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Abstract

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, cardiovascular disease and also for Chronic Kidney Disease. A high body mass index is one of the strongest risk factors for new-onset 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 ten-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 makes preventive behaviors an affordable option.

Keywords

obesity, chronic kidney disease, nephrolithiasis, kidney cancer, prevention

Abbreviations and Acronyms

Normal weight: BMI 18.5 to 24.9 kg/m2
overweight: BMI 25.0 to 29.9 kg/m2
class I obesity: BMI 30.0 to 34.9 kg/m2
class II obesity: BMI 35.0 to 39.9 kg/m2
class III obesity: BMI ≥40 kg/m2
BMI: body mass index
CKD: chronic kidney disease
DM: diabetes mellitus
eGFR: estimated glomerular filtration rate
ESRD: end stage renal disease
HR: hazard ratio
OR: odds ratio
UACR: urine albumin-creatinine ratio

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 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 (BMI ≥25 kg/m2) worldwide has increased substantially [1]. In the US, the age-adjusted prevalence of obesity in 2013-2014 was 35% among men and 40.4% among women [2]. The problem of obesity also affects children. In the US in 2011-2014, the prevalence of obesity was 17% and extreme obesity 5.8% among youth 2-19 years of age. The rise 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 United States did decades ago [5]. This increasing prevalence of obesity has implications for cardiovascular disease (CVD) and also for CKD. A high body mass index (BMI) is one of the strongest 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 his or her 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 as overweight, and a BMI of >30 kg/m2 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 (WC) and a waist hip ratio (WHR) of >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.

Association of obesity with CKD 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 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 GFR, [9,10,13] with more rapid loss of estimated GFR 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 higher girth and albuminuria, [20] decreased GFR [8] or incident ESRD [21] independent of BMI level.

Table 1. Studies examining the association of obesity with various measures of CKD

Study Patients Exposure Outcomes Results Comments
Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study8 7,676 Dutch individuals without diabetes Elevated BMI (overweight and obese*), and central fat distribution (waist-hip ratio) -Presence of urine albumin 30-300 mg/24h

-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

Cross sectional analysis
Multinational study of hypertensive outpatients20 20,828 patients from 26 countries BMI and waist circumference Prevalence of albuminuria by dip stick Higher waist circumference associated with albuminuria independent of BMI Cross sectional analysis
Framingham Multi-Detector Computed Tomography (MDCT) cohort22 3,099 individuals Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) Prevalence of UACR >25 mg/g in women and >17 mg/g in men VAT associated with albuminuria in men, but not in women Cross sectional analysis
CARDIA (Coronary Artery Risk Development in Young Adults) study11 2,354 community-dwelling individuals with normal kidney function aged 28-40 years -Obesity (BMI >30 kg/m2)

-Diet and lifestyle-related factors

Incident microalbuminuria Obesity (OR 1.9) and unhealthy diet (OR 2.0) associated with incident albuminuria Low number of events
Hypertension Detection and Follow-Up Program10 5,897 hypertensive adults Overweight and obese BMI* vs. normal BMI Incident CKD (1+ or greater proteinuria on urinalysis and/or an eGFR <60 mL/min/1.73 m2) Both overweight (OR 1.21) and obesity (OR 1.40) associated with incident CKD Results unchanged after excluding diabetics
Framingham Offspring Study9 2,676 individuals free of CKD stage 3 High vs. normal BMI* -Incident CKD stage 3

-Incident proteinuria

-Higher BMI not associated with CKD3 after adjustments

-Higher BMI associated with increased odds of incident proteinuria

Predominantly white, limited geography
Physicians’ Health Study13 11,104 initially healthy men in US -BMI quintiles

-Increase in BMI over time (vs. stable BMI)

Incident eGFR <60 mL/min/1.73 m2 -Higher baseline BMI and increase in BMI over time both associated with higher risk of incident CKD Exclusively men
Nation-wide US Veterans Administration cohort14 3,376,187 US veterans with baseline eGFR ≥60 mL/min/1.73 m2 BMI categories from <20 to >50 kg/m2 Rapid decline in kidney function (negative eGFR slope of >5 mL/min/1.73 m2) BMI >30 kg/m2 associated with rapid loss of kidney function Associations more accentuated in older individuals
Nation-wide population-based study from Sweden12 926 Swedes with moderate/advanced CKD compared to 998 controls BMI ≥25 vs. <25 kg/m2

 

