Hidden Consequences of the Epidemic

Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes mellitus, cardiovascular disease, and also for chronic kidney disease. A high body mass index is one of the strongest risk factors for newonset chronic kidney disease. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing chronic kidney disease in the long-term. The incidence of obesity-related glomerulopathy has increased 10-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year, the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option.


Obesity and Kidney Disease
Hidden Consequences of the Epidemic Csaba P Kovesdy, 1,2 Susan Furth, 3 Carmine Zoccali 4 ; on behalf of the World Kidney Day Steering Committee* Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade.This increasing prevalence has implications for the risk of diabetes mellitus, cardiovascular disease, and also for chronic kidney disease.A high body mass index is one of the strongest risk factors for newonset chronic kidney disease.In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight.The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing chronic kidney disease in the long-term.The incidence of obesity-related glomerulopathy has increased 10-fold in recent years.Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer.This year, the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option.

INTRODUCTION
In 2014, over 600 million adults worldwide, 18 years and older, were obese.Obesity is a potent risk factor for the development of kidney disease.It increases the risk of developing major risk factors for chronic kidney disease (CKD), like diabetes mellitus and hypertension, and it has a direct impact on the development of CKD and end-stage renal disease (ESRD).In individuals affected by obesity, a (likely) compensatory mechanism of hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight.The increase in intraglomerular pressure can damage the kidney structure and raise the risk of developing CKD in the long-term.
The good news is that obesity, as well as the related CKD, are largely preventable.Education and awareness of the risks of obesity and a healthy lifestyle, including proper nutrition and exercise, can dramatically help in preventing obesity and kidney disease.This article reviews the association of obesity with kidney disease on the occasion of the 2017 World Kidney Day.

EPIDEMIOLOGY OF OBESITY IN ADULTS AND CHILDREN
Over the last 3 decades, the prevalence of overweight and obese adults (body mass index [BMI] ≥ 25 kg/m 2 ) worldwide has increased substantially. 1 In the United States, the age-adjusted prevalence of obesity in 2013-2014 was 35% among men and 40.4% among women. 2The problem of obesity also affects children.In the United States in 2011-2014, the prevalence of obesity was 17% and extreme obesity 5.8% among youth 2 to 19 years of age.The rise in obesity prevalence is also a worldwide concern, 3,4  to overweight and obesity as parts of Europe and the United States did decades ago. 5 This increasing prevalence of obesity has implications for cardiovascular disease and also for CKD.A high BMI is one of the strongest risk factors for new-onset CKD. 6,7efinitions of obesity are most often based on BMI (ie, weight [kilograms] divided by the square of height [meters]).A BMI between 18.5 kg/m 2 and 25 kg/m 2 is considered by the World Health Organization (WHO) to be normal weight, a BMI between 25 kg/m 2 and 30 kg/m 2 as overweight, and a BMI greater than 30 kg/m 2 as obese.Although BMI is easy to calculate, it is a poor estimate of fat mass distribution, as muscular individuals or those with more subcutaneous fat may have a BMI as high as individuals with larger intraabdominal (visceral) fat.The latter type of high BMI is associated with substantially higher risk of metabolic and cardiovascular disease.Alternative parameters to more accurately capture visceral fat include waist circumference and a waist-hip ratio (WHR) greater than 102 cm and 0.9, respectively, for men and greater than 88 cm and 0.8, respectively, for women.Waist-hip ratio has been shown to be superior to BMI for the correct classification of obesity in CKD.

