Obesity and kidney disease: hidden consequences of the epidemic

In 2014, >600 million adults worldwide ≥18 years of age, 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 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 increased body weight. The increase in intraglomerular pressure can damage the kidney structure and increase the risk of developing CKD in the long term. The good news is that obesity, as well as the related CKD, is 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. Over the last 3 decades, the prevalence of overweight and obese adults [body mass index (BMI) ≥25 kg/m2] worldwide has increased substantially [1]. In the USA, the age-adjusted prevalence of obesity in 2013–14 was 35% among men and 40.4% among women [2]. The problem of obesity also affects children. In the USA in 2011–14, the prevalence of obesity was 17% and extreme obesity was 5.8% among youth 2–19 years of age. The increase in obesity prevalence is also a worldwide concern [3, 4], as it is projected to grow by 40% across the globe in the next decade. Low- and middle-income countries are now showing evidence of transitioning from normal weight to overweight and obesity as parts of Europe and the USA did decades ago [5]. This increasing prevalence of obesity has implications for cardiovascular disease (CVD) and also for CKD. A high BMI is one of the greatest risk factors for new-onset CKD [6, 7]. Definitions of obesity are most often based on BMI [i.e. weight (kilograms) divided by the square of the person's height (meters)]. A BMI between 18.5 and 25 kg/m2 is considered by the World Health Organization (WHO) to be normal weight, a BMI between 25 and 30 kg/m2 is overweight and a BMI >30 kg/m2 is 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 amounts of intraabdominal (visceral) fat. The latter type of high BMI is associated with substantially higher risk of metabolic disease and CVD. Alternative parameters to more accurately capture visceral fat include waist circumference (WC) and a waist:hip ratio (WHR) >102 cm and 0.9, respectively, for men and >88 cm and >0.8, respectively, for women. WHR has been shown to be superior to BMI for the correct classification of obesity in CKD. Numerous population-based studies have shown an association between measures of obesity and both the development and the progression of CKD (Table 1). Higher BMI is associated with the presence [8] and development [9–11] of proteinuria in individuals without kidney disease. Furthermore, in numerous large population-based studies, higher BMI appears associated with the presence [8, 12] and development of low estimated glomerular filtration rate (eGFR) [9, 10, 13], with more rapid loss of eGFR over time [14] and with the incidence of ESRD [15–18]. 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 WHR or WC with CKD describe an association between greater girth and albuminuria [20], decreased GFR [8] or incident ESRD [21] independent of BMI. Studies examining the association of obesity with various measures of CKD Presence of urine albumin 30–300 mg/24 h Elevated and diminished GFR Obese + central fat: higher risk of albuminuria Obese ± central fat: higher risk of elevated GFR Central fat ± obesity associated with diminished filtration Obesity (BMI >30 kg/m2) Diet and lifestyle-related factors Incident CKD stage 3 Incident proteinuria Higher BMI not associated with CKD stage 3 after adjustments Higher BMI associated with increased odds of incident proteinuria BMI quintiles Increase in BMI over time (versus stable BMI) Higher baseline BMI and increase in BMI over time both associated with higher risk of incident CKD Risk strongest in diabetics, but also significantly higher in nondiabetics Cross-sectional analysis Incidence of ESRD Doubling of serum creatinine Slopes of eGFR BMI above normal not associated with ESRD after adjustment for WC Higher WC associated with ESRD Presence of urine albumin 30–300 mg/24 h Elevated and diminished GFR Obese + central fat: higher risk of albuminuria Obese ± central fat: higher risk of elevated GFR Central fat ± obesity associated with diminished filtration Obesity (BMI >30 kg/m2) Diet and lifestyle-related factors Incident CKD stage 3 Incident proteinuria Higher BMI not associated with CKD stage 3 after adjustments Higher BMI associated with increased odds of incident proteinuria BMI quintiles Increase in BMI over time (versus stable BMI) Higher baseline BMI and increase in BMI over time both associated with higher risk of incident CKD Risk strongest in diabetics, but also significantly higher in nondiabetics Cross-sectional analysis Incidence of ESRD Doubling of serum creatinine Slopes of eGFR BMI above normal not associated with ESRD after adjustment for WC Higher WC associated with ESRD Normal weight: BMI 18.5–24.9 kg/m2; overweight: BMI 25.0–29.9 kg/m2; class I obesity: BMI 30.0–34.9 kg/m2; class II obesity: BMI 35.0–39.9 kg/m2; class III obesity: BMI ≥40 kg/m2. CARDIA, Coronary Artery Risk Development in Young Adults; DM, diabetes mellitus; HR, hazard ratio; MDCT, multidetector computed tomography; OR, odds ratio; PREVEND, Prevention of Renal and Vascular End-stage Disease; REGARDS, Reasons for Geographic and Racial