism becomes a difficult issue for even the most dedicated dieter. Most obese adults will have difficulty maintaining even a minimal to moderate weight loss and may not ever reach, let alone maintain, an ideal BMI. Weight loss medication may be used as an adjunctive therapy when diet and exercise alone have failed.89 However, additional weight loss from pharmacological agents is usually modest.57 Several drugs are used for the treatment of obesity, but none has been adequately tested in adults with stage 3 to 5 CKD. A tabulation of medications that have been investigated for weight loss in at least 1 randomized trial is listed in Table 3. Some anorexic medications, which include phentermine, diethylpropion, and sibutramine along with other medications now off the market, have been associated with the development of primary pulmonary hypertension and valvular heart disease. These drugs also can increase blood pressure and should not be used in patients with a history of cardiovascular disease, cardiac arrhythmia, or stroke.90 Considering the high prevalence of cardiovascular diseases in adults with CKD, these drugs probably should be avoided in adults with kidney disease, as well. To achieve weight loss with the selective serotonin reuptake inhibitors (fluoxetine and sertraline), high doses usually are required, which may not necessarily be safe in a patient with CKD for long-term use. Rimonabant antagonizes the CB-1 cannabinoid receptor, reduces consumption of sweet and high-fat foods, and enhances weight loss with caloric-restricted diets.90 The drug was approved by the European Medical Agency in 2006 to aid weight loss with diet and exercise in obese adults, but because of increased risk of mood disorders, the drug has not been approved for use in the United States.91

Table 3.

Review of Medications Evaluated for Weight Loss


Drug	Mechanism of Action	Potential Side Effects	Drug Interactions	Safe in Kidney Disease
Orlistat⁎	Lipase inhibitor	Fecal incontinence, fat-soluble vitamin deficiency	Cyclosporine, amiodarone	Probably†
Sibutramine⁎	Combined norepinephrine and serotonin reuptake inhibitor, anorexic	CNS stimulation, tachycardia, increased blood pressure	Serotonergic agents, erythromycin, ketoconazole	No, if severe renal impairment; questionable, if mild to moderate renal impairment
Diethylpropion,⁎ Phentermine⁎	Stimulate release of norepinephrine, anorexic	CNS stimulation, sleep disorders, tachycardia, increased blood pressure, abuse potential	MAO inhibitor therapy, concurrent use with other anorectic agents, carbonic anhydrase inhibitors	Questionable Approved for short-term use only because of abuse potential Avoid in patients with advanced arteriosclerosis and severe hypertension
Fluoxetine, Sertraline	Selective serotonin reuptake inhibitors	Anxiety, tremors, sleep disorders, nausea, increased suicide risk in those aged < 24 y	MAO inhibitors	Safety of prolonged administration in stage 4-5 CKD unknown. High doses required for weight loss, but dose reduction suggested with severe renal impairment
Rimonabant	Cannabinoid receptor antagonist	Depressed mood, nausea, fatigue	Limited data	Yes, but not available in United States
Bupropion	Dopamine-reuptake inhibitor	Dry mouth, insomnia	MAO inhibitors	Reduce dose with stage 5 CKD

Abbreviations: CKD, chronic kidney disease; CNS, central nervous system; MAO, monoamine oxidase.

Adapted from Li et al.89

⁎

Food and Drug Administration approved as a weight-loss drug.

†

Case report of enteric hyperoxaluria and renal oxalosis leading to acute kidney injury.98

Orlistat, a reversible inhibitor of gastric and pancreatic lipases, blocks approximately 30% of triglyceride gastrointestinal absorption and may be safe for use in many patients with CKD. The drug is characterized by very limited systemic absorption, with doses up to 800 mg/d yielding minimal plasma concentrations.92 Studies have shown that the addition of orlistat to a caloric-restricted diet leads to greater weight reduction compared with the addition of a placebo.93, 94 Orlistat is available without a prescription, and the 60-mg tablet is taken 3 times daily within an hour of each meal. Because the drug interferes with cyclosporine absorption,95, 96 it should not be prescribed to patients using calcineurin inhibitors. Use of orlistat leads to incremental reductions in free fatty acid, total cholesterol, and low density lipoprotein cholesterol levels and improves insulin resistance beyond that expected with weight reduction.92, 97 This may be a function of the drug's beneficial effects on free fatty acids and subsequent improvements in insulin resistance.97

The social consequences of orlistat could be substantial for a given patient. Fat intake must be limited to less than 30% of total calories at each meal; otherwise, individuals are likely to experience diarrhea and fecal incontinence if the drug is taken with a high-fat meal. One study noted that 16% of persons using orlistat reported fecal incontinence,93 but this side effect is usually temporary.80 Fat-soluble vitamin deficiencies may also occur, and fat-soluble vitamin supplementation is usually required with long-term orlistat therapy.93 Although warfarin use is not a contraindication for orlistat use, clinicians need to consider increasing the surveillance of prothombin times, especially when orlistat is used for a prolonged period. Orlistat use also was associated with acute kidney injury caused by renal oxalosis in an adult with CKD.98 Thus, patients with CKD who use this drug should be monitored closely.