Association of Obesity With Chronic Kidney Disease and Other Renal Complications
Numerous population-based studies have shown an association between measures of obesity and both the development and the progression of CKD (Table ).6][17][18] Elevated BMI levels, class II obesity and above, have been associated with more rapid progression of CKD in patients with pre-existing CKD.19 A few studies examining the association of abdominal obesity using waist-hip ratio or waist circumference with CKD, describe an association between higher girth and albuminuria, 20 decreased GFR, 8  Higher visceral adipose tissue measured by computed tomography has been associated with a higher prevalence of albuminuria in men.22 The observation of a BMI-independent association between abdominal obesity and poorer renal outcomes is also described in relationship with mortality in patients with ESRD and kidney transplant, 23,24 and suggests a direct role of visceral adiposity. Ineneral, the associations between obesity and poorer renal outcomes persist even after adjustments for possible mediators of obesity's cardiovascular and metabolic effects, such as high blood pressure and diabetes mellitus, suggesting that obesity may affect kidney function through mechanisms in part unrelated to these complications (vide infra).
The deleterious effect of obesity on the kidneys extends to other complications such as nephrolithiasis and kidney malignancies.6][27] Furthermore, weight gain over time and higher baseline waist circumference were also associated with higher incidence of nephrolithiasis. 27Obesity is associated with various types of malignancies, particularly cancers of the kidneys.In a population-based study of 5.24 million individuals from the United Kingdom, a 5 kg/m 2 higher BMI was associated with a 25% higher risk of kidney cancers, with 10% of all kidney cancers attributable to excess weight. 28Another large analysis examining the global burden of obesity on malignancies estimated that 17% and 26% of all kidney cancers in men and women, respectively, were attributable to excess weight. 29The association between obesity and kidney cancers was consistent in both men and women, and across populations from different parts of the world in a meta-analysis that included data from 221 studies (of which 17 examined kidney cancers). 30Among the cancers examined in this meta-analysis, kidney cancers had the third highest risk associated with obesity (relative risk per 5 kg/ m 2 higher BMI, 1.24; 95% confidence interval, 1.20 to 1.28, P < .001). 30

Mechanisms of Action Underlying the Renal Effects of Obesity
Obesity results in complex metabolic abnormalities which have wide-ranging effects on diseases affecting the kidneys.The exact mechanisms whereby obesity may worsen or cause CKD remain unclear.The fact that most obese individuals never develop CKD, and the distinction of up to as many as 25% of obese individuals as "metabolically healthy" suggests that increased weight alone is not sufficient to induce kidney damage. 313][34] These include the development of inflammation, 35 oxidative stress, 36 abnormal lipid metabolism, 37 activation of the renin-angiotensinaldosterone system, 38 and increased production of insulin and insulin resistance. 39,40hese various effects result in specific pathologic changes in the kidneys, 41 which could underlie the higher risk of CKD seen in observational studies.These include ectopic lipid accumulation 42 and increased deposition of renal sinus fat, 43,44 the development of glomerular hypertension and increased glomerular permeability caused by hyperfiltration-related glomerular filtration barrier injury, 45 and ultimately the development of glomerulomegaly, 46 and focal or segmental glomerulosclerosis (Figure 2). 41The incidence of the so-called "obesity-related glomerulopathy" has increased ten-fold between 1986 and 2000. 41mportantly, obesity-related glomerulopathy often presents along with pathophysiologic processes related to other conditions or advanced age, conspiring to result in more accentuated kidney damage in patients with high blood pressure or in the elderly. 14,39,47besity is associated with a number of risk factors contributing to the higher incidence and prevalence of nephrolithiasis.9][50] Diets richer in protein and sodium may lead to a more acidic urine and decrease in urinary citrate, also contributing to kidney calculus risk.3][54] Complicating the picture is the fact that some weight loss therapies result in a worsening, rather than an improvement in the risk for kidney stone formation; eg, gastric surgery can lead to a substantial increase in enteral oxalate absorption and enhanced risk of nephrolithiasis. 55he mechanisms behind the increased risk of kidney cancers observed in obese individuals are less well characterized.Insulin resistance and the consequent chronic hyperinsulinemia and increased production of insulin-like growth factor 1 and numerous complex secondary humoral effects may exert stimulating effects on the growth of various types of tumor cells. 56More recently, the endocrine functions of adipose tissue, 57 its effects on immunity, 58 and the generation of an inflammatory milieu with complex effects on cancers 59,60 have emerged as additional explanations.

