The Obesity Paradox in Kidney Disease: How to Reconcile It With Obesity Management
2017; Elsevier BV; Volume: 2; Issue: 2 Linguagem: Inglês
10.1016/j.ekir.2017.01.009
ISSN2468-0249
AutoresKamyar Kalantar‐Zadeh, Connie M. Rhee, Jason Chou, Seyed‐Foad Ahmadi, Jongha Park, Joline L.T. Chen, Alpesh Amin,
Tópico(s)Muscle and Compartmental Disorders
ResumoObesity, a risk factor for de novo chronic kidney disease (CKD), confers survival advantages in advanced CKD. This so-called obesity paradox is the archetype of the reverse epidemiology of cardiovascular risks, in addition to the lipid, blood pressure, adiponectin, homocysteine, and uric acid paradoxes. These paradoxical phenomena are in sharp contradistinction to the known epidemiology of cardiovascular risks in the general population. In addition to advanced CKD, the obesity paradox has also been observed in heart failure, chronic obstructive lung disease, liver cirrhosis, and metastatic cancer, as well as in elderly individuals. These are populations in whom protein−energy wasting and inflammation are strong predictors of early death. Both larger muscle mass and higher body fat provide longevity in these patients, whereas thinner body habitus and weight loss are associated with higher mortality. Muscle mass appears to be superior to body fat in conferring an even greater survival. The obesity paradox may be the result of a time discrepancy between competing risk factors, that is, overnutrition as the long-term killer versus undernutrition as the short-term killer. Hemodynamic stability of obesity, lipoprotein defense against circulating endotoxins, protective cytokine profiles, toxin sequestration of fat mass, and antioxidation of muscle may play important roles. Despite claims that the obesity paradox is a statistical fallacy and a result of residual confounding, the consistency of data and other causality clues suggest a high biologic plausibility. Examining the causes and consequences of the obesity paradox may help uncover important pathophysiologic mechanisms leading to improved outcomes in patients with CKD. Obesity, a risk factor for de novo chronic kidney disease (CKD), confers survival advantages in advanced CKD. This so-called obesity paradox is the archetype of the reverse epidemiology of cardiovascular risks, in addition to the lipid, blood pressure, adiponectin, homocysteine, and uric acid paradoxes. These paradoxical phenomena are in sharp contradistinction to the known epidemiology of cardiovascular risks in the general population. In addition to advanced CKD, the obesity paradox has also been observed in heart failure, chronic obstructive lung disease, liver cirrhosis, and metastatic cancer, as well as in elderly individuals. These are populations in whom protein−energy wasting and inflammation are strong predictors of early death. Both larger muscle mass and higher body fat provide longevity in these patients, whereas thinner body habitus and weight loss are associated with higher mortality. Muscle mass appears to be superior to body fat in conferring an even greater survival. The obesity paradox may be the result of a time discrepancy between competing risk factors, that is, overnutrition as the long-term killer versus undernutrition as the short-term killer. Hemodynamic stability of obesity, lipoprotein defense against circulating endotoxins, protective cytokine profiles, toxin sequestration of fat mass, and antioxidation of muscle may play important roles. Despite claims that the obesity paradox is a statistical fallacy and a result of residual confounding, the consistency of data and other causality clues suggest a high biologic plausibility. Examining the causes and consequences of the obesity paradox may help uncover important pathophysiologic mechanisms leading to improved outcomes in patients with CKD. Patients with advanced chronic kidney disease (CKD), that is, with an estimated glomerular filtration rate (eGFR) of 30 kg/m2, especially in the context of metabolic syndrome and insulin resistance, is associated with higher risk of de novo CKD.19Rhee C.M. Ahmadi S.F. Kalantar-Zadeh K. The dual roles of obesity in chronic kidney disease: a review of the current literature.Curr Opin Nephrol Hypertens. 