REVIEWS

Obesity-related glomerulopathy:
clinical and pathologic characteristics
and pathogenesis
Vivette D. D’Agati1, Avry Chagnac2, Aiko P.J. de Vries3, Moshe Levi4, Esteban Porrini5,
Michal Herman-Edelstein6 and Manuel Praga7
Abstract | The prevalence of obesity-related glomerulopathy is increasing in parallel with
the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental
glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to
obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and
tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3‑kinase/Akt and mTOR
signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid
accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses
to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or
slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage
renal disease. Renin–angiotensin–aldosterone blockade is effective in the short-term but weight
loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic
antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol
metabolism are increasingly recognized as key mediators of renal lipid accumulation,
inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism,
including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold
therapeutic promise.

Obesity and diabetes mellitus occurring in the context Pathology of ORG

Correspondence to
V.D.D. vdd1@columbia.edu
doi:10.1038/nrneph.2016.75
Published online 6 June 2016
of obesity — known as diabesity — are now leading
causes of chronic kidney disease (CKD)1–8. Between 1978
and 2013, the proportion of overweight and obese adults
(BMI ≥25 kg/m2) worldwide increased from 28.8% to
36.9% among men, and from 29.8% to 38.0% among
women9. In the USA, the prevalence of obesity (BMI
≥30 kg/m2) among adults aged 20–74 years has more
than doubled over the past three decades, from 15% to
35% in 2011–2012 (REF. 10). This increase occurred in
men and women of all age groups and across diverse
ethnicities. Estimates suggest that by 2030 more than
50% of the US population will be obese and either at
risk of, or experiencing, obesity-related complications11,
resulting in a substantial economic burden12. The obesity
epidemic has led to an increased incidence of obesity-
related glomerulopathy (ORG), a distinct entity featuring
proteinuria, glomerulomegaly, progressive glomerulo­
sclerosis and renal functional decline. Here we review
the pathologic and clinical features of ORG as well as the
pathogenesis and potential therapeutic targets.
Biopsy incidence
The obesity epidemic has led to an increase in the num-
ber of renal biopsies performed in obese patients. Early
case reports of ORG were limited to autopsy studies13,
which identified an association between extreme obesity
and the development of glomerular hypertrophy (glo-
merulomegaly). In 1974, an association between mas-
sive obesity and nephrotic-range proteinuria was first
described14. The full spectrum of ORG emerged from
detailed clinical–pathologic studies15–17, and from stud-
ies that contrasted ORG with primary focal segmental
glomerulosclerosis (FSGS)16. The frequency of ORG
has increased in US, European and Asian cohorts over
the past 30 years15–17. A retrospective study that evalu-
ated native kidney biopsy samples received at Columbia
University, New York, USA, reported a 10‑fold increase
in the incidence of ORG from 0.2% in 1986–1990 to
2.0% in 1996–2000 (REF. 16), with a further rise to 2.7% in
2001–2015 (V. D’Agati, unpublished data). In this study
all ORG biopsies were performed for overt renal disease:

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

Key points segmental sclerosis typically affect hypertrophied glo-

• The incidence of obesity-related glomerulopathy (ORG) is increasing in parallel
with the worldwide obesity epidemic
• Pathologic features of ORG include glomerulomegaly and focal segmental
glomerulosclerosis (FSGS), particularly the perihilar variant; the degree of foot
process effacement in ORG is usually less than in primary FSGS
• Subnephrotic proteinuria is the most common clinical presentation of ORG; some
patients have nephrotic-range proteinuria and progressive loss of renal function but
full nephrotic syndrome is highly unusual
• Major renal physiologic responses to obesity include increases in glomerular filtration
rate, renal plasma flow, filtration fraction and tubular reabsorption of sodium
• Adipokines and ectopic lipid accumulation in the kidney promote maladaptive
responses of renal cells to the mechanical forces of hyperfiltration, leading to
podocyte depletion, proteinuria, FSGS and interstitial fibrosis
• Therapeutic interventions include renin–angiotensin–aldosterone inhibition and
weight loss; novel strategies involve administration of small molecules that
specifically modulate deleterious pathways of fatty acid and cholesterol metabolism
56% of patients had proteinuria and 44% had protein­uria
and renal insufficiency. The criteria for a diagnosis of
ORG were BMI ≥30 kg/m2 and the presence of glomerulo­
megaly with or without FSGS. The mean BMI of patients
with ORG was 41.7 kg/m2 (range 30.9–62.7 kg/m2);
46% had class 1 or class 2 obesity and 54% had class 3
obesity (BOX 1). This study, therefore, made the important
observation that ORG is not restricted to patients with
morbid (class 3) obesity 16.
Histology
Glomerulomegaly and FSGS. Identification of glomer-
ulomegaly requires measurement of the diameters of
all glomeruli sampled or of those sectioned through the
hilus — the epicentre of the glomerular globe. Other
stereo­logical methods estimate glomerular volume using
serial sections of individual glomeruli18. In the Columbia
series, mean glomerular diameter in biopsy samples from
patients with ORG was 226 μm versus 169 μm in age and
sex-matched normal control samples16. Across all age
groups (from the first to the ninth decade of life), glo-
merular diameter in patients with ORG was on average
1.34‑fold greater than that of non-obese normal controls.
FSGS is defined as a segmental consolidation of the
glomerular tuft by extracellular matrix and/or hyaline,
causing capillary obliteration19. In ORG, lesions of
meruli (FIG. 1). They are often perihilar (contiguous with
the glomerular vascular pole) but might involve any
portion of the glomerular globe. In the Columbia study,
exclusively perihilar lesions were found in 19% and
admixture of perihilar and peripheral lesions in 81% of
ORG biopsy samples16. The percentage of glomeruli that
are affected by segmental sclerosis tends to be lower in
ORG (range 3–50%; mean 12%) than in primary FSGS
(mean 39%), supporting the view that ORG is a milder,
more indolent form of FSGS16. In a Chinese cohort of
patients with ORG, the mean percentage of glomeruli
with FSGS was as low as 6%15.
Among the five histologic subtypes of FSGS (not
other­wise specified, perihilar, cellular, tip and collaps-
ing), ORG exhibits a predominance of the perihilar
variant 20. This predilection for perihilar sclerosis might
reflect the greater ultrafiltration pressure (that is, the
difference between glomerular capillary hydrostatic and
oncotic pressure) at the afferent end than at the efferent
end of the glomerular capillary bed. Such differences are
likely exaggerated under conditions of increased filtra-
tion demand and reflex dilatation of the afferent arteri-
ole21. Correspondingly, ORG biopsy samples may show
increased luminal diameter of the afferent arteriole and
the glomerular capillaries22. As the glomeruli enlarge, the
numerical density of podocytes decreases. In one study,
podocyte density was 55% lower (134 per 106 μm2 versus
245 per 106 μm2) and mean glomerular volume was 158%
higher (4.64 × 106 μm2 versus 2.94 × 106 μm2) in patients
with ORG than in non-obese kidney donors22. Reduced
podocyte density in this context might reflect both adap-
tive hypertrophic responses to glomerulomegaly and
ongoing podocyte depletion that has not yet reached a
threshold for the development of segmental sclerosis23,24.
In experimental models of ORG, such as in Fischer
rats fed an ad libitum diet, glomerular tuft volume
increases exponentially with body weight 25. Podocyte
cellular volume also increases in relation to body weight
gain, consistent with adaptive podocyte hypertrophy,
but at a lower rate than the increase in glomerular tuft
volume, indicating mismatch between these two varia-
bles25. As podocytes cannot proliferate and their ability
to hypertrophy is limited, the mechanical strain on these
cells resulting from stretch tension and shear stress as
glomerular volume expands, reaches a breakpoint.