CKD vs. no CKD Higher BMI associated with 3x higher risk of CKD -Risk strongest in diabetics, but also significantly higher in non-diabetics

-Cross sectional analysis

Nation-wide population based study in Israel17 1,194,704 adolescent males and females examined for military service Elevated BMI (overweight and obesity) vs. normal BMI* Incident ESRD Overweight (HR 3.0) and obesity (HR 6.89) associated with higher risk of ESRD Associations strongest for diabetic ESRD, but also significantly higher for non-diabetic ESRD
The Nord-Trøndelag Health Study (HUNT-1)15 74,986 Norwegian adults BMI categories* Incidence of ESRD or renal death BMI >30 kg/m2 associated with worse outcomes Associations not present in individuals with BL <120/80 mmHg
Community-based screening in Okinawa, Japan16 100,753 individuals >20 years old BMI quartiles Incidence of ESRD Higher BMI associated with increased risk of ESRD in men, but not in women Average BMI lower in Japan compared to Western countries
Nation-wide US Veterans Administration cohort19 453,946 US veterans with baseline eGFR<60 ml/min per 1.73 m2 BMI categories from <20 to >50 kg/m2 -Incidence of ESRD

-Doubling of serum creatinine

-Slopes of eGFR

Moderate and severe obesity associated with worse renal outcomes Associations present but weaker in patients with more advanced CKD
Kaiser Permanente Northern California18 320,252 adults with and without baseline CKD Overweight, class I, II and extreme obesity; vs. normal BMI* Incidence of ESRD Linearly higher risk of ESRD with higher BMI categories Associations remained present after adjustment for DM, hypertension and baseline CKD
REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study21 30,239 individuals Elevated waist circumference or BMI Incidence of ESRD BMI above normal not associated with ESRD after adjustment for waist circumference

-Higher waist circumference associated with ESRD

Association of waist circumference with ESRD became on-significant after adjustment for comorbidities and baseline eGFR and proteinuria

 

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 [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 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%CI 1.20-1.28, p<0.0001) [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 [31] Some of the deleterious renal consequences of obesity may be mediated by downstream comorbid conditions such as diabetes mellitus or hypertension, but there are also effects of adiposity which could impact the kidneys directly, induced by the endocrine activity of the adipose tissue via production of (among others) adiponectin, [32] leptin [33] and resistin [34] (Figure 1). These include the development of inflammation, [35] oxidative stress, [36] abnormal lipid metabolism, [37] activation of the renin-angiotensin-aldosterone system,[38] and increased production of insulin and insulin resistance [39,40].

Figure 1. Putative mechanisms of action whereby obesity causes chronic kidney disease

Figure 1. Putative mechanisms of action whereby obesity causes chronic kidney disease

These 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 [41] (Figure 2). The incidence of the so-called obesity-related glomerulopathy (ORG) has increased ten-fold between 1986 and 2000. [41] Importantly, ORG 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 [47] or in the elderly. [14-39].

Figure 2. Obesity-related perihilar focal segmental glomerulosclerosis on a background of glomerulomegaly. Periodic Acid-Schiff stain, original magnification 400x

Figure 2. Obesity-related perihilar focal segmental glomerulosclerosis on a background of glomerulomegaly. Periodic Acid-Schiff stain, original magnification 400x

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 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.

Obesity in patients with advanced kidney disease: The need for a nuanced approach

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 old 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 non-adipose 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 [23,24]. Higher muscle mass has also been shown to explain at least some of the positive effects attributed to elevated BMI [63, 68]. However, there is also evidence to suggest that higher adiposity, especially subcutaneous (non-visceral) 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 vs. 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, and 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].

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 USA [77] and in Europe [78]. Strategies 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 CKD 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 (ISN), International Federation of the Kidney Foundation (IFKF), the 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 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 [79] constitute the third, fundamental element for establishing efficacious CKD prevention plans at population level.

A successful surveillance system for CKD has already been implemented in some places such as the United Kingdom (UK [80]. A campaign to disseminate and apply K-DOQI CKD guidelines in primary care within the UK National Health Service was launched. This progressively increased the adoption of K-DOQI guidelines and, also 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 and angiotensin receptor blockers [80]. This 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 CKD progression in obese people with CKD

Observational studies in metabolically healthy obese subjects show that the 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, a 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, HbA1c, and systolic BP. 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 hyper-filtration and proteinuria [81]. A thorough post-hoc analysis of the REIN 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 have 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, recommendation of weight loss in the minority of metabolically healthy, non-hypertensive 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.