2016; 25: 208-216Crossref PubMed Scopus (75) Google Scholar In a national cohort of more than 3 million US veterans without previously known renal insufficiency (eGFR >60 ml/min/1.73 m2), higher BMI > 30 kg/m2 was associated with loss of kidney function across different ages.20Lu J.L. Molnar M.Z. Naseer A. et al.Association of age and BMI with kidney function and mortality: a cohort study.Lancet Diabetes Endocrinol. 2015; 3: 704-714Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar The lowest risk for loss of kidney function was noted in patients with BMI levels between 25 and 30 kg/m2, whereas a consistent U-shaped association between BMI and rapid loss of kidney function was noted for BMI levels 30 kg/m2, which was more prominent with advanced age, except in the patients who were younger than 40 years, in whom BMI was not predictive of renal function impairment.20Lu J.L. Molnar M.Z. Naseer A. et al.Association of age and BMI with kidney function and mortality: a cohort study.Lancet Diabetes Endocrinol. 2015; 3: 704-714Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar The investigators concluded that obesity, defined by a BMI of >30 kg/m2, was associated with a rapid loss of kidney function in patients with eGFR > 60 ml/min/1.73 m2.20Lu J.L. Molnar M.Z. Naseer A. et al.Association of age and BMI with kidney function and mortality: a cohort study.Lancet Diabetes Endocrinol. 2015; 3: 704-714Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Emerging data suggest that weight loss interventions may prevent de novo CKD or may slow or reverse early CKD progression, although some bariatric surgical interventions may result in an initial drop in eGFR, which may be due to improvement in glomerular hyperfiltration and hence favorable sequelae.21Friedman A.N. Wolfe B. Is bariatric surgery an effective treatment for type II diabetic kidney disease?.Clin J Am Soc Nephrol. 2016; 11: 528-535Crossref PubMed Scopus (52) Google Scholar, 22Friedman A.N. Quinney S.K. Inman M. et al.Influence of dietary protein on glomerular filtration before and after bariatric surgery: a cohort study.Am J Kidney Dis. 2014; 63: 598-603Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Although the pathogenesis of CKD in obesity remains obscure, studies indicate that excess body fat can result in kidney disease by means of different mechanisms including secondary focal segmental glomerulosclerosis.23Kovesdy C.P. Furth S.L. Zoccali C. World Kidney Day Steering Committee. Obesity and kidney disease: hidden consequences of the epidemic.Kidney Int. 2016; https://doi.org/10.1016/j.kint.2016.10.019Abstract Full Text Full Text PDF Scopus (34) Google Scholar Meta-analyses suggest that once CKD develops, overweight and obese ranges of BMI are paradoxically associated with greater survival in advanced predialysis (eGFR<30 ml/min/1.73 m2) and dialysis-dependent CKD patients,24Ahmadi S.F. Zahmatkesh G. Ahmadi E. et al.Association of body mass index with clinical outcomes in non-dialysis-dependent chronic kidney disease: a systematic review and meta-analysis.Cardiorenal Med. 2015; 6: 37-49Crossref PubMed Scopus (79) Google Scholar whereas a pooled analysis showed that higher pretransplantation BMI was associated with higher mortality in kidney transplantation recipients.25Ahmadi S.F. Zahmatkesh G. Streja E. et al.Body mass index and mortality in kidney transplant recipients: a systematic review and meta-analysis.Am J Nephrol. 2014; 40: 315-324Crossref PubMed Scopus (68) Google Scholar In dialysis patients, the obesity paradox data are quite consistent, especially in maintenance hemodialysis patients, as has been reviewed elsewhere.11Park J. Ahmadi S.F. Streja E. et al.Obesity paradox in end-stage kidney disease patients.Prog Cardiovasc Dis. 2014; 56: 415-425Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 26Park J. Jin D.C. Molnar M.Z. et al.Mortality predictability of body size and muscle mass surrogates in Asian vs white and African American hemodialysis patients.Mayo Clin Proc. 2013; 88: 479-486Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Hence, it is important to acknowledge the role of obesity as an important risk factor for de novo CKD. However, once CKD has occurred, there appears to be a consistent association between obesity and better outcomes including lower mortality in those with advanced CKD, particularly among patients receiving hemodialysis therapy, suggesting that the reverse epidemiology of obesity is robust (Figure 2). Having a larger body size means having either greater solid weight or water weight. It is relatively well known that higher fluid retention is associated with poorer outcomes, particularly in dialysis patients.27Kalantar-Zadeh K. Regidor D.L. Kovesdy C.P. et al.Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis.Circulation. 2009; 119: 671-679Crossref PubMed Scopus (401) Google Scholar A 2-year cohort of 34,107 hemodialysis patients who had an average weight gain of at least 0.5 kg above their postdialysis dry weight by the time of their subsequent hemodialysis treatment showed that higher weight gain increments were associated with higher risk of all-cause and cardiovascular mortality, so that the hazard ratios of cardiovascular death for weight gains of 4.0 kg (compared with 1.5−2.0 kg as the reference) were 0.67 (95% confidence interval: 0.58−0.76) and 1.25 (1.12−1.39), respectively.27Kalantar-Zadeh K. Regidor D.L. Kovesdy C.P. et al.Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis.Circulation. 2009; 119: 671-679Crossref PubMed Scopus (401) Google Scholar The mechanisms by which fluid retention influences cardiovascular death in hemodialysis patients may be similar to that of the heart failure population and warrants further research.27Kalantar-Zadeh K. Regidor D.L. Kovesdy C.P. et al.Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis.Circulation. 2009; 119: 671-679Crossref PubMed Scopus (401) Google Scholar Because the bone and viscera typically cannot expand, having a larger solid weight or weight gain is due to having or gaining more skeletal muscle mass or larger fat mass. A gain in fat mass is often the dominating development after a hypercatabolic event or acute illness has resolved or upon higher protein and calorie intake.28Kalantar-Zadeh K. Ahmadi S.F. Carrying a heavier weight is healthy: obesity-reinforced fitness hypothesis in metabolically healthy obesity.Obesity (Silver Spring). 2016; 24: 281-282Crossref PubMed Scopus (6) Google Scholar Indeed, the Minnesota study in volunteer soldiers who agreed to starve for days showed that, after losing weight with proportional losses of fat and muscle, regaining the same weight back to baseline was associated with disproportionally higher fat versus muscle regain.29Dulloo A.G. Jacquet J. Girardier L. Autoregulation of body composition during weight recovery in human: the Minnesota Experiment revisited.Int J Obes Relat Metab Disord. 1996; 20: 393-405PubMed Google Scholar Dullo et al. showed that in so-called yo-yo dieting, losing and gaining back the same amount of weight is invariably associated with more fat and less muscle mass accumulation, and is often associated with an even higher risk of insulin resistance, metabolic syndrome, and diabetes mellitus.30Dulloo A.G. A role for suppressed skeletal muscle thermogenesis in pathways from weight fluctuations to the insulin resistance syndrome.Acta Physiol Scand. 2005; 184: 295-307Crossref PubMed Scopus (40) Google Scholar Gaining muscle is much more difficult and requires resistance exercise along with anabolic support such as high protein intake with high biologic value and sometimes anabolic steroids in chronic disease populations and those of older age. Several studies have shown that any gain in body weight is associated with better survival in CKD, whereas both fat mass and fat-free lean body mass, the latter of which is essentially representative of muscle mass, also confer survival advantage. There remains considerable challenge in differentiating fat and muscle mass routinely in the clinical setting. Fat mass can be assessed using dual energy x-ray absoptiometry (DEXA)31Oreopoulos A. Kalantar-Zadeh K. McAlister F.A. et al.Comparison of direct body composition assessment methods in patients with chronic heart failure.J Card Fail. 2010; 16: 867-872Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 32Bross R. Chandramohan G. Kovesdy C.P. et al.Comparing body composition assessment tests in long-term hemodialysis patients.Am J Kidney Dis. 2010; 55: 885-896Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar or near-infrared interactance.33Kalantar-Zadeh K. Dunne E. Nixon K. et al.Near infra-red interactance for nutritional assessment of dialysis patients.Nephrol Dial Transplant. 