Author addresses
1
Department of Pathology, Columbia University Medical Center, 630 W. 168th Street, Room VC14‑224, New York, New York 10032, USA.
2
Department of Nephrology and Hypertension, Rabin Medical Center, 39 Jabotinsky Street, 4941492, Petah Tikva, Israel and Sackler
School of Medicine, Tel Aviv University, Tel Aviv, Israel.
3
Department of Medicine, Division of Nephrology, Leiden University Medical Center and Leiden University, Room C7‑036, PO Box
9600, 2300 RC, Leiden, Netherlands.
4
Department of Medicine, Physiology, and Biophysics and Bioengineering, Division of Renal Diseases and Hypertension, University of
Colorado, Denver, CO and University of Colorado Hospital, 12605 E 16th Ave, Aurora, Colorado 80045, USA.
5
Center for Biomedical Research of the Canary Islands CIBICAN, University of La Laguna; Nephrology Service, Hospital Universitario de
Canarias, c/OFRA s/n, 38320, La Laguna, Tenerife, Spain.
6
Felsenstein Medical Research Center and Department of Nephrology, Rabin Medical Center, 39 Jabotinsky Street, 4941492, Petah
Tikva, Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
7
Department of Medicine, Complutense University, Instituto de Investigación, Hospital 12 de Octubre, Madrid, Spain and Department of
Nephrology, Hospital 12 de Octubre. Avda de Córdoba s/n. 28041 Madrid, Spain