Bariatric Surgery

Facilitating weight loss in morbidly obese patients is frustrating because nonsurgical interventions fail in the majority.99 For patients with BMI of 40 kg/m2 or greater or BMI of 35 kg/m2 or greater and diabetes or another obesity-related comorbid condition, bariatric surgery should be considered for treatment of obesity.57, 59, 99, 100 Bariatric surgery procedures (Fig 2) include those that divert food from the stomach into lower parts of the digestive tract, limiting absorption, and those that restrict gastric capacity.99 The Roux-en-Y and biliopancreatic diversion both reduce stomach size and divert food from the stomach into the lower part of the digestive tract.99 During adjustable gastric banding procedures, a band is placed around the upper part of the stomach, and the band may be adjusted by injecting or removing saline through a port positioned underneath the skin.99 In 2006, Medicare agreed to provide coverage for open and laparoscopic Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and open and laparoscopic biliopancreatic diversion with duodenal switch for adults with BMI of 35 kg/m2 or greater and at least 1 obesity-related comorbid condition in whom nonsurgical treatments failed. However, coverage is limited to procedures performed at facilities certified by the American College of Surgeons as a level 1 bariatric surgery center or certified by the American Society for Bariatric Surgery as a Bariatric Surgery Center of Excellence99 because of substantially greater mortality rates when these procedures are performed by inexperienced surgeons and centers.101 A list of approved facilities is listed on the Centers for Medicare & Medicaid Services website (www.cms.hhs.gov/center/coverage.asp).99 Other procedures, such as intestinal bypass and gastric balloon procedures, are not covered because of safety concerns and efficacy.99 Mortality rates after gastric bypass procedure are less than 2%, with greater rates in those with BMI greater than 50 kg/m2.102, 103 Laparoscopic gastric banding appears to be the safest, with mortality rates less than 0.5% in the hands of an experienced surgeon.102, 103

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Figure 2. Graphic description of (A) Roux-en-Y gastric bypass procedure and (B) adjustable gastric banding. During a Roux-en-Y bypass procedure, staples are used to create a small stomach pouch that drains food directly into the lower intestine, limiting caloric absorption. Conversely, gastric banding reduces the functional size of the stomach by placing an adjustable band around the stomach neck. The stomal diameter may be changed by adjusting the inflatable silicone ring.

Maximal weight loss is usually noted after 1 to 2 years regardless of the type of surgery.103, 104 Biliopancreatic diversion or duodenal switch procedures yield the greatest percentage of excess weight loss (70.1%), whereas excess weight loss associated with gastric banding procedures average 47.5%.103 Intentional weight loss, even small to moderate amounts, is associated with multiple beneficial effects on such cardiovascular risk factors as fasting glucose level and blood pressure.105 Reflecting the substantial weight loss that may occur with bariatric surgery, such chronic conditions as type 2 diabetes may resolve, defined by the presence of normal glucose levels without medications, in up to 98% of individuals undergoing gastric bypass and 48% undergoing gastric banding.103 Both systolic and diastolic blood pressure are reduced after bariatric surgery, and the majority of hypertensive adults will have either improved or resolved hypertension.103 Other comorbid conditions, including dyslipidemias, sleep apnea, and fatty liver, may also improve or resolve after bariatric surgery.102 Most importantly, bariatric surgery appears to lengthen the survival of morbidly obese adults.106, 107

Patients considering bariatric surgery for obesity management must be fully cognizant of the potential surgical complications associated with these procedures. In general, adults with CKD may be at greater risk of complications because of the propensity for infections108 and the presence of comorbid conditions. Older adults and those with established cardiovascular disease are at high risk of complications,107 with up to 20% of adults older than 65 years experiencing an adverse event after bariatric surgery.109 The most common complications are gastrointestinal tract related, with more than half the bariatric surgical patients hospitalized for digestive disorders within a 5-year postoperative period in 1 series.110 Nutritional complications, including iron, calcium, vitamin B, and fat-soluble vitamin deficiencies, are common after gastric bypass procedures, whereas nutritional deficiencies after banding procedures can usually be managed by using a multivitamin.102

