Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA; Nephrology Section, Memphis VA Medical Center, Memphis, TN, USAUnited States
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAUnited States
CNR-IFC Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Reggio Calabria, ItalyItaly
Also available as PDF (figures and tables appear in the PDF).
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 (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. 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 CKD 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; Obesity; Chronic kidney disease; Nephrolithiasis; Kidney cancer; Prevention
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
©2017 World Kidney Day Steering impact on the development of CKD and end-stage renal disease (ESRD). In individuals affected
Committee. This is an open ac- by obesity, a (likely) compensatory mechanism of hyperfiltration occurs to meet
cess article distributed under the metabolic demands of the increased body weight. The increase in intraglomerular pressure can
Creative Commons Attribution 4.0 damage the kidney structure and raise the risk of developing CKD in the long-term.
International License (CC BY 4.0),
which permits unrestricted use,
distribution, and reproduction in The good news is that obesity, as well as the related CKD, are largely preventable.
any medium, provided the original Education and awareness of the risks of obesity and a healthy lifestyle, including proper
work is properly cited.
nutrition and exercise, can dramatically help in preventing obesity and kidney disease. This the heightened
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 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 BMI is one of the strongest risk factors for new-onset
6,7 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
2 2 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 intra abdominal (visceral) fat. The latter type of high BMI is associated with substantially higher risk of
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.
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 and development of proteinuria in individuals without
kidney disease. Furthermore, in numerous large population-based studies, higher BMI appears associated with the presence8,12 and
development of low estimated glomerular filtration rate (GFR), with more rapid loss of estimated GFR over time, and with the
15-18 incidence of ESRD. 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, decreased GFR or incident ESRD independent of
Prevention of Renal Elevated BMI albumin 30-300 mg/24h
and Vascular (overweight and obese*), -Obese +/- central fat: higher 7,676 Dutch individuals End-Stage Disease and central fat -Elevated and diminished risk of elevated GFR without diabetes (PREVEND) distribution (waist-hip GFR
Study ratio) -Central fat +/- obesity
Multinational study of Higher waist circumference 20,828 patients from 26 BMI and waist Prevalence of hypertensive associated with albuminuria 20 countries circumference albuminuria by dip stick outpatients independent of BMI
Framingham Visceral adipose tissue Prevalence of UACR >25 Multi-Detector VAT associated with albumin- 3,099 individuals (VAT) and subcutaneous mg/g in women and >17 Computed Tomography uria in men, but not in women 22 adipose tissue (SAT) mg/g in men (MDCT) cohort
CARDIA (Coronary 2,354 communitydwelling -Obesity (BMI >30 kg/m ) Obesity (OR 1.9) and
Artery Risk individuals with normal unhealthy diet (OR 2.0)
Development in Young kidney function aged 28-40 -Diet and lifestyle-related associated with incident
Adults) study years factors albuminuria
Hypertension greater proteinuria on Both overweight (OR 1.21) and Overweight and obese Detection and 5,897 hypertensive adults urinalysis and/or an obesity (OR 1.40) associated 10 BMI* vs. normal BMI Follow-Up Program eGFR <60 mL/min/1.73 with incident CKD 3,4
weight, a BMI
metabolic and
8 9-11
8,12
9,10,13 14
20 8 21 BMI level.
-Obese + central fat: higher
-Presence of urine risk of albuminuria
Cross sectional
analysis
associated with diminished
filtration
Cross sectional
analysis
Cross sectional
analysis
Low number of Incident microalbuminuria events
Incident CKD (1+ or
unchanged
after excluding
2 diabetics m )
Framingham Offspring 2,676 individuals free of 9 High vs. normal BMI* Study CKD stage 3 -Higher BMI associated with
-BMI quintiles -Higher baseline BMI and
Physicians’ Health 11,104 initially healthy men Incident eGFR <60 mL/ increase in BMI over time both 13 2 Study in US -Increase in BMI over min/1.73 m associated with higher risk of
time (vs. stable BMI) incident CKD
Nation-wide US 3,376,187 US veterans with 2 BMI categories from <20 function (negative eGFR BMI >30 kg/m associated with Veterans Administration baseline eGFR ≥60 mL/ 2 14 2 to >50 kg/m slope of >5 mL/min/1.73 rapid loss of kidney function cohort min/1.73 m 2
Nation-wide 926 Swedes with moderate/ BMI ≥25 vs. <25 kg/m
population-based advanced CKD compared to CKD vs. no CKD 12 higher risk of CKD study from Sweden 998 controls
1,194,704 adolescent males Elevated BMI (overweight Overweight (HR 3.0) and Nation-wide population 17 and females examined for and obesity) vs. normal Incident ESRD obesity (HR 6.89) associated based study in Israel military service BMI* with higher risk of ESRD
The Nord-Trøndelag 2
Health Study 74,986 Norwegian adults BMI categories* 15 renal death worse outcomes (HUNT-1)
Community-based Higher BMI associated with 100,753 individuals >20 screening in Okinawa, BMI quartiles Incidence of ESRD increased risk of ESRD in 16 years old Japan men, but not in women
Nation-wide US 453,946 US veterans with Moderate and severe obesity BMI categories from <20 -Doubling of serum Veterans Administration baseline eGFR<60 ml/min 2 associated with worse renal 19 2 to >50 kg/m creatinine cohort per 1.73 m outcomes
Overweight, class I, II Kaiser Permanente 320,252 adults with and Linearly higher risk of ESRD 18 and extreme obesity; vs. Incidence of ESRD Northern California without baseline CKD with higher BMI categories normal BMI*
REGARDS (Reasons
for Geographic and Elevated waist circumfer- 30,239 individuals Incidence of ESRD circumference Racial Differences in ence or BMI
Stroke) Study
*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.