2 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Individual podocytes fail and detach, causing localized
denudation of the glomerular basement membrane, sub-
sequent adhesions to the Bowman capsule and parietal
cell coverage, forming a nidus for the development of
segmental sclerosis26,27. In the Fischer rat model, pro-
teinuria and glomerulosclerosis were linearly related
to increasing body weight and could be accelerated
by unilateral nephrectomy, which promotes further
compensatory filtration demand25.
In addition to increased glomerular volume, ORG
biopsy samples show reduced glomerular density com-
pared to samples from non-obese kidney donors and
patients with glomerulonephritis28. In so far as glo-
merular density can be used as a surrogate marker for
nephron endowment, these data support the hypothesis
of low nephron endowment as a potential risk factor or
priming event for the development of ORG. Autopsy
studies have shown that the number of nephrons at
birth varies widely in children without known kid-
ney diseases29. The number of glomeruli per normal
kidney ranges from approximately 225,000 to 1,825,000:
an eight‑fold difference30. Glomerular endowment
strongly and inversely correlates with birth weight 31,32,
such that lower birth weight is associated with fewer
nephrons and increased glomerular volume30. Precise
quantification of nephron number using the ‘gold stand-
ard’ dissector/fractionator system at autopsy would,
however, be needed to differentiate to what extent the
reduced glomerular density seen in 2D histologic sec-
tions from patients with ORG reflects low nephron
endowment versus tubular hypertrophy.
Approximately 50% of patients with ORG have mild
‘diabetoid’ changes despite a lack of clinically evident
glucose intolerance16. These changes include focal or
diffuse increases in mesangial matrix and thickening of
the glomerular basement membrane that is visible by
light and electron microscopy, resembling mild diabetic
glomerulosclerosis. In addition, focal intracellular lipid
vacuoles might accumulate in mesangial cells, podocytes
and proximal tubular epithelial cells, as highlighted by
Oil-Red‑O staining 33. These morphologic findings are
consistent with the transcriptional profiles of micro­
dissected ORG glomeruli, which indicate shared molec-
ular pathways in ORG and diabetic glomerulosclerosis34.
Tubular atrophy and/or interstitial fibrosis (mean 1.26
on a scale of 0–3+) and arteriosclerosis (mean 1.42 on
a scale of 0–3+) are common features, but the tubulo­
interstitial scarring and inflammation are generally less
severe than in primary FSGS and may be minimal16.
Immunofluorescence and electron microscopy find-
ings. In ORG biopsy samples, immunofluorescence
reveals nonspecific trapping of IgM and complement
C3 in lesions of sclerosis and hyalinosis; however, no
immune-complex-type deposits are seen. Podocytes
overlying lesions of sclerosis may contain intracytoplas-
mic protein resorption droplets that stain for IgG, IgA
and albumin. Using electron microscopy, corresponding
protein and lipid resorption droplets can be identified
focally within podocytes, where they might promote
endoplasmic reticulum (ER), oxidative, and autophagic
Box 1 | BMI-based definitions of obesity
• Normal weight: BMI 18.5–24.9 kg/m2
• Overweight: BMI 25–29.9 kg/m2
• Obesity: BMI ≥30 kg/m2
• Class 1 (or grade 1) obesity: BMI 30–34.9 kg/m2
• Class 2 (or grade 2) obesity: BMI 35–39.9 kg/m2
• Class 3 (or grade 3) or morbid obesity: BMI ≥40 kg/m2
cellular stress35. Focal lipid vacuoles may also accumu-
late in the cytoplasm of mesangial cells and of tubular
epithelial cells, particularly in the proximal tubule8.
A distinctive and diagnostically helpful feature of
ORG is the presence of relatively mild effacement
of foot processes compared to primary FSGS. In a com-
parative study, mean foot process effacement was 40%
in ORG versus 75% in primary FSGS16. In some ORG
biopsy samples, effacement can be as low as 25% despite
nephrotic-range proteinuria. In this respect, ORG
resembles other adaptive forms of FSGS36, such as those
that occur in patients with solitary kidney 37 or very low
birth weight 38. Foot process width is also greater in pri-
mary FSGS than in adaptive forms, such as ORG39. This
difference likely reflects the underlying mechanisms of
podocyte injury. In primary FSGS, a presumably circu-
lating ‘permeability factor’ theoretically affects all podo-
cytes uniformly, causing podocyte dysregulation and
toxicity, whereas in adaptive FSGS podocyte injury is
more heterogeneous and less severe, reflecting different
stages of glomerular adaptation19,35. Animal models of
ORG show predominantly intact foot processes with the
exception of podocyte denudation in foci of irreversible
podocyte stress25. Cell‑to‑cell propagation of podocyte
injury contiguous with the initial foci of podocyte deple-
tion might be mediated by interruption of pro-survival
signalling via nephrin or increased noxious stimuli,
such as stretch tension and angiotensin II40,41. Spreading
fields of podocyte stress could promote enlargement of
segmental lesions, eventually resulting in global sclerosis.
ORG superimposed on other renal disease
Obesity is a risk factor for CKD and CKD progression in
renal diseases other than ORG (BOX 2), and the develop­
ment of ORG does not preclude the development of
other renal diseases. Thus ORG-associated glomerulo­
megaly and FSGS might occur superimposed on IgA
nephropathy or other renal conditions42. Moreover
obesity has been identified as an independent risk fac-
tor for end-stage renal disease (ESRD) in multivariable
models after adjustment for multiple epidemiologic
and clinical features including the presence of diabetes
mellitus and hypertension43. In a large historical cohort
study that used the Kaiser Permanente database, the
adjusted relative risk for ESRD was 1.87 in overweight
individuals, 3.57 in those with class 1 obesity, 6.12 in
those with class 2 obesity and 7.07 in those with class 3
obesity compared to individuals with normal BMI at
baseline43. These data support the hypothesis of obesity
and probable ORG as potential cofactors in the progres-
sion of CKD of various aetiologies, and these trends

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 3

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

a b are borne out in clinical practice. Among 620 patients

with diabetes whose renal biopsy samples were ana-
lysed in 2011 at Columbia University, 33% had diabetic
nephropathy alone, 27% had diabetic nephropathy plus
a super­imposed nondiabetic renal disease, and 36% had
nondiabetic renal disease alone44. FSGS accounted for
22% of the cases of nondiabetic renal disease and 13%
of the cases of diabetic nephropathy plus nondiabetic
renal disease. In the majority (87%) of diabetic patients
with FSGS lesions, these lesions were attributed to ORG.

