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MOP 300201

REVIEW

CURRENT
OPINION Obesity and chronic kidney disease
Edward Nehus

Purpose of review
To review recent advances in the epidemiology, pathophysiology, clinical features, and treatment of
obesity-related kidney disease.
Recent findings
Studies have confirmed that obesity is associated with increased risk of developing chronic kidney disease
(CKD). This risk extends to those who are metabolically healthy, indicating that obesity per se contributes to
CKD independent of the metabolic syndrome. Recent developments in the pathophysiology of obesity-
related kidney disease indicate that chronic inflammation and abnormal lipid metabolism contribute to
kidney cell injury. Children with severe obesity have increased prevalence of early kidney abnormalities,
including albuminuria, decreased kidney function, and elevated biomarkers of early kidney injury. For
these patients, bariatric surgery has emerged as a treatment option to consider. Longitudinal studies in
children and adults have demonstrated that in patients with obesity-related kidney disease, kidney function
and albuminuria improve following bariatric surgery.
Summary
The injurious renal effects of obesity are present in childhood, although the natural history and clinical
spectrum of obesity-related kidney disease in children are not known. In obese children with early kidney
disease, identification of kidney injury, implementation of preventive strategies, and prompt treatment are
essential to improving clinical outcomes.
Keywords
bariatric surgery, kidney disease, metabolic syndrome, obesity

INTRODUCTION ESRD later in life. Morbidly obese adults have a four

Childhood obesity has become a global epidemic.
The prevalence of obesity increased eight-fold over
the last 4 decades and now affects about 124 million
&&
children worldwide [1 ]. In the Unites States, the
prevalence of obesity in school-age children and
adolescents tripled from 1980 to 2000 and remains
high at 17% [2]. This obesity epidemic witnessed in
recent decades has been paralleled by an increase in
chronic kidney disease (CKD). Concurrent with the
rise in obesity from 1980 to 2000, the incidence of
end-stage renal disease (ESRD) nearly quadrupled [3].
Obesity has therefore emerged as a leading cause of
CKD, with recent estimates indicating that 24–33%
of all US kidney disease is attributable to obesity [4].
This review will provide a summary of the epidemi-
ology, pathophysiology, clinical features, and treat-
ment of obesity-related kidney disease, with
particular focus on recent advances in this field.
EPIDEMIOLOGY OF KIDNEY DISEASE AND
OBESITY
Epidemiologic studies have demonstrated that obe-
sity is strongly associated with the development of
to five-fold higher risk of developing ESRD com-
pared with lean adults [5,6]. Vivante et al. investi-
gated the association of obesity with incident ESRD
in 1.2 million adolescents followed for a mean of 25
years. They reported that being obese at age 17 was
associated with a six-fold higher risk of developing
ESRD. In these studies, the relationship between
obesity and kidney disease remained after adjusting
for comorbid conditions, including diabetes melli-
tus and hypertension, indicating obesity per se is a
cause of ESRD [7].
Recently, a meta-analysis was undertaken to
investigate the association of obesity with more
mild kidney disease, including proteinuria (CKD
stages 1–2) and low kidney function [estimated
Division of Nephrology and Hypertension, Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio, USA
Correspondence to Edward Nehus, Division of Nephrology and Hyper-
tension, Cincinnati Children’s Hospital Medical Center, 3333 Burnet
Avenue, ML 7022, Cincinnati, OH 45229, USA. Tel: +1 513 636 4531;
fax: +1 513 636 7407; e-mail: edward.nehus@cchmc.org
Curr Opin Pediatr 2018, 30:000–000
DOI:10.1097/MOP.0000000000000586

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MOP 300201
Nephrology
KEY POINTS
 Obesity and the metabolic syndrome are significant risk
factors for the development of CKD.
 The pathophysiology of obesity-related kidney disease
is multifactorial and includes hemodynamic factors
(hypertension and hyperfiltration), inflammation, and
renal lipotoxicity.
 Children with severe obesity have increased prevalence
of early kidney abnormalities, including albuminuria
and decreased estimated glomerular filtration rate.
 Bariatric surgery has emerged as a treatment option for
patients with severe obesity and obesity-related
kidney disease.
 Strategies to promote the early identification and
prompt management of obesity-related kidney disease
are needed to improve outcomes in children with
this condition.
glomerular filtration rate (eGFR) <60 ml/min/
1.73 m2]. Importantly, only patients without preex-
isting kidney disease were included to specifically
address the role of obesity as a risk factor for new
onset CKD. In this study of more than 600 000
patients with an average follow-up greater than
6 years, obesity increased the risk of low eGFR and
albuminuria by 28 and 51%, respectively. This rela-
tionship persisted even after adjusting for potential
moderators of kidney disease, including baseline
kidney function and the metabolic syndrome, fur-
ther supporting the concept that obesity is a direct
&&
cause of CKD [8 ].