1999; 14: 169-175Crossref PubMed Scopus (62) Google Scholar Lean body mass can be estimated using imaging studies, anthropometry such as mid-arm muscle circumference,34Noori N. Kopple J.D. Kovesdy C.P. et al.Mid-arm muscle circumference and quality of life and survival in maintenance hemodialysis patients.Clin J Am Soc Nephrol. 2010; 5: 2258-2268Crossref PubMed Scopus (231) Google Scholar, 35Kalantar-Zadeh K. Block G. Kelly M.P. et al.Near infra-red interactance for longitudinal assessment of nutrition in dialysis patients.J Ren Nutr. 2001; 11: 23-31Abstract Full Text PDF PubMed Scopus (34) Google Scholar or equations based on serum creatinine.36Noori N. Kovesdy C.P. Bross R. et al.Novel equations to estimate lean body mass in maintenance hemodialysis patients.Am J Kidney Dis. 2011; 57: 130-139Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Serum creatinine has been shown to correlate closely with muscle mass, especially in dialysis patients,37Patel S.S. Molnar M.Z. Tayek J.A. et al.Serum creatinine as a marker of muscle mass in chronic kidney disease: results of a cross-sectional study and review of literature.J Cachexia Sarcopenia Muscle. 2013; 4: 19-29Crossref PubMed Scopus (230) Google Scholar and equations have been created that use serum creatinine and certain demographic data to estimate lean body mass, as published by Noori et al.36Noori N. Kovesdy C.P. Bross R. et al.Novel equations to estimate lean body mass in maintenance hemodialysis patients.Am J Kidney Dis. 2011; 57: 130-139Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar In a study in 535 adult hemodialysis patients whose body fat was directly measured with near-infrared interactance, low baseline body fat percentage and fat loss over time were independently associated with higher mortality even after adjustment for demographics and surrogates of muscle mass and inflammation, whereas a tendency toward a worse quality of life was seen with a higher body fat percentage.38Kalantar-Zadeh K. Kuwae N. Wu D.Y. et al.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: 202-210Crossref PubMed Scopus (279) Google Scholar In a cohort of 742 hemodialysis patients comprising 391 males and 351 females who were separately divided into 4 quartiles of near-infrared interactance−measured lean body mass and fat mass, the highest versus lowest quartiles of fat mass and lean body mass were strongly associated with lower mortality in women, whereas the highest versus lowest quartiles of fat mass and percentage fat but not of lean body mass were associated with greater survival in men.39Noori N. Kovesdy C.P. Dukkipati R. et al.Survival predictability of lean and fat mass in men and women undergoing maintenance hemodialysis.Am J Clin Nutr. 2010; 92: 1060-1070Crossref PubMed Scopus (86) Google Scholar Cubic spline survival analyses showed greater survival with higher fat mass percentage and higher “fat mass minus lean body mass percentiles” in both sexes, whereas a higher lean body mass was protective in women. This study suggested that the survival advantage of fat mass was superior to that of lean body mass.39Noori N. Kovesdy C.P. Dukkipati R. et al.Survival predictability of lean and fat mass in men and women undergoing maintenance hemodialysis.Am J Clin Nutr. 2010; 92: 1060-1070Crossref PubMed Scopus (86) Google Scholar There are, however, other studies suggesting that both higher lean body mass and BMI are related to greater survival in hemodialysis patients. In a large cohort of 117,683 hemodialysis patients, higher estimated lean body mass, defined by creatinine based equations developed by Noori et al.,36Noori N. Kovesdy C.P. Bross R. et al.Novel equations to estimate lean body mass in maintenance hemodialysis patients.Am J Kidney Dis. 2011; 57: 130-139Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar was linearly associated with lower mortality.40Wang