c d Subclinical renal changes

e f
g h
Nature Reviews (ORG).
Figure 1 | Pathologic features of obesity-related glomerulopathy | Nephrology
The
glomeruli of patients with ORG a | are hypertrophied in comparison to b | glomeruli
from non-obese age-matched control individuals (Jones methenamine silver stain,
×400). c | In patients with ORG, lesions of segmental sclerosis (arrow) tend to form
at the vascular pole (perihilar) and segmentally obliterate the capillary lumina
(Periodic acid–Schiff stain, ×400). d | Focal dilatation of the afferent arteriole and
the glomerular perihilar capillaries provides morphologic evidence for a high
single-nephron filtration rate (Periodic acid–Schiff stain, ×400). e | Some patients
with ORG show a mild increase in mesangial matrix and thickening of glomerular
basement membranes consistent with ‘diabetoid’ features (Jones methenamine
silver stain, ×400). f | Glomerulus from a patient with advanced ORG showing a
large segmental lesion of sclerosis (arrow) involving nearly half the tuft with
prominent tubular atrophy, interstitial fibrosis and chronic inflammation (Masson
trichrome stain, ×200). g | Electron micrograph (×6,000) showing very mild
(approximately 15%) foot process effacement in a patient with ORG who had urine
protein of 2.8 g per day. The podocyte cell body appears hypertrophied. h | The
mesangial cells contain focal intracytoplasmic lipid vacuoles (arrows). A mild
increase in mesangial matrix and moderate foot process effacement are also
visible (electron micrograph, ×4000).
Systematic renal biopsies performed in morbidly obese
patients presenting for bariatric surgery have provided
a unique window onto early, subclinical renal changes.
In a Spanish study of 95 extremely obese patients
(mean BMI 53.6 kg/m2) with normal renal function, the
mean duration of obesity was 20 years, 39 (41%) patients
had microalbuminuria and four (4%) had albuminuria
(300–500 mg per day)45. Pathologic findings included
glomerulomegaly in 38% and FSGS lesions in only 5%
of patients. Using light microscopy, mesangial sclerosis
was identified in 60%, mild tubular atrophy and inter-
stitial fibrosis in 11% and arteriolosclerosis in 40% of the
pre-surgical biopsy samples45. An electron microscopy
study reported mild mesangial sclerosis, sparse parame-
sangial hyaline densities, glomerular basement mem-
brane thickening and variable podocyte effacement in the
majority of protocol biopsy samples from 13 morbidly
obese (BMI >50 mg/m2) patients without proteinuria who
were undergoing Roux‑en‑Y bypass surgery 46. Together,
these findings support the hypothesis that clinically
overt ORG is the ‘tip of the iceberg’ and that mild renal
pathologic alterations are already established in many
patients with morbid obesity and no clinically evident
renal disease47. Longer prospective follow‑up is needed
to determine whether patients with microalbuminuria
are at increased risk of developing ORG, analogous to the
greater risk of diabetic nephropathy that microalbum­
inuria confers among diabetic patients. As protocol renal
biopsies have been performed only in extremely obese
patients, little is known about the potential for subclinical
renal disease in those with class 1 or class 2 obesity.
Clinical features of ORG
Incidence and prevalence
The true incidence of ORG is unknown because renal
biopsy policy in obese patients with proteinuria varies
widely between countries and centres, ORG can be pres-
ent without clinical renal manifestations45, and in obese
patients with type 2 diabetes mellitus (T2DM), it is often
difficult to determine whether diabetes or obesity has a
predominant role in the development of proteinuria. In
the absence of histological confirmation, the presence of
persistent proteinuria in obese patients is generally con-
sidered to be a surrogate marker of ORG, provided that
other renal diseases are not suspected. Observational
and epidemiological studies have reported that pro-
teinuria (semiquantative grade 1+ or greater) or macro­
albuminuria (albumin: creatinine ratio >300 mg/g) are
prevalent in 4–10% of obese patients48–50.

4 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Presentation Box 2 | Obesity as a risk factor for renal diseases

Isolated proteinuria with or without renal impair-
ment is the most characteristic clinical presentation of
ORG15–17,51,52. Other common findings are hypertension
(50–75% of patients) and dyslipidaemia (70–80% of
patients)15–17,51,52. Subnephrotic proteinuria is found in
the majority of patients with ORG, particularly in stud-
ies performed in China and Japan15,51,52. The reported
percentage of patients with nephrotic-range protein-
uria ranges from 10% to 48%, but the presence of full
nephrotic syndrome is distinctly unusual (0–6%), even
in patients with massive proteinuria. The reasons why
patients with ORG do not develop the typical findings
of nephrotic syndrome (hyperlipidaemia, hypoalbu-
minaemia and oedema) probably relate to the type of
podocyte injury and the fairly slow development of
proteinuria in adaptive forms of FSGS16,17,53. The rarity
of full nephrotic syndrome is a characteristic that ORG
shares with other entities in which glomerular hyper-
filtration has a predominant pathogenic role, such as
reflux nephropathy and FSGS secondary to reduced
renal mass53–55. Some studies have suggested that the
tubular handling of proteins also might differ in these
hyperfiltering nephropathies15,53.
The absence of full nephrotic syndrome despite sub-
stantial proteinuria in patients with ORG has important
clinical implications; a progressive increase in protein-
uria can go undetected for years, leading to late clinical
recognition. On the other hand, this peculiar character-
istic of ORG is very useful diagnostically; obese patients
may suffer diverse glomerular diseases16 and the pres-
ence of full nephrotic syndrome helps to distinguish
ORG from primary FSGS16,17,54,56 (TABLE 1).
Disease course
Few studies have examined the long-term outcomes of
patients with ORG16,17,51. In the absence of therapeutic
intervention, the clinical course is characterized by stable
or slowly progressive proteinuria. Despite this indolent
evolution, a substantial number of patients (10–33%)
may develop progressive renal failure and ESRD;
this percentage seems to increase with longer follow‑
up16,17,51. Factors that are associated with progression of
renal failure include age and levels of serum creatinine
and proteinuria at presentation as well as time-averaged
proteinuria during follow‑up16,17,51. Comparative studies
have shown a more sudden and aggressive disease pres-
entation in patients with primary FSGS than in those
with ORG as well as significantly lower renal survival
in the former group (50% at 5 years and 25% at 10 years
versus 75% at 5 years and 50% at 10 years)16,17.
Clinical–pathologic correlations
A correlation between the percentage of glomeruli with
FSGS and the amount of proteinuria or albuminuria has
been reported in patients with ORG17,45. However, ORG
lesions can be found in patients without clinical evidence
of renal disease45, and some patients with glomerulomeg-
aly as the only histological manifestation of ORG have
substantial proteinuria16. Renal functional impairment
and progression to ESRD correlate with the percentage
Obesity is a significant risk factor for the progression of
renal diseases other than ORG, particularly diabetic
nephropathy and IgA nephropathy. For example, in IgA
nephropathy, obesity increases the risk of hypertension,
proteinuria, severe histologic lesions and end-stage renal
disease, and weight loss can result in reductions in
proteinuria305.
of glomeruli showing FSGS and global glomeruloscle-
rosis as well as with the severity of tubulo­interstitial
fibrosis and tubular atrophy 16,17,51,57. Correlations have
also been found between BMI and the extent of mesan-
gial proliferation and podocyte hypertrophy in obese
patients without overt renal disease45, and between
reduced podocyte number (related in turn to the degree
of glomerulomegaly) and proteinuria in patients with
ORG22. Low calorie diet-induced weight loss and other
therapeutic interventions ameliorated renal histological
lesions in animal models of obesity 58,59, but no infor-
mation is available on the effect of weight loss on his-
tological changes in patients with ORG. A single case
report of repeat biopsy in an obese child suggests that
glomerulomegaly might be at least partially reversible
following diet-induced weight loss60.
Predisposing factors
A critical reduction in the number of functioning
nephrons is the central pathogenic factor in hyperfil-
tering nephropathies. Although some patients with
substantial reductions in renal mass (owing to reflux
nephropathy, unilateral renal agenesis or extensive sur-
gical removal of renal parenchyma) develop proteinuria,
FSGS lesions and ESRD61, others maintain lifelong nor-
mal renal function without proteinuria. As a close linear
correlation between BMI and glomerular hyperfiltration
exists62, obesity could theoretically have a synergistic,
detrimental role in patients with reduced renal mass.
Supporting this hypothesis, in a series of patients who
had undergone unilateral nephrectomy, the only statis-
tically significant difference between those who later
developed proteinuria and progressive renal impairment
and those who maintained normal renal function with
no proteinuria was a higher mean BMI in the former
group, both at the time of nephrectomy and during
follow‑up63. In a retrospective study of patients with
unilateral renal agenesis or a severe reduction of renal
mass as a result of medical or surgical causes, BMI at
presentation and treatment with angiotensin-converting
enzyme (ACE) inhibitors were the only factors that were
associated with the development of proteinuria and loss
of renal function64.
Numerous experimental, clinical and epidemiologi-
cal studies have shown that low birth weight, prematu-
rity and intrauterine growth restriction are significantly
associated with increased risks of hypertension, cardio-
vascular events, T2DM, albuminuria and kidney disease
later in life; low nephron endowment is likely one of the
main pathogenic mechanisms that underlies this predis-
position31,65–69. Obesity might have a synergistic role in