MECHANISMS OF KIDNEY INJURY IN
OBESITY
Despite the burgeoning evidence linking obesity
with CKD, the mechanism of obesity-mediated kid-
ney injury has remained somewhat elusive. The
pathophysiology of obesity-related kidney disease
is probably multifactorial, and several pathways of
kidney injury have been proposed. First, hemody-
namic factors such as hypertension and hyperfiltra-
tion may contribute to glomerulomegaly and
podocyte stress, eventually leading to glomerulo-
sclerosis [9]. Second, metabolic effects – including
inflammation, insulin resistance, and adipokine
dysregulation – may directly or indirectly affect
renal structure and function [10,11]. Finally,
chronic kidney damage may be caused by renal
lipotoxicity, which involves the intracellular accu-
mulation of free fatty acids (FAs) and triglycerides in
renal glomerular and tubulointerstitial cells [12].
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Of recent interest has been the interplay among
inflammation, lipid accumulation, and mitochon-
drial injury in the pathogenesis of obesity-related
kidney disease. Yang et al. studied the effect of
inflammatory stress on lipotoxic kidney injury in
mice fed a high-fat diet (HFD). This study demon-
strated that chronic inflammation increases cellular
FA uptake, which triggers glomerular and tubular
&
damage [13 ]. In another study, Szeto et al. investi-
gated the pathologic effects of obesity on mitochon-
drial structure. This was accomplished by
administering SS-31, a peptide that protects mito-
chondria from oxidative injury, to HFD-fed mice.
Mice treated with SS-31 were protected from the
pathologic effects of diet-induced obesity, including
glomerular injury, inflammation, and lipid accumu-
lation. Treatment with SS-31 also prevented mito-
chondrial damage induced by a HFD, such as
reduced mitochondrial size and loss of cristae mem-
&&
brane [14 ]. Taken together, these results suggest
that inflammation promotes intracellular FA accu-
mulation and the subsequent production of reactive
oxygen species. This in turn causes oxidative dam-
age to mitochondria, which are the site of FA b-
oxidation. Mitochondrial injury therefore promotes
additional free-FA accumulation in a feedback loop
of lipotoxic cellular injury [15].
Many of the purported mechanisms of obesity-
related kidney disease are components of the meta-
bolic syndrome (i.e., hypertension, insulin resis-
tance, and dyslipidemia), which has been
independently associated with the development of
CKD [16]. Therefore, recent studies have investigated
the mediating role of the metabolic syndrome in the
relationship between obesity and CKD. In a cohort of
over 20 000 adult participants in the Reasons for
Geographic and Racial Differences in Stroke
(REGARDS) Study, the associations of BMI and meta-
bolic health with ESRD were investigated. Increasing
BMI was strongly associated with higher risk of devel-
oping ESRD; however, this association was signifi-
cantly modified by metabolic health. In adjusted
analyses, obese participants with the metabolic syn-
drome were over twice as likely to develop ESRD
compared with metabolically healthy individuals
of normal weight. However, obese participants with-
out the metabolic syndrome had decreased risk of
&
developing ESRD [17 ]. In a similar analysis of the
REGARDS cohort, the associations between waist
circumference, BMI, and ESRD were explored. In this
study, higher waist circumference was significantly
associated with increased risk of developing ESRD,
with those in the highest category of waist circum-
ference demonstrating a four-fold higher hazard rate
after adjusting for BMI. However, after adjusting for
waist circumference, no association between BMI
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&
and ESRD incidence was apparent [18 ]. Taken
together, these studies suggested that central adipos-
ity and the metabolic syndrome may lie in the causal
pathway between obesity and CKD. A potential
explanation is the strong association between vis-
ceral adiposity and inflammation, adipokine dysre-
gulation, and abnormal lipid metabolism, all of
which have been implicated in the pathogenesis of
obesity-related kidney disease [19–22].
The implication that metabolic disturbances,
rather than excess adiposity per se, cause kidney
disease has given rise to the possible existence of a
subset obese individuals who are not at increased
risk to develop CKD. This phenotype of obesity,
which is termed ‘metabolically healthy but obese’
(MHO), is characterized by a favorable metabolic
profile despite increased BMI [23]. Recent studies
have investigated the long-term risk of CKD in this
population. In a prospective study of 62 249 meta-
bolically healthy adults (mean age 36 years), Chang
et al. evaluated the risk of developing CKD
(eGFR < 60 ml/min/1.73 m2) across categories of
BMI. Metabolic health was defined as the absence
any component of the metabolic syndrome and a
homeostasis model of insulin resistance level less
than 2.5. Compared with normal weight individu-
als, the adjusted 5-year increase in the cumulative
incidence of CKD in metabolically healthy over-
weight and obese subjects was 3.5 and 6.7 cases
&&
per 1000 persons, respectively [24 ]. In a similar
analysis, Jung et al. investigated the incidence of
CKD in 41 194 subjects who were stratified accord-
ing to BMI and metabolic health. Compared with
lean, metabolically healthy subjects, MHO subjects
had increased risk of CKD (hazard ratio of 1.38).