References

  1. GBD 2013 Risk Factors Collaborators, Forouzanfar MH, Alexander L, Anderson HR, Bachman VF, et al. (2015) Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386: 2287-2323. [crossref]
  2. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL1 (2016) Trends in Obesity Among Adults in the United States, 2005 to 2014. JAMA 315: 2284-2291. [crossref]
  3. Cattaneo A, Monasta L, Stamatakis E, Lioret S, Castetbon K, et al. (2010) Overweight and obesity in infants and pre-school children in the European Union: a review of existing data. Obes Rev 11: 389-398. [crossref]
  4. Olaya B1,2, Moneta MV3,4, Pez O5, et al. (2015) Country-level and individual correlates of overweight and obesity among primary school children: a cross-sectional study in seven European countries. BMC Public Health 15: 475. [crossref]
  5. Subramanian SV, Perkins JM, Özaltin E, Davey Smith G (2011) Weight of nations: a socioeconomic analysis of women in low- to middle-income countries. Am J Clin Nutr 93: 413-421. [crossref]
  6. Tsujimoto T, Sairenchi T, Iso H, Irie F, Yamagishi K, et al. (2014) The dose-response relationship between body mass index and the risk of incident stage >/=3 chronic kidney disease in a general japanese population: the Ibaraki prefectural health study (IPHS). J Epidemiol 24: 444-45.
  7. Elsayed EF, Sarnak MJ, Tighiouart H, Griffith JL, Kurth T, et al. (2008) Waist-to-hip ratio, body mass index, and subsequent kidney disease and death. Am J Kidney Dis 52: 29-38. [crossref]
  8. Pinto-Sietsma SJ, Navis G, Janssen WM, de Zeeuw D, Gans RO, et al. (2003) A central body fat distribution is related to renal function impairment, even in lean subjects. Am J Kidney Dis 41: 733-741. [crossref]
  9. Foster MC, Hwang SJ, Larson MG, Lichtman JH, Parikh NI, et al. (2008) Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis 52: 39-48. [crossref]
  10. Kramer H, Luke A, Bidani A, Cao G, Cooper R, et al. (2005) Obesity and prevalent and incident CKD: the Hypertension Detection and Follow-Up Program. Am J Kidney Dis 46: 587-594. [crossref]
  11. Chang A, Van HL, Jacobs DR, Liu K, Muntner P, et al. (2013) Lifestyle-related factors, obesity, and incident microalbuminuria: the CARDIA (Coronary Artery Risk Development in Young Adults) study. Am J Kidney Dis 62:267-275.
  12. Ejerblad E, Fored CM, Lindblad P, Fryzek J, McLaughlin JK, et al. (2006) Obesity and risk for chronic renal failure. J Am Soc Nephrol 17: 1695-1702. [crossref]
  13. Gelber RP, Kurth T, Kausz AT, Manson JE, Buring JE, et al. (2005) Association between body mass index and CKD in apparently healthy men. Am J Kidney Dis 46: 871-880. [crossref]
  14. Lu JL, Molnar MZ, Naseer A2, Mikkelsen MK, Kalantar-Zadeh K3, et al. (2015) Association of age and BMI with kidney function and mortality: a cohort study. Lancet Diabetes Endocrinol 3: 704-714. [crossref]
  15. Munkhaugen J, Lydersen S, Widerøe TE, Hallan S (2009) Prehypertension, obesity, and risk of kidney disease: 20-year follow-up of the HUNT I study in Norway. Am J Kidney Dis 54: 638-646. [crossref]
  16. Iseki K, Ikemiya Y, Kinjo K, Inoue T, Iseki C, et al. (2004) Body mass index and the risk of development of end-stage renal disease in a screened cohort. Kidney Int 65: 1870-1876. [crossref]
  17. Vivante A, Golan E, Tzur D, Leiba A, Tirosh A, et al. (2012) Body mass index in 1.2 million adolescents and risk for end-stage renal disease. Arch Intern Med 172: 1644-1650. [crossref]
  18. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS (2006) Body mass index and risk for end-stage renal disease. Ann Intern Med 144: 21-28. [crossref]
  19. Lu JL, Kalantar-Zadeh K2, Ma JZ3, Quarles LD, Kovesdy CP4 (2014) Association of body mass index with outcomes in patients with CKD. J Am Soc Nephrol 25: 2088-2096. [crossref]
  20. Thoenes M, Reil JC, Khan BV, Bramlage P, Volpe M, et al. (2009) Abdominal obesity is associated with microalbuminuria and an elevated cardiovascular risk profile in patients with hypertension. Vasc Health Risk Manag 5: 577-585. [crossref]