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 5

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

Table 1 | Clinical and pathologic differences between ORG-related and primary FSGS
Characteristic ORG-related FSGS
Age at presentation Most common in middle-aged adults
(mean age 37–46 years15–17,51,52), but may be
present in children and older adults
Clinical presentation Slowly progressive proteinuria
Proteinuria and serum • Sub-nephrotic proteinuria in 52–90% of
albumin patients
• Normal serum albumin levels
Full nephrotic syndrome* Unusual (<5% of patients) even in patients
with massive proteinuria
Clinical course • Slower progression than primary FSGS
• Renal survival 75% at 5 years and 50% at
10 years16,17
Glomeruli with FSGS Fewer than in primary FSGS (mean 12% of
lesions glomeruli16)
FSGS variants Perihilar variant more common
Glomerulomegaly Defining feature of ORG (100% of cases16)
Foot process effacement Usually <50% glomerular surface area
*Hypoalbuminaemia, hyperlipidaemia and oedema. ESRD, end-stage renal disease; FSGS, focal segmental glomerulosclerosis;
ORG, obesity-related glomerulopathy.
Primary FSGS
Most common in children and young adults
Sudden onset of proteinuria with full
nephrotic syndrome in most cases
• Nephrotic-range proteinuria in most
patients
• Hypoalbuminaemia is common
Common
• Faster progression than ORG-related FSGS
• Renal survival 50% at 5 years and 25% at
10 years16,17
More frequent than in ORG-related FSGS
(mean 39% of glomeruli16)
Not otherwise specified, tip and collapsing
variants more common
Variable (10% of cases16)
Usually >50% glomerular surface area

the development of renal complications in patients with
a reduced nephron endowment. A retrospective study in
children with proteinuric kidney diseases showed that
both obesity and preterm birth significantly increased
the risk and rate of progression of renal disease70. Further
aggravating the problem, epidemiological studies have
shown that low birth weight is associated with increased
weight gain during late childhood and adolescence, and
that individuals who experience cardiovascular events
often have a profile of low birth weight and subsequent
obesity 71,72. The combination of low birth weight, child-
hood malnutrition and adult obesity is particularly prev-
alent in developing countries and has been proposed as
one of the main causes of the increased prevalence of
CKD in these areas73.
Treatment of ORG
As in other chronic proteinuric nephropathies, a sig-
nificant reduction in proteinuria is assumed to have a
renoprotective effect in ORG. Renin–angiotensin–aldos-
terone system (RAAS) blockade and weight reduction,
either diet-induced or promoted by bariatric surgery, are
the most studied therapeutic antiproteinuric measures.
RAAS blockade
In retrospective studies, treatment of obese patients with
proteinuria or biopsy-proven ORG using ACE inhibi-
tors or angiotensin-receptor blockers (ARBs) induced
a substantial decrease in proteinuria to 30–80% of base-
line values16,17,51,53,54,64. Moreover, a post hoc analysis of
the REIN trial showed that the antiproteinuric effect
of ramipril was significantly greater in obese and over-
weight patients than in those with normal BMI74. The
reduction in incidence of ESRD with ramipril compared
to placebo was also significantly greater in obese patients
than in those who were overweight or had normal BMI
(reductions of 86%, 45% and 42%, respectively). These
data suggest that obese patients might be more sensitive
to the renoprotective effect of RAAS blockade than non-
obese patients. In some retrospective studies with longer
follow‑up, however, the beneficial effects of RAAS block-
ers became exhausted over time, partly due to further
weight gain in some participants17,51.
Accumulating data suggest that mineralocorticoid
receptor activation has a key role in obesity and the
metabolic syndrome75. Although very few studies have
addressed the effect of mineralocorticoid-receptor
blockers on the renal complications of obesity, a short-
term study showed that the addition of spironolactone
to an ACE inhibitor reduced albuminuria and blood
pressure in obese patients76.
Weight loss
Non-surgical interventions. The effect of diet-induced
weight loss in obese patients with proteinuria has been
evaluated in nonrandomized prospective studies57,77,78,
in randomized controlled trials (RCTs) that compared
low calorie versus standard diets79–81, and in systematic
reviews and meta-analyses82–84. Some of these studies
included obese patients with T2DM77–80, and in some
studies hypocaloric diets were accompanied by pro-
grammed exercise. Mean BMI ranged from 30–38 kg/m2
at study entry and decreased significantly during follow‑
up in most studies, although there were notable differ-
ences between studies and patients depending on the
type of diet, study duration and patient compliance.
The most important overall finding was that weight
loss induced a significant decrease in proteinuria — the
greater the weight loss, the greater the decrease. Notably, a
reduction in proteinuria was evident after only a few days