J. Streja E. Rhee C.M. et al.Lean body mass and survival in hemodialysis patients and the roles of race and ethnicity.J Ren Nutr. 2016; 26: 26-37Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Compared with the reference group (48.4 to <50.5 kg), patients with the lowest estimated lean body mass (<41.3 kg) had a 1.4-fold higher risk of mortality. A similar linear association was seen among patients with BMI < 35 kg/m2 and in non-Hispanic Caucasian and African American subgroups. However, higher estimated lean body mass was not associated with improved survival in Hispanic patients or those with BMI > 35 kg/m2.40Wang J. Streja E. Rhee C.M. et al.Lean body mass and survival in hemodialysis patients and the roles of race and ethnicity.J Ren Nutr. 2016; 26: 26-37Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar To better examine the role of different types of fat, a landmark study was conducted by Italian colleagues led by Zoccali et al. in a prospective cohort of 537 dialysis patients, in whom waist circumference was used as surrogate of intra-abdominal or visceral (truncal) fat.41Postorino M. Marino C. Tripepi G. Zoccali C. Abdominal obesity and all-cause and cardiovascular mortality in end-stage renal disease.J Am Coll Cardiol. 2009; 53: 1265-1272Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar In this study, each 10-cm increase in waist circumference was associated with 10% and 37% higher all-cause and cardiovascular death.41Postorino M. Marino C. Tripepi G. Zoccali C. Abdominal obesity and all-cause and cardiovascular mortality in end-stage renal disease.J Am Coll Cardiol. 2009; 53: 1265-1272Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar To determine whether dry weight gain accompanied by an increase in muscle mass is associated with a survival benefit in a nationally representative 5-year cohort of 121,762 maintenance hemodialysis patients, 3-month averaged serum creatinine levels and their changes over time were used as muscle mass and as muscle mass change, respectively.42Kalantar-Zadeh K. Streja E. Kovesdy C.P. et al.The obesity paradox and mortality associated with surrogates of body size and muscle mass in patients receiving hemodialysis.Mayo Clin Proc. 2010; 85: 991-1001Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar Dry weight loss or gain over time exhibited a graded association with higher rates of mortality or survival, respectively, as did changes in serum creatinine level over time. Among a subcohort of 50,831 patients who survived the first 6 months, those who lost weight but had an increased serum creatinine level had a greater survival rate than those who gained weight but had a decreased creatinine level.42Kalantar-Zadeh K. Streja E. Kovesdy C.P. et al.The obesity paradox and mortality associated with surrogates of body size and muscle mass in patients receiving hemodialysis.Mayo Clin Proc. 2010; 85: 991-1001Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar These data suggest that there is a superiority of lean body mass to fat mass, in that larger body size with more muscle mass was associated with better survival, whereas a discordant muscle gain with weight loss over time conferred greater survival benefit as compared with weight gain while losing muscle.42Kalantar-Zadeh K. Streja E. Kovesdy C.P. et al.The obesity paradox and mortality associated with surrogates of body size and muscle mass in patients receiving hemodialysis.Mayo Clin Proc. 2010; 85: 991-1001Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar Additional analyses of the same cohort using more sophisticated analytic techniques confirmed the superiority of muscle mass while overall weight gain or loss maintained parallel associations with survival and mortality, respectively.43Kalantar-Zadeh K. Streja E. Molnar M.Z. et al.Mortality prediction by surrogates of body composition: an examination of the obesity paradox in hemodialysis patients using composite ranking score analysis.Am J Epidemiol. 2012; 175: 793-803Crossref PubMed Scopus (121) Google Scholar A decline in muscle mass appeared to be a stronger predictor of mortality than weight loss. These studies suggest that a consi
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