  21. Kramer H, Gutiérrez OM2, Judd SE3, Muntner P4, Warnock DG5, et al. (2016) Waist Circumference, Body Mass Index, and ESRD in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study. Am J Kidney Dis 67: 62-69. [crossref]
  22. Foster MC, Hwang SJ, Massaro JM, Hoffmann U, DeBoer IH, et al. (2011) Association of subcutaneous and visceral adiposity with albuminuria: the Framingham Heart Study. Obesity (Silver Spring) 19:1284-1289.
  23. Postorino M, Marino C, Tripepi G, Zoccali C; CREDIT (Calabria Registry of Dialysis and Transplantation) Working Group (2009) Abdominal obesity and all-cause and cardiovascular mortality in end-stage renal disease. J Am Coll Cardiol 53: 1265-1272. [crossref]
  24. Kovesdy CP, Czira ME, Rudas A, Ujszaszi A, Rosivall L, et al. (2010) Body mass index, waist circumference and mortality in kidney transplant recipients. Am J Transplant 10: 2644-2651. [crossref]
  25. Scales CD Jr, Smith AC, Hanley JM, Saigal CS; Urologic Diseases in America Project (2012) Prevalence of kidney stones in the United States. Eur Urol 62: 160-165. [crossref]
  26. Curhan GC, Willett WC, Rimm EB, Speizer FE, Stampfer MJ (1998) Body size and risk of kidney stones. J Am Soc Nephrol 9: 1645-1652. [crossref]
  27. Taylor EN, Stampfer MJ, Curhan GC (2005) Obesity, weight gain, and the risk of kidney stones. JAMA 293: 455-462. [crossref]
  28. Bhaskaran K, Douglas I2, Forbes H2, dos-Santos-Silva I2, Leon DA2, et al. (2014) Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet 384: 755-765. [crossref]
  29. Arnold M, Pandeya N2, Byrnes G3, Renehan AG4, Stevens GA5, et al. (2015) Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol 16: 36-46. [crossref]
  30. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371:569-578.
  31. Blüher M (2010) The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol 21: 38-43. [crossref]
  32. Sharma K (2009) The link between obesity and albuminuria: adiponectin and podocyte dysfunction. Kidney Int 76: 145-148. [crossref]
  33. Wolf G, Ziyadeh FN (2006) Leptin and renal fibrosis. Contrib Nephrol 151: 175-183. [crossref]
  34. Ellington AA, Malik AR, Klee GG, Turner ST, Rule AD, et al. (2007) Association of plasma resistin with glomerular filtration rate and albuminuria in hypertensive adults. Hypertension 50:708-714.
  35. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, et al. (2006) Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 17:4-12, 2006
  36. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, et al. (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114: 1752-1761. [crossref]
  37. Ruan XZ, Varghese Z, Moorhead JF (2009) An update on the lipid nephrotoxicity hypothesis. Nat Rev Nephrol 5: 713-721. [crossref]
  38. Ruster C, Wolf G (2013) The role of the renin-angiotensin-aldosterone system in obesity-related renal diseases. 33:44-53, 2013
  39. Oterdoom LH, de Vries AP, Gansevoort RT, de Jong PE, Gans RO, et al. (2007) Fasting insulin modifies the relation between age and renal function. Nephrol Dial Transplant 22: 1587-1592. [crossref]
  40. Reaven GM (1988) Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37: 1595-1607. [crossref]
  41. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD (2001) Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 59: 1498-1509. [crossref]
  42. de Vries AP, Ruggenenti P, Ruan XZ, Praga M, Cruzado JM, et al. (2014) Fatty kidney: emerging role of ectopic lipid in obesity-related renal disease. Lancet Diabetes Endocrinol 2:417-426.
  43. Foster MC, Hwang SJ, Porter SA, Massaro JM, Hoffmann U, et al. (2011) Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58:784-790.
  44. Henegar JR, Bigler SA, Henegar LK, Tyagi SC, Hall JE (2001) Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol 12: 1211-1217. [crossref]