6 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

or weeks of a low-calorie diet and proteinuria decreased
to remarkably low levels in those patients who experi-
enced the greatest weight losses. For instance, a RCT
showed a mean weight loss of 4% and a mean protein-
uria decrease of 30% after 5 months of hypocaloric diet,
but those patients who achieved weight losses of >6–10%
showed reductions in proteinuria to >60–70% of baseline
values80. A meta-analysis of nonsurgical weight-loss inter-
ventions in patients with CKD reported a mean reduction
in BMI of 3.6 kg/m2 and a mean reduction in proteinuria
of 1.3 g per day during a mean follow‑up of 7.4 months82.
Overall, no significant change in glomerular filtration
rate (GFR) was observed, although some RCTs showed
a trend towards a favourable effect of weight loss80,82. The
antiproteinuric effects of hypocaloric diets were accom-
panied by substantial improvements in blood pressure,
lipid abnormalities, fasting glucose levels and insulin
resistance57,77–84. However, the study durations were short
(4 weeks to 2 years) and most included few patients.
Two RCTs have compared the effects of weight loss
(induced by low calorie diet or orlistat treatment) with
those of RAAS blockade in obese patients with protein-
uria85,86. In these studies both interventions resulted in
similar reductions in proteinuria.
Bariatric surgery
Several RCTs have demonstrated favourable effects of bar-
iatric surgery in obese patients with T2DM87,88. Moreover
the results of several uncontrolled studies suggest that
bariatric surgery might be beneficial in ORG82–84,89–96.
These studies used various surgical procedures,
including Roux‑en‑Y gastric bypass, adjustable gastric
banding and sleeve gastrectomy. In comparison to the
participants of the dietary intervention studies discussed
above57,77–84, patients who underwent bariatric surgery
had more severe obesity (BMI 44–53 kg/m2) and expe-
rienced more dramatic weight loss (reduction in BMI
of 11–21 kg/m2). A consistent finding was normaliza-
tion of GFR after bariatric surgery in patients with glo-
merular hyperfiltration. Although the vast majority of
patients in the study cohorts had normoalbuminuria or
microalbuminuria, bariatric surgery reportedly induced
consistent and significant decreases in albuminuria and
proteinuria or even their resolution. These beneficial
renal effects were accompanied by important improve-
ments in blood pressure and glycaemic control as well
as favourable changes in metabolic and inflammatory
markers that persisted for 1–5 years after surgery. A RCT
in obese patients with CKD confirmed these findings,
but the number of participants was very small (n = 11)97.
Box 3 | Correction of GFR
Glomerular filtration rate (GFR) measurements are commonly corrected for body surface
area (BSA) in order to account for differences in body size. Indexing for BSA, however,
leads to a systematic underestimation of GFR in patients with severe obesity that
conceals glomerular hyperfiltration306. The main reason not to scale according to BSA is
that the number of nephrons does not increase in parallel with adiposity. The increased
GFR associated with obesity is the result of a raised single nephron GFR; non-corrected
GFR reflects this phenomenon, whereas it is obscured by indexing GFR for BSA. Thus, the
use of BSA-indexed GFR should generally be abandoned in obese persons.
Dramatic favourable effects of bariatric surgery in
patients with massive proteinuria and ORG have been
described in clinical case reports98,99. Bariatric surgery
may, however, be followed by severe renal complications,
such as nephrolithiasis, oxalate nephropathy and acute
kidney injury 93,100,101. Retrospective studies have shown
an association between the number of postoperative
complications and the presence of CKD101. Moreover, the
incidence of complications increased with CKD stage,
ranging from 4.6% in those with normal renal func-
tion or stage 1 CKD to 9.9% in those with stage 5 CKD.
Controlled studies of sufficient magnitude and duration
in patients with substantial proteinuria, biopsy-proven
ORG and CKD are needed to confirm the favourable
effects of bariatric surgery in these populations.
Pathogenesis of ORG
Altered renal haemodynamics
Renal plasma flow, glomerular filtration rate and filtra-
tion fraction. The first cases of glomerular hyperfiltra-
tion in patients with ORG were reported 40 years ago14.
Since then, nine publications have reported GFR meas-
urements in obese and lean participants21,102–109. These
studies investigated renal haemodynamics in obese
individuals with preserved renal function; they were not
designed to investigate renal function in ORG. One study
did not report data on proteinuria and albuminuria102 and
five studies included participants with microalbuminu-
ria21,103,104,107,108. As renal biopsies were not performed,
the possibility cannot be excluded that some of the
microalbuminuric participants had ORG. In seven of
the studies21,102,103,106–109, GFR uncorrected for body size
(BOX 3) was 12–61% higher in obese participants than in
lean participants.
Among 11 studies21,103–112 that assessed renal plasma
flow (RPF) in obese and lean participants, eight stud-
ies showed a 9–33% increase in RPF21,103,106–109,111,112, two
showed no difference105,110, and one showed a decrease
in RPF in those who were obese104. In three studies
filtration fraction (defined as GFR/RPF) was 9–29%
higher in obese than in lean participants21,107,108, whereas
a fourth study showed no difference in filtration fraction
between obese and lean groups103. Notably, two studies
demonstrated that these renal haemodynamic changes
appear at an early stage of adiposity, when BMI is
<30 kg/m2. The first of these studies showed that BMI
is an independent predictor of filtration fraction and of
height-indexed GFR in a lean and overweight popula-
tion62. The second reported that GFR, RPF and filtration
fraction are ~11%, ~9% and ~4% higher, respectively, in
overweight than in lean particpants108.
The fact that RPF increases to a lesser extent than
GFR in response to obesity implies the presence of renal
vasodilation mainly or solely involving the afferent
arteriole. As the transcapillary hydraulic pressure dif-
ference and ultrafiltration coefficient cannot be meas-
ured in humans, changes in these variables in obese
patients have been estimated using measured GFR, RPF
and the fractional urinary excretion of intravenously
administered neutral dextran21. Analysis of these data
using a theoretical model of dextran transport through