Intestinal bypass procedures can result in enteric hyperoxaluria leading to kidney stones and renal oxalosis, with irreversible kidney damage.111, 112, 113, 114 Nasr et al112 reported 11 cases of adults who developed oxalate nephropathy after Roux-en-Y gastric bypass procedures, and 8 of these patients eventually required dialysis. The majority of these patients had mild CKD at baseline112; thus, clinicians must be aware that CKD may worsen after gastric bypass procedures. The clinical effects of oxalate hyperabsorption in patients dialysis are uncertain; however, oxalate-induced anemia in a patient with enteric hyperoxaluria caused by Crohn disease has been reported.115 One study from a single institution reported that of 491 patients who underwent gastric bypass surgery, acute kidney injury, defined as a 50% increase in serum creatinine level during the first 3 postoperative days or requirement of dialysis during the postoperative period, occurred in 8.5%. Two patients who developed acute kidney injury died while in the hospital.116 Information for baseline kidney function in these patients was not delineated. Until a study systematically determines mortality and adverse-event rates by the presence of kidney disease, the overall safety of bariatric surgery in adults with CKD is unknown. Despite its potential risk, bariatric surgery has shown clinical benefit in adults with CKD. Successful kidney transplantation after facilitation of weight loss by means of bariatric surgery has been reported in morbidly obese dialysis dependent adults.117 In 1 patient, kidney failure resolved after gastric bypass surgery in a morbidly obese patient with glomerulonephritis.118 Bariatric surgery has also been useful in adults who gain substantial weight after kidney transplantation.117, 119, 120

Psychosocial Aspects of Obesity

Depression and other psychiatric disorders frequently accompany obesity, especially morbid obesity.121, 122, 123 Up to 30% of adults seeking bariatric surgery report depression symptoms.124 Facilitation of weight loss with bariatric surgery has been shown to improve symptoms of depression and self-esteem.122, 125, 126 Although preoperative depression does not appear to negatively influence weight loss, all patients should be evaluated for depression and other mood disorders before surgery, and behavioral and/or pharmacologic therapy should be offered.124 Persons with a history of chronic depression before surgery will probably have persistence of a mood disorder after surgery despite weight loss, and suicide risk may be heightened after surgery.124 A multidisciplinary approach must be used to evaluate patients desiring bariatric surgery, and mood disorders must be included in the overall patient assessment.

Summary

All adults, including those with and without CKD, should receive counseling on the benefits of a healthy lifestyle, which includes a healthy diet, physical activity, and smoking cessation. In people with CKD who are overweight, but not obese, potential benefits of weight loss to the recommended “ideal” range are uncertain. Nevertheless, obesity is associated with increased inflammation, insulin resistance, hypertension, and dyslipidemia, and overweight adults with CKD should be counseled about the risks of weight gain. In persons with CKD and generalized or abdominal obesity, weight loss should be encouraged. For patients on dialysis therapy, survival can be greatly increased with kidney transplantation. Patients who are not eligible for transplantation because of obesity should receive lifestyle and medical interventions for weight loss. If nutritional and medical management fails, bariatric surgery by an experienced surgeon at a certified center may be considered. When eligibility for transplantation is not an issue for an obese patient on dialysis therapy, individualized approaches are needed and interventions should emphasize a healthy lifestyle and exercise that can increase muscle mass. Studies are urgently needed to define the benefits and risks of weight loss by means of lifestyle interventions, medications, and surgery for obese patients with CKD.

Acknowledgements

The authors greatly appreciate the assistance of Tom Mattix, who did the graphic artwork for this manuscript.

Support: None.

Financial Disclosure: None.

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1 Department of Preventive Medicine, Division of Nephrology and Hypertension, Loyola Medical Center, Maywood, IL

2 Department of Medicine, Division of Nephrology and Hypertension, Loyola Medical Center, Maywood, IL

3 Providence Medical Research Center, Sacred Heart Medical Center, University of Washington School of Medicine, Spokane, WA

4 Medical Service, Salt Lake VA Healthcare System, Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, UT

Address correspondence to Holly Kramer, MD, MPH, Department of Preventive Medicine, Loyola University Medical Center, 2160 First Ave, Maywood, IL 60153

PII: S0272-6386(08)01472-8

doi:10.1053/j.ajkd.2008.10.003

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