  45. Knight SF, Quigley JE, Yuan J, Roy SS, Elmarakby A, et al. (2008) Endothelial dysfunction and the development of renal injury in spontaneously hypertensive rats fed a high-fat diet. Hypertension 51: 352-359. [crossref]
  46. Tsuboi N, Utsunomiya Y, Kanzaki G, Koike K, Ikegami M, et al. (2012) Low glomerular density with glomerulomegaly in obesity-related glomerulopathy. Clin J Am Soc Nephrol 7: 735-741. [crossref]
  47. Ribstein J, du Cailar G, Mimran A (1995) Combined renal effects of overweight and hypertension. Hypertension 26: 610-615. [crossref]
  48. Maalouf NM, Sakhaee K, Parks JH, Coe FL, Adams-Huet B, et al. (2004) Association of urinary pH with body weight in nephrolithiasis. Kidney Int 65: 1422-1425. [crossref]
  49. Lemann J, Jr., Pleuss JA, Worcester EM, Hornick L, Schrab D, et al. (1996) Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 49:200-208.
  50. Siener R, Glatz S, Nicolay C, Hesse A (2004) The role of overweight and obesity in calcium oxalate stone formation. Obes Res 12: 106-113. [crossref]
  51. Taylor EN, Stampfer MJ, Curhan GC (2005) Diabetes mellitus and the risk of nephrolithiasis. Kidney Int 68: 1230-1235. [crossref]
  52. Klisic J, Hu MC, Nief V, Reyes L, Fuster D, Moe OW, et al. (2002) Insulin activates Na(+)/H(+) exchanger 3: biphasic response and glucocorticoid dependence. Am J Physiol Renal Physiol 283: F532-F539.
  53. Chobanian MC, Hammerman MR (1987) Insulin stimulates ammoniagenesis in canine renal proximal tubular segments. Am J Physiol 253: F1171-F1177.
  54. Daudon M, Lacour B, Jungers P (2006) Influence of body size on urinary stone composition in men and women. Urol Res 34: 193-199. [crossref]
  55. Sinha MK, Collazo-Clavell ML, Rule A, Milliner DS, Nelson W, et al. (2007) Hyperoxaluric nephrolithiasis is a complication of Roux-en-Y gastric bypass surgery. Kidney Int 72:100-107.
  56. Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4: 579-591. [crossref]
  57. Dalamaga M, Diakopoulos KN, Mantzoros CS (2012) The role of adiponectin in cancer: a review of current evidence. Endocr Rev 33: 547-594. [crossref]
  58. Lamas O, Marti A, Martínez JA (2002) Obesity and immunocompetence. Eur J Clin Nutr 56 Suppl 3: S42-45. [crossref]
  59. Lim C, Savan R (2014) The role of the IL-22/IL-22R1 axis in cancer. Cytokine Growth Factor Rev 25: 257-271. [crossref]
  60. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140: 883-899. [crossref]
  61. Kovesdy CP, Anderson JE, Kalantar-Zadeh K (2007) Paradoxical association between body mass index and mortality in men with CKD not yet on dialysis. Am J Kidney Dis 49: 581-591. [crossref]
  62. Kalantar-Zadeh K, Kuwae N, Wu DY, Shantouf RS, Fouque D, et al. (2006) Associations of body fat and its changes over time with quality of life and prospective mortality in hemodialysis patients. Am J Clin Nutr 83: 202-210. [crossref]
  63. Beddhu S, Pappas LM, Ramkumar N, Samore M (2003) Effects of body size and body composition on survival in hemodialysis patients. J Am Soc Nephrol 14: 2366-2372. [crossref]
  64. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, et al. (2005) The obesity paradox: body mass index and outcomes in patients with heart failure. Arch Intern Med 165: 55-61. [crossref]
  65.  Wilson DO, Rogers RM, Wright EC, Anthonisen NR (1989) Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis 139:1435-1438.
  66. Escalante A, Haas RW, del Rincón I (2005) Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch Intern Med 165: 1624-1629. [crossref]
  67. Kalantar-Zadeh K, Kilpatrick RD, Kuwae N, Wu DY (2005) Reverse epidemiology: a spurious hypothesis or a hardcore reality? Blood Purif 23: 57-63. [crossref]
  68. Noori N, Kopple JD, Kovesdy CP, Feroze U, Sim JJ, et al. (2008) Mid-arm muscle circumference and quality of life and survival in maintenance hemodialysis patients. Clin J Am Soc Nephrol 5:2258-2268.
  69. Dekker FW, de Mutsert R, van Dijk PC, Zoccali C, Jager KJ (2008) Survival analysis: time-dependent effects and time-varying risk factors. Kidney Int 74: 994-997. [crossref]