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 7

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

a heteroporous membrane showed that an increase in
transcapillary hydraulic pressure difference is the pre-
dominant factor that accounts for an increase in GFR in
the setting of obesity 21.
Systemic hypertension is highly prevalent in indi-
viduals who are overweight or obese113. The findings of
renal vasodilation and increased transcapillary hydraulic
pressure difference21 in obese patients suggest that sys-
temic hypertension might contribute to the pathogenesis
of hyperfiltration in these patients as an abnormal trans-
mission of increased arterial pressure to the glomerular
capillaries through a dilated afferent arteriole is expected
to augment transcapillary hydraulic pressure difference
and thus increase GFR21.
A small study assessed renal haemodynamics in
eight patients with severe obesity before and 1 year after
bariatric surgery 89. Following surgery, the mean BMI of
these patients decreased from 48 kg/m2 to 32 kg/m2, their
arterial pressure normalized and their GFR, RPF and
filtration fractions decreased by means of 24%, 13%
and 11%, respectively. This investigation demonstrates that
obesity-related glomerular hyperfiltration is reversible
following weight loss.
Tubular sodium reabsorption. In obese individuals
the filtered sodium load is increased in proportion to
the degree of hyperfiltration; therefore, increased reab-
sorption of salt along the nephron is indispensable to pre-
vent volume depletion. In the setting of obesity; however,
salt is reabsorbed to excess. BMI and waist circumference
are independent predictors of the proximal reabsorption
of sodium114, and this reabsorption is increased in white
patients with obesity 107,115. Data from experimental stud-
ies suggest that increased sodium reabsorption in the
setting of obesity might result from increased activation
of sodium transporters along the nephron116,117.
Glomerular hyperfiltration. Two concepts have been
proposed to explain obesity-related glomerular abnor-
malities (FIG. 2). The classic concept is the primary hae-
modynamic hypothesis, in which the primary event is
vasodilation of the afferent arteriole, resulting in glomer-
ular hyperfiltration118. The second proposed mechanism
is the tubulocentric hypothesis119–121, in which the primary
event is increased proximal reabsorption of salt and water,
resulting in decreased solute delivery to the macula densa,
deactivation of tubuloglomerular feedback, preglomerular
vasodilation and consequent glomerular hyperfiltration.
Proximal sodium reabsorption is increased in the set-
ting of obesity 107,114,115,122 and the carboanhydrase inhib-
itor acetazolamide was shown to decrease GFR by 21%
in nondiabetic, severely obese patients123. These effects
are compatible with the tubulocentric theory, but do not
prove or disprove either concept.
Hormonal and neurohormonal activation. In the set-
ting of obesity the RAAS is overactivated and levels of
RAAS components are increased in the circulation124–129
and in renal tissue126,130. This finding is explained in
part by the capacity of fat cells to synthesize RAAS
components130–132.
RAAS overactivation might be involved in the patho-
genesis of hyperfiltration. Firstly, angiotensin II133 and
aldosterone134 vasoconstrict glomerular arterioles and
have a greater effect on the efferent than the afferent arte-
rioles, which is expected to increase transcapillary hydrau-
lic pressure difference and GFR133. Moreover aldosterone
has been shown to increase GFR in humans135. Secondly,
angiotensin II increases sodium reabsorption proximally,
by stimulation of the luminal Na+-H+ exchanger and the
basolateral Na+-K+-ATPase, and distally, by activation
of the epithelial Na+ channel (ENaC)136. Angiotensin II
might also directly activate the mineralocorticoid recep-
tor 137, resulting in increased sodium reabsorption and
a positive sodium balance. RAAS overactivation might
therefore lead to excessive sodium reabsorption and
resulting hypertension and hyperfiltration138,139.
In obese individuals the renal sympathetic nervous
system (RSNS) is also overactivated140,141 and induces
sodium retention142. Three factors that are associated with
obesity activate the RSNS: leptin, low adiponectin levels
and obstructive sleep apnea (OSA). Circulating leptin
levels are increased in obesity and activate the RSNS143,144,
which promotes sodium retention and hypertension145.
Consistent with this causal role, mice that were deficient
in the leptin receptor did not develop hypertension when
they became obese146, and even severely obese patients
with loss-of-function mutations in the leptin receptor
have low blood pressure147. Low adiponectin levels in
obese patients might also activate the RSNS and promote
salt retention148. Moreover OSA is frequently associated
with obesity and overactivates the RSNS. A study showed
that a group of patients with moderate to severe OSA
had normal GFRs with low RPFs149. Treatment with con-
tinuous positive airway pressure increased RPF, whereas
GFR remained unchanged. The decreased RPF before
treatment is at variance with the more frequent vasodi-
lation pattern seen in severe obesity, probably reflecting
the very high degree of RSNS activity induced by OSA.
Hyperinsulinaemia secondary to insulin resistance
probably also has a role in obesity-associated renal
dysfunction. Although experimental studies suggest
direct effects of insulin on the glomerular microcircu-
lation150–152, these effects do not fit with the glomerular
haemodynamics found in obese individuals. Insulin
increases the tubular reabsorption of sodium by stim-
ulating the activity of ENaC in the late distal tubule153,
and less prominently in the proximal tubule154 and the
loop of Henle155,156. Together these effects contribute to
the pathogenesis of salt retention in obesity.
Protein intake. A large population-based survey that
used 24 h urine collections identified protein intake
as a predictor of GFR, independent of obesity and salt
intake157. Most experimental human and animal stud-
ies have shown that habitual protein intake modulates
GFR158,159. A study in obese individuals reported that
switching from a low-protein to a high-protein diet
induced only a <5% increase in GFR160, suggesting that
glomerular hyperfiltration is mostly determined by fac-
tors that are unrelated to protein intake, at least in the
short-term.