Those who were nonobese but metabolically
unhealthy had a similar risk of CKD (hazard ratio
1.37), whereas metabolically unhealthy obese sub-
jects had the highest risk of CKD (hazard ratio 1.56)
&
[25 ]. In contrast to the results from the REGARD
study mentioned above, these studies provide
strong evidence that the phenotype of MHO is
not a harmless condition and is associated with
long-term development of CKD.
How then can these results be reconciled with
the findings from the REGARDS cohort, which indi-
cated that obesity was not independently associated
with ESRD after adjusting for metabolic disease?
First, studies in the REGARD cohort investigated
the outcome of ESRD as opposed to the develop-
ment of CKD, and only 247 participants developed
the study outcome. Therefore, power may have been
limited in detecting the association of BMI with
ESRD in those who were metabolically healthy (only
69 subjects). A more important distinction, how-
ever, is the difference in study cohorts. The REGARD
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Obesity and chronic kidney disease Nehus
study was designed to investigate regional and racial
differences in stroke mortality, and therefore
enrolled patients greater than 45 years of age (mean
age of 65 years), 16% of whom had preexisting CKD
[26]. Thus, the REGARD study may have been con-
founded by the ‘obesity paradox’, a well described
association of improved outcomes in obese patients
with chronic conditions, especially the elderly [27].
In contrast, the aforementioned studies that dem-
onstrated an increased risk of incident CKD in obese
subjects included much younger subjects without
preexisting CKD. These studies likely represented a
more accurate estimation of the cumulative risk of
obesity on CKD in healthy subjects with minimal
comorbid conditions.
To summarize, well-designed studies have pro-
vided strong evidence that obesity is associated with
CKD independent of the metabolic syndrome. Nev-
ertheless, the metabolic syndrome does confer addi-
tional risk of kidney disease in obese subjects
compared with those who are metabolically
healthy, which likely underlies the stronger associ-
ation of waist circumference with ESRD when com-
pared with BMI. Therefore, physicians should
consider both metabolic health and obesity when
evaluating the risk of CKD.
CLINICAL FEATURES OF OBESITY-
RELATED KIDNEY DISEASE
The prevalence and clinical spectrum of obesity-
related kidney disease is not known with certainty,
as kidney disease in obese patients is often clinically
silent and may go undetected for years prior to
presentation. The first reports of obesity-related kid-
ney disease included patients with significant clini-
cal manifestations, such as nephrotic-range
proteinuria or decreased renal function. These stud-
ies described the extent histologic injury in those
with advanced obesity-related kidney disease, which
included glomerulosclerosis and chronic tubuloin-
terstitial damage [28,29]. The prognosis of this con-
dition – termed obesity-related glomerulopathy –
was poor, with up to 50% progressing to ESRD
within 10 years of diagnosis [29].
It is currently thought, however, that these ear-
lier studies represented only the ‘tip of the iceberg’
of obesity-related kidney disease – that is, only those
most severely affected. Several studies indicate that
mild kidney injury occurs in obese patients without
clinically evident disease. In asymptomatic obese
patients undergoing bariatric surgery, pathologic
changes including glomerulomegaly, glomerulo-
sclerosis, podocyte hypertrophy, and foot process
effacement are commonly present [30,31]. Further-
more, studies of healthy young adults (ages 18–30)
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Nephrology
have demonstrated that obesity is associated with an
increased prevalence of microalbuminuria [32,33].
To evaluate the prevalence of early kidney abnor-
malities in adolescents with severe obesity, Xiao
et al. performed a cross-sectional analysis of the
Teen-Longitudinal Assessment of Bariatric Surgery
(Teen-LABS) cohort. The Teen-LABS study is a pro-
spective observational study of 242 adolescents, ages
13–19, who underwent bariatric surgery. Prior to
surgery, 17% of study participants had increased
urinary albumin-to-creatinine ratio (ACR), and 3%
had an eGFR of less than 60 ml/min/1.73 m2. These
numbers were significantly elevated when com-
pared with healthy cohorts [34]. In another study,
urinary biomarkers of early kidney injury were
investigated in 22 adolescents undergoing bariatric
surgery without clinical renal disease (normal ACR
and kidney function). Urine neutrophil gelatinase-
associated lipocalin, IL-18, and kidney injury mole-
cule-1 were significantly elevated in obese subjects
prior to surgery compared with lean controls [35].
Taken together, these findings indicated that a con-
cerning number of severely obese adolescents have
evidence of early kidney injury, although long-term
kidney outcomes in this population are not known.