  70. Snyder JJ, Foley RN, Gilbertson DT, Vonesh EF, Collins AJ (2003) Body size and outcomes on peritoneal dialysis in the United States. Kidney Int 64: 1838-1844. [crossref]
  71. Lee PS, Sampath K, Karumanchi SA, Tamez H, Bhan I, et al. (2009) Plasma gelsolin and circulating actin correlate with hemodialysis mortality. J Am Soc Nephrol 20: 1140-1148. [crossref]
  72. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, et al. (2001) The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 38: 789-795. [crossref]
  73. Stenvinkel P, Marchlewska A, Pecoits-Filho R, Heimburger O, Zhang Z, et al. (2004) Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin. Kidney Int 65:274-28.
  74. Mohamed-Ali V, Goodrick S, Bulmer K, Holly JM, Yudkin JS, Coppack SW (1999) Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo. Am J Physiol 277: E971-E975.
  75. Rauchhaus M, Coats AJ, Anker SD (2000) The endotoxin-lipoprotein hypothesis. Lancet 356: 930-933. [crossref]
  76. Jandacek RJ, Anderson N, Liu M, Zheng S, Yang Q, et al. (2005) Effects of yo-yo diet, caloric restriction, and olestra on tissue distribution of hexachlorobenzene. Am J Physiol Gastrointest Liver Physiol 288: G292-299. [crossref]
  77. Kramer HJ, Saranathan A, Luke A, Durazo-Arvizu RA, Guichan C, et al. (2006) Increasing body mass index and obesity in the incident ESRD population. J Am Soc Nephrol 17: 1453-1459. [crossref]
  78. Postorino M, Mancini E, D’Arrigo G, Marino C, Vilasi A, et al. (2016) Body mass index trend in haemodialysis patients: the shift of nutritional disorders in two Italian regions. Nephrol Dial Transplant.
  79. Chimeddamba O, Peeters A, Walls HL, et al. (2015) Noncommunicable Disease Prevention and Control in Mongolia: A Policy Analysis. BMC Public Health 15: 660. [crossref]
  80. O’Donoghue DJ, Stevens PE (2012) A decade after the KDOQI CKD/guidelines: a perspective from the United Kingdom. Am J Kidney Dis 60: 740-742. [crossref]
  81. Bolignano D, Zoccali C (2013) Effects of weight loss on renal function in obese CKD patients: a systematic review. Nephrol Dial Transplant 28 Suppl 4: iv82-iv98.
  82. Chang Y, Ryu S, Choi Y, Zhang Y, Cho J, et al. (2016) Metabolically Healthy Obesity and Development of Chronic Kidney Disease: A Cohort Study. Ann Intern Med 164:305-312.
  83. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al. (2013) Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 369:145-154.
  84. Mallamaci F, Ruggenenti P, Perna A, Leonardis D, Tripepi R, et al. (2011) ACE inhibition is renoprotective among obese patients with proteinuria. J Am Soc Nephrol 22: 1122-1128. [crossref]
  85. Friedman AN, Wolfe B2 (2016) Is Bariatric Surgery an Effective Treatment for Type II Diabetic Kidney Disease? Clin J Am Soc Nephrol 11: 528-535. [crossref]
  86. Chang AR, Chen Y2, Still C3, Wood GC3, Kirchner HL4, et al. (2016) Bariatric surgery is associated with improvement in kidney outcomes. Kidney Int 90: 164-171. [crossref]
  87. Jamal MH, Corcelles R, Daigle CR, Rogula T, Kroh M, et al. (2015) Safety and effectiveness of bariatric surgery in dialysis patients and kidney transplantation candidates. Surg Obes Relat Dis 11:419-423.
  88. Ahmadi SF, Zahmatkesh G, Ahmadi E, Streja E, Rhee CM. et al. (2015) Association of Body Mass Index with Clinical Outcomes in Non-Dialysis-Dependent Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Cardiorenal Med 6:37-49.

Article Type

Research Article

Publication history

Received: March 03, 2017
Accepted: March 20, 2017
Published: March 18, 2017

Citation

Csaba P. Kovesdy, Susan Furth and Carmine Zoccali (2017) Obesity and Kidney Disease: Hidden Consequences of the Epidemic. Internal Med Res Open J Volume 2(1): 1–6.

Corresponding author

World Kidney Day
International Society of Nephrology,
in collaboration with International Federation of Kidney Foundation,
Rue de Fabriques 1B, 1000, Brussels,
Belgium