8 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Systemic • High salt diet

hypertension • Low nephron
Systemic or local number
Deactivation of • High protein diet
tubuloglomerular intrarenal factor(s)
feedback
?
↓ Solute delivery Afferent ↑ Single nephron ± Efferent arteriole
to macula densa arteriole dilation plasma flow constriction

↑ Glomerular • Ang II
pressure • Aldosterone

↑ Filtrate flow (single ↑ Glomerular

nephron filtration rate) capillary wall
tension stress
Shear stress on podocytes
↑ Proximal tubular Basement
salt reabsorption membrane
Mechanotransduction:
↑ Ang II, AT1R, TGF-β and TGF-βR distension

• Ang II Podocyte hypertrophy Capillary growth and

• Renal sympathetic and apoptosis Mismatch glomerulomegaly
nervous system
• Insulin
• ↑ Peritubular Podocyte detachment
oncotic pressure
• Microvilli
mechanosensing
and transduction Focal segmental glomerulosclerosis—obesity-related glomerulopathy

Figure 2 | Haemodynamic alterations in obesity. Primary dilatation of the afferent arteriole and variable constriction of
Nature in
the efferent arteriole via activation of angiotensin II (Ang II) and aldosterone contribute to increases Reviews | Nephrology
single nephron
plasma flow, glomerular intracapillary hydrostatic pressure, and filtration rate. The major driver of afferent arteriolar
dilatation is unknown, but deactivation of tubuloglomerular feedback via increased proximal tubular salt reabsorption
and decreased delivery to the macula densa likely has a role. A host of factors, including Ang II, the renal sympathetic
nervous system, insulin, an increase in postglomerular oncotic pressure due to increased filtration fraction, and
mechanosensors of tubular flow rates, mediate the increased tubular reabsorption of sodium. The increase in filtrate
flow (single nephron filtration rate) in turn promotes glomerular capillary wall stretch tension, glomerulomegaly, and
maladaptive podocyte stress leading to obesity-related glomerulopathy and focal segmental glomerulosclerosis. AT1R,
type 1 angiotensin II receptor; TGF‑β, transforming growth factor β; TGF‑βR, TGF‑β receptor.

Physiologic consequences. The prevalence of albuminu-
ria is increased in people who are obese161,162. Various
factors contribute to this increased albumin excretion:
increased capillary pressure and transcapillary hydraulic
pressure difference, increased wall tension, glomerular
tuft enlargement and stretching of glomerular cells. In
addition, angiotensin II might directly affect glomeru-
lar permselectivity 163 independently of filtration pres-
sure. Other factors, such as low circulating adiponectin,
might induce albuminuria164,165 through a direct action
on podocytes.
Increased peritubular oncotic pressure also affects
salt handling. Obesity-associated hyperfiltration is
usually associated with an increased filtration fraction.
The expected consequence is haemoconcentration in
the postglomerular circulation and an increase in the
oncotic pressure of the plasma entering the peritubular
capillaries. As one of the major determinants of proximal
tubular reabsorption is the pressure gradient determined
by Starling forces, this augmented oncotic pressure is
expected to promote proximal tubular sodium reabsorp-
tion166–168. In a study of obese individuals, those who had
filtration fractions within the normal range had normal
proximal reabsorption of sodium, whereas those with
high filtration fractions had high proximal reabsorption
of sodium107. Thus, glomerular hyperfiltration might
enhance sodium reabsorption by raising peritubular
oncotic pressures.
Increased GFR leads to increased proximal tubular
flow. The apical microvilli of the proximal tubular epi-
thelia function as a flow sensor, leading to activation of
sodium transporters and increased sodium reabsorp-
tion169. In this manner, increased axial luminal flow in
obesity-induced hyperfiltration might directly modulate
proximal tubule sodium transporters.
Structural consequences. Increased hydrostatic pressure
in the glomerular capillaries (glomerular hypertension)
drives an increased