TREATMENT OF OBESITY-RELATED
KIDNEY DISEASE
The treatment of obesity-related kidney disease
requires early recognition of kidney injury and a
multifaceted approach to prevent disease progres-
sion. Weight loss remains the cornerstone of ther-
apy, which begins with dietary management and
exercise interventions [36]. Weight loss programs in
overweight patients with kidney disease have
resulted in a 30–50% reduction in proteinuria,
although improvement in renal function has not
been observed [37–39]. However, poor adherence
with diet and exercise treatment commonly occurs
and is a limiting factor to therapeutic effectiveness.
Adjunctive treatment with angiotensin-converting
enzyme inhibitors is also indicated in the treatment
of obesity-related kidney disease and can mitigate
the progression of kidney disease [40].
Conservative management, however, often has
limited effectiveness in treating children and ado-
lescents with the most severe forms of obesity.
Therefore, surgical procedures have gained popular-
ity for the treatment of severely obese adolescents
with obesity-related comorbidities. Short-term out-
comes of bariatric surgery are excellent, including a
25–35% reduction in weight and improvement in
dyslipidemia, hypertension, and diabetes [41]. As
the relationship between kidney disease and obesity
has become more apparent, the effect of bariatric
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surgery on kidney outcomes has been a topic of
recent interest.
High-quality observational analyses using pro-
pensity score matching indicate bariatric surgery has
a long-term beneficial effect on kidney health.
&&
Chang et al. [42 ] compared the risk of adverse renal
outcomes in a cohort of 985 adults who underwent
bariatric surgery with a cohort of 985 matched
controls who did not undergo surgical intervention.
The mean age of the cohort was 45 years, 33% had
an eGFR less than 90 ml/min/1.73 m2, and Roux-en-
Y gastric bypass was used in 97% of the surgical
patients. Over a median follow-up of 4.4 years,
bariatric surgery patients demonstrated a 58% lower
risk of eGFR decline (30% of baseline value) and a
57% risk reduction in the doubling of serum creati-
nine or progression to ESRD. In those patients with a
baseline eGFR less than 90 ml/min/1.73 m2, an
improvement of 13.8 ml/min/1.73 m2 was evident
within the 1st year following surgery. After 1 year,
eGFR began to gradually decline but still demon-
strated a 7.8 ml/min/1.73 m2 improvement at 5
years. In a similar analysis using propensity score
&&
matching, Imam et al. [43 ] investigated the bene-
ficial effect of bariatric surgery on patients with
more advanced kidney disease, including only
patients with CKD stages 3 and 4. The mean patient
age was 58 years, the mean eGFR was 48 ml/min/
1.73 m2, and surgical procedures included both
Roux-en-Y gastric bypass and sleeve gastrectomy.
Patients who received bariatric surgery had a
9.8 ml/min/1.73 m2 greater eGFR than controls at
3 years follow-up. The greatest improvement was
seen in those who underwent gastric bypass, who
had a 6.6 ml/min/1.73 m2 improvement compared
with those who underwent sleeve gastrectomy at 3
years. Similar to the analysis by Chang et al., eGFR
improvement occurred within 1 year following bar-
iatric surgery. These studies provided strong evi-
dence that bariatric surgery can prevent the
progression of kidney disease in those with normal
renal function, and even improve kidney function
in patients with more advanced CKD.
To investigate the effect of bariatric surgery on
kidney outcomes in adolescents with severe obesity,
&
Nehus et al. [44 ] recently conducted a longitudinal
analysis of the Teen-LABS cohort up to 3 years follow-
ing bariatric surgery. In adolescents with a baseline
eGFR less than 90 ml/min/1.73 m2, kidney function
improved from 76 ml/min/1.73 m2 preoperatively to
102 ml/min/1.73 m2 at 3 years. Similarly, in those with
increased albuminuria at baseline (ACR  30 mg/g),
the ACR improved from 74 to 17 mg/g. In participants
without any evidence of preoperative kidney disease,
kidney function and albuminuria remained stable
during the 3-year follow-up period. Considering
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MOP 300201
severely obese adolescents are at high risk to develop
ESRD, this study indicated that bariatric surgery is an
effective treatment to improve kidney outcomes in
this population.
CONCLUSION
Obesity is now recognized as a significant cause of
CKD, including among those who are metabolically
healthy. The mechanism of obesity-related kidney
disease remains elusive, although inflammation,
renal lipid accumulation, and mitochondrial injury
likely contribute to kidney damage. Further research
is needed to more completely characterize the
pathophysiology and clinical spectrum of obesity-
related kidney disease. Bariatric surgery has emerged
treatment option for those with severe obesity and
significant kidney disease. However, future research
efforts aimed at early identification and preventive
strategies are essential to improving clinical out-
comes in obese children with kidney disease.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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