Table 1. Studies examining the association of obesity with various measures of CKD.
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 ESRD23 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 -Higher BMI not associated
with CKD3 after adjustments -Incident CKD stage 3 Predominantly
white, limited
-Incident proteinuria geography increased odds of incident
proteinuria
Exclusively men
Rapid decline in kidney Associations
more
accentuated in
m ) older individuals
-Risk strongest
in diabetics, but
2 also significantly
Higher BMI associated with 3x higher in
non-diabetics
-Cross sectional
analysis
Associations
strongest for
diabetic ESRD,
but also
significantly
higher for
non-diabetic
ESRD
Associations not
present in Incidence of ESRD or BMI >30 kg/m associated with individuals with
BL <120/80
mmHg
Average BMI
lower in Japan
compared to
Western
countries
-Incidence of ESRD Associations
present but
weaker in
patients with
more advanced
-Slopes of eGFR CKD
Associations
remained present
after adjustment
for DM,
hypertension and
baseline CKD
Association of
waist
BMI above normal not circumference
associated with ESRD after with ESRD
adjustment for waist became
on-significant
after adjustment
-Higher waist circumference for comorbidities
associated with ESRD and baseline
eGFR and
proteinuria
23 24
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 and incidence 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%
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
rd 2 cancers had the 3 highest risk associated with obesity (relative risk per 5 kg/m higher BMI: 1.24, 95% CI 1.20-1.28, p<0.0001).
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, leptin and resistin
(Figure 1). These include the development of inflammation, oxidative stress, abnormal lipid metabolism, activation of the renin-
38 39,40 angiotensin-aldosterone system, and increased production of insulin and insulin resistance.
These various effects result in specific pathologic changes in the kidneys41 which could underlie the higher risk of CKD seen
in observational studies. These include ectopic lipid accumulation and increased deposition of renal sinus fat, the development
of glomerular hypertension and increased glomerular permeability caused by hyperfiltration-related glomerular filtration barrier
45 46 41 injury, and ultimately the development of glomerulomegaly, and focal or segmental glomerulosclerosis (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
47 14,39 kidney damage in patients with high blood pressure or in the elderly.
Obesity is associated with a number of risk factors contributing to the higher incidence and prevalence of nephrolithiasis.
48 49 Higher body weight is associated with lower urine pH and increased urinary oxalate, uric acid, sodium and phosphate excretion
diets richer in protein and sodium may lead to a more acidic urine and decrease in urinary citrate, also contributing to kidney stone 25 26,27
and 26% of all
32 33 34 35 36 37
42 43,44
Courtesy of Dr. Patrick D. Walker, MD; Arkana Laboratories, Little Rock AR.
Figure 2. Obesity-related perihilar focal segmental glomerulosclerosis on a back- ground of glomerulomegaly. Periodic Acid-Schiff stain, original magnification 400x.
risk. The insulin resistance characteristic of obesity may also predispose to nephrolithiasis51 through its impact on tubular Na-H
52 53 54 exchanger and ammoniagenesis, and the promotion of an acidic milieu. 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 (IGF-1)
and numerous complex secondary humoral effects may exert stimulating effects on the growth of various types of tumor cells.56
57 58 More recently, the endocrine functions of adipose tissue,57 its effects on immunity,58 and the generation of an inflammatory milieu
59,60 with complex effects on cancers 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 and
62,63 ESRD. Similar “paradoxical” associations have also been described in other populations, such as in patients with congestive
64 65 66 67 heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, and even in old individuals. 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. Higher muscle mass
has also been shown to explain at least some of the positive effects attributed to elevated BMI. 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 capacity63 and lower circulating actin and higher plasma gelsolin
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
73 74 adiponectines73 and soluble tumor necrosis factor alfa receptors74 by adipose tissue neutralizing the adverse effects of
factor alfa; enhanced binding of circulating endotoxins75 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 strongest
risk factors for CKD. Perhaps due to the survival advantage of obesity in CKD, the prevalence of end stage kidney disease is on 19,61
23,24
63,68
levels,71 which
tumor necrosis
77 78 the rise both in the USA77 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
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
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
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 1st step towards developing public health interventions.
Acquiring evidence that current interventions to reduce CKD risk in the obese are efficacious and deployable, is an
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 deployed79 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
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
Observational studies in metabolically healthy obese subjects show that the obese phenotype unassociated with metabolic
abnormalities per se predicts a higher risk for incident CKD82 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
85-87 transplantation.
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 (T2D), recommendation of weight loss in the minority of metabolically healthy,
non-hypertensive obese patients remains unwarranted. These considerations suggest that a therapeutic approach
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. today’s health
by major renal
obese patients,
st
urgent priority
obesity-related to overweight
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.
The authors declare that they have no conflicts of interest.