Obesity in Patients With Advanced Kidney Disease: The Need for a Nuanced Approach
5][66][67] It is possible that the seemingly protective effect of a high BMI is the result of the imperfection of BMI as a measure of obesity, as it does not differentiate the effects of adiposity from those of higher nonadipose tissue.Indeed, studies that separated the effects of a higher waist circumference from those of higher BMI showed a reversal of the inverse association with mortality. 23,24Higher muscle mass has also been shown to explain at least some of the positive effects attributed to elevated BMI. 63,68However, there is also evidence to suggest that higher adiposity, especially subcutaneous (nonvisceral) fat, may also be associated with better outcomes in ESRD patients. 62Such benefits may indeed be present in patients who have very low short-term life expectancy, such as most ESRD patients. 69Indeed, some studies that examined the association of BMI with time-dependent survival in ESRD have shown a marked contrast between protective short-term effects versus deleterious longer-term effects of higher BMI. 70There are several putative short-term benefits that higher body mass could portend, especially to sicker individuals.These include a benefit from the better nutritional status typically seen in obese individuals, which provides better protein and energy reserves in the face of acute illness, and a higher muscle mass with enhanced antioxidant capacity and lower circulating actin and higher plasma gelsolin levels, 63,71 which are associated with better outcomes.Other hypothetically beneficial characteristics of obesity include a more stable hemodynamic status with mitigation of stress responses and heightened sympathetic and reninangiotensin activity 72 ; increased production of adiponectines and soluble tumor necrosis factor alfa receptors by adipose tissue neutralizing the adverse effects of tumor necrosis factor alfa 73,74 ; enhanced binding of circulating endotoxins by the characteristically higher cholesterol levels seen in obesity 75 ; and sequestration of uremic toxins by adipose tissue. 76

Potential Interventions for Management of Obesity
Obesity engenders kidney injury via direct mechanisms through deranged synthesis of various adipose tissue cytokines with nephrotoxic potential, as well as indirectly by triggering diabetes and hypertension, i.e. two conditions that rank among the strongest risk factors for CKD.Perhaps due to the survival advantage of obesity in CKD, the prevalence of end stage kidney disease is on the rise both in the United States and in Europe. 77,78trategies for controlling the obesity related CKD epidemic at population level and for countering the evolution of CKD toward kidney failure in obese patients represent the most tantalizing task that today's health planners, health managers and nephrologists face.

Countering Chronic Kidney Disease at Population Level
Calls for public health interventions in the community to prevent and treat CKD at an early stage have been made by major renal associations, including the International Society of Nephrology, the International Federation of the Kidney Foundation, the European Renal Association, and various national societies.In the United States, Healthy People 2020, a program that sets 10-year health targets for health promotion and prevention goals, focuses both on CKD and obesity.Surveys to detect obese patients, particularly those with a high risk of CKD (eg, hypertensive or diabetic obese people) and those receiving suboptimal care to inform these patients of the potential risk for CKD they are exposed to, is the first step towards developing public health interventions.Acquiring evidence that current interventions to reduce CKD risk in the obese are efficacious and deployable, is an urgent priority to set goals and means for risk modification.Appropriate documentation of existing knowledge distilling the risk and the benefits of primary and secondary prevention interventions in obese people, and new trials in this population to fill knowledge gaps (see below) are needed.Finally, surveillance programs that monitor progress on the detection of at-risk individuals and the effectiveness of prevention programs being deployed constitute the third, fundamental element for establishing efficacious CKD prevention plans at population level. 79 successful surveillance system for CKD has already been implemented in some places such as the United Kingdom. 80A campaign to disseminate and apply the Kidney Disease Outcomes Quality Initiative CKD guidelines in primary care within the United Kingdom National Health Service was launched.This progressively increased the adoption of the Kidney Disease Outcomes Quality Initiative guidelines and, also thanks to specific incentives for United Kingdom general physicians to detect CKD, led to an impressive improvement in the detection and care of CKD, ie, better control of hypertension and increased use of angiotensinconverting enzyme and angiotensin receptor blockers. 80This system may serve as a platform to improve the prevention of obesity-related CKD.Campaigns aiming at reducing the obesity burden are now at center stage worldwide and are strongly recommended by the WHO and it is expected that these campaigns will reduce the incidence of obesity-related complications, including CKD.However, obesity-related goals in obese CKD patients remain vaguely formulated, largely because of the paucity of high-level evidence intervention studies to modify obesity in CKD patients. 81