Differences in Stroke; SAT, subcutaneous adipose tissue; UACR, urine albumin:creatinine ratio; VAT, visceral adipose tissue. Studies examining the association of obesity with various measures of CKD Presence of urine albumin 30–300 mg/24 h Elevated and diminished GFR Obese + central fat: higher risk of albuminuria Obese ± central fat: higher risk of elevated GFR Central fat ± obesity associated with diminished filtration Obesity (BMI >30 kg/m2) Diet and lifestyle-related factors Incident CKD stage 3 Incident proteinuria Higher BMI not associated with CKD stage 3 after adjustments Higher BMI associated with increased odds of incident proteinuria BMI quintiles Increase in BMI over time (versus stable BMI) Higher baseline BMI and increase in BMI over time both associated with higher risk of incident CKD Risk strongest in diabetics, but also significantly higher in nondiabetics Cross-sectional analysis Incidence of ESRD Doubling of serum creatinine Slopes of eGFR BMI above normal not associated with ESRD after adjustment for WC Higher WC associated with ESRD Presence of urine albumin 30–300 mg/24 h Elevated and diminished GFR Obese + central fat: higher risk of albuminuria Obese ± central fat: higher risk of elevated GFR Central fat ± obesity associated with diminished filtration Obesity (BMI >30 kg/m2) Diet and lifestyle-related factors Incident CKD stage 3 Incident proteinuria Higher BMI not associated with CKD stage 3 after adjustments Higher BMI associated with increased odds of incident proteinuria BMI quintiles Increase in BMI over time (versus stable BMI) Higher baseline BMI and increase in BMI over time both associated with higher risk of incident CKD Risk strongest in diabetics, but also significantly higher in nondiabetics Cross-sectional analysis Incidence of ESRD Doubling of serum creatinine Slopes of eGFR BMI above normal not associated with ESRD after adjustment for WC Higher WC associated with ESRD Normal weight: BMI 18.5–24.9 kg/m2; overweight: BMI 25.0–29.9 kg/m2; class I obesity: BMI 30.0–34.9 kg/m2; class II obesity: BMI 35.0–39.9 kg/m2; class III obesity: BMI ≥40 kg/m2. CARDIA, Coronary Artery Risk Development in Young Adults; DM, diabetes mellitus; HR, hazard ratio; MDCT, multidetector computed tomography; OR, odds ratio; PREVEND, Prevention of Renal and Vascular End-stage Disease; REGARDS, Reasons for Geographic and Racial Differences in Stroke; SAT, subcutaneous adipose tissue; UACR, urine albumin:creatinine ratio; VAT, visceral adipose tissue. Greater 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 relation to mortality in patients with ESRD [23] and kidney transplant [24] and suggests a direct role of visceral adiposity. In general, 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. Higher BMI is associated with an increased prevalence [25] and incidence [26, 27] of nephrolithiasis. Furthermore, weight gain over time and higher baseline WC were also associated with a higher incidence of nephrolithiasis [27]. Obesity is associated with various types of malignancies, particularly cancers of the kidneys. In a population-based study of 5.24 million individuals from the UK, a 5 kg/m2 higher BMI was associated with a 25% higher risk of kidney cancers, with 10% of all kidney cancers attributable to excess weight [28]. Another 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 [29]. The 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) [30]. Among the cancers examined in this meta-analysis, kidney cancers had the third highest risk associated with obesity {relative risk per 5 kg/m2 higher BMI: 1.24 [95% confidence interval (CI) 1.20–1.28], P < 0.0001} [30]. Putative mechanisms of action whereby obesity causes CKD. Obesity-related perihilar focal segmental glomerulosclerosis on a background of glomerulomegaly. Periodic acid–Schiff stain, original magnification ×400. Courtesy of Patrick D. Walker, MD, Arkana Laboratories, Little Rock, AR, USA. Obesity is associated with a number of risk factors contributing to the higher incidence and prevalence of nephrolithiasis. Higher body weight is associated with lower urine pH [48] and increased urinary oxalate [49], uric acid, sodium and phosphate excretion [50]. Diets richer in protein and sodium may lead to a more acidic urine and decrease in urinary citrate, also contributing to kidney stone risk. The insulin resistance characteristic of obesity may also predispose individuals to nephrolithiasis [51] through its impact on tubular Na/H exchanger [52] and ammoniagenesis [53] and the promotion of an acidic milieu [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; e.g. gastric surgery can lead to a substantial increase in enteral oxalate absorption and enhanced risk of nephrolithiasis [55]. The 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 [56]. More 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. Considering the above evidence about the overwhelmingly deleterious effects of obesity on various disease processes, it is seemingly counterintuitive that obesity has been consistently associated with lower mortality rates in patients with advanced CKD [19, 61] and ESRD [62, 63]. Similar ‘paradoxical’ associations have also been described in other populations, such