Prevention of Chronic Kidney Disease Progression in Obese People
O b s e r v a t i o n a l s t u d i e s i n m e t a b o l i c a l l y healthy obese patients show that the obese p h e n o t y p e u n a s s o c i a t e d w i t h m e t a b o l i c abnormalities per se predicts a higher risk for incident CKD, 82  engender kidney dysfunction and kidney damage even without diabetes mellitus or hypertension (vide supra).In overweight or obese diabetic patients, a lifestyle intervention including caloric restriction and increased physical activity compared with a standard follow-up based on education and support to sustain diabetes mellitus treatment reduced the risk for incident CKD by 30%, although it did not affect the incidence of cardiovascular events. 83Such a protective effect was partly due to reductions in body weight, glycated hemoglobin, and systolic blood pressure.No safety concerns regarding kidney-related adverse events were seen. 83In a recent meta-analysis collating experimental studies in obese CKD patients, interventions aimed at reducing body weight showed coherent reductions in blood pressure, glomerular hyperfiltration, and proteinuria. 81A thorough post hoc analysis of the REIN study showed that the nephron-protective effect of angiotensin-converting enzyme inhibition in proteinuric CKD patients was maximal in obese CKD patients, but minimal in CKD patients with normal or low BMI. 84][87] Globally, these experimental findings provide a proof of concept for the usefulness of weight reduction and angiotensin-converting enzyme inhibition interventions in the treatment of CKD in the obese.Studies showing a survival benefit of increased BMI in CKD patients, however, remain to be explained. 88These findings limit our ability to make strong recommendations about the usefulness and the safety of weight reduction among individuals with more advanced stages of CKD.Lifestyle recommendations to reduce body weight in obese people at risk for CKD and in those with early CKD appear justified, particularly recommendations for the control of diabetes and hypertension.As the independent effect of obesity control on the incidence and progression of CKD is difficult to disentangle from the effects of hypertension and type 2 diabetes, recommendation of weight loss in the minority of metabolically healthy nonhypertensive obese patients remains unwarranted.These considerations suggest that a therapeutic approach to overweight and obesity in patients with advanced CKD or other significant comorbid conditions has to be pursued carefully, with proper considerations of the expected benefits and potential complications of weight loss over the life span of the individual patient.

CONCLUSIONS
The worldwide epidemic of obesity affects the Earth's population in many ways.Diseases of the kidneys, including CKD, nephrolithiasis and kidney cancers are among the more insidious effects of obesity, but which nonetheless have wide ranging deleterious consequences, ultimately leading to significant excess morbidity and mortality and excess costs to individuals and the entire society.Population-wide interventions to control obesity could have beneficial effects in preventing the development, or delaying the progression of CKD.It is incumbent upon the entire healthcare community to devise long-ranging strategies towards improving the understanding of the links between obesity and kidney diseases, and to determine optimal strategies to stem the tide.The 2017 World Kidney Day is an important opportunity to increase education and awareness to that end.
suggesting that obesity per se may Iranian Journal of Kidney Diseases | Volume 11 | Number 2 | March 2017 as it is projected to grow by 40% across the globe in the next decade.Lowand middle-income countries are now showing evidence of transitioning from normal weight Iranian Journal of Kidney Diseases | Volume 11 | Number 2 | March 2017

21 Study Patients Exposure Outcomes Results Comments
or incident ESRD independent of BMI level.
Studies Examining the Association of Obesity With Various Measures of Chronic Kidney Disease* Iranian Journal of Kidney Diseases | Volume 11 | Number 2 | March 2017 *BMI indicates body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; GFR, glomerular filtration rate; ESRD, end-stage renal disease; and UACR, urine albumin-creatinine ratio.† Iranian Journal of Kidney Diseases | Volume 11 | Number 2 | March 2017