as in patients with congestive heart failure [64], chronic obstructive pulmonary disease [65], rheumatoid arthritis [66] and even in older individuals [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 WC from those of higher BMI showed a reversal of the inverse association with mortality [23, 24]. Greater muscle mass has also been shown to explain at least some of the positive effects attributed to elevated BMI [53, 68]. However, there is also evidence to suggest that higher adiposity, especially subcutaneous (nonvisceral) fat, may also be associated with better outcomes in ESRD patients [62]. Such benefits may indeed be present in patients who have very low short-term life expectancy, such as most ESRD patients [69]. Indeed, 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 [70]. There 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 [63] and lower circulating actin and higher plasma gelsolin levels [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 renin–angiotensin activity [72], increased production of adiponectines [73] and soluble tumor necrosis factor alfa receptors [74] by adipose tissue neutralizing the adverse effects of tumor necrosis factor alfa, enhanced binding of circulating endotoxins [75] by the characteristically higher cholesterol levels seen in obesity and sequestration of uremic toxins by adipose tissue [76]. 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 greatest risk factors for CKD. Perhaps due to the survival advantage of obesity in CKD, the prevalence of ESRD is on the rise both in the USA [77] and in Europe [78]. Strategies for controlling the obesity-related CKD epidemic at the 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. 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 (ISN), International Federation of the Kidney Foundation (IFKF), European Renal Association (ERA-EDTA) and various national societies. In the USA, 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 (e.g. hypertensive and/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 toward 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 [79] constitute the third fundamental element for establishing efficacious CKD prevention plans at the population level. A successful surveillance system for CKD has already been implemented in some places, such as the UK [80]. A campaign to disseminate and apply Kidney Disease Outcomes Quality Initiative (KDOQI) CKD guidelines in primary care within the UK National Health Service was launched. This progressively increased the adoption of KDOQI guidelines and, thanks to specific incentives for UK general physicians to detect CKD, led to an impressive improvement in the detection and care of CKD, i.e. better control of hypertension and increased use of angiotensin-converting enzyme (ACE) and angiotensin receptor blockers [80]. This system may serve as a platform to improve the prevention of obesity-related CKD. Campaigns aimed 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 from intervention studies to modify obesity in CKD patients [81]. Observational studies in metabolically healthy obese subjects show that an obese phenotype unassociated with metabolic abnormalities per se predicts a higher risk for incident CKD [82], suggesting that obesity per se may engender renal dysfunction and kidney damage even without diabetes or hypertension (vide supra). In overweight or obese diabetic patients, lifestyle intervention including caloric restriction and increased physical activity compared with a standard follow-up based on education and support to sustain diabetes treatment reduced the risk for incident CKD by 30%, although it did not affect the incidence of cardiovascular events [83]. Such a protective effect was partly due to reductions in body weight, hemoglobin A1c and systolic blood pressure. No safety concerns regarding kidney-related adverse events were seen [83]. In 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 [81]. A thorough posthoc analysis of the Ramipril Efficacy In Nephropathy study showed that the nephron-protective effect of ACE inhibition in proteinuric CKD patients was maximal in obese CKD patients but minimal in CKD patients with normal or low BMI [84]. Of note, bariatric surgical intervention has been suggested for selected CKD and ESRD patients, including dialysis patients who are waitlisted for kidney transplantation [85–87]. Globally, these experimental findings provide a proof of concept for the usefulness of weight reduction and ACE 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 [88]. These 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; a 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 The worldwide epidemic of obesity affects the population in of the including CKD, nephrolithiasis and kidney cancers, are among the more effects of obesity, but have deleterious to significant excess and mortality and excess to individuals and interventions to control obesity could have beneficial effects in preventing the development or the progression of CKD. It is the health care community to to improve our of the between obesity and kidney and to to the The 2017 World Kidney is an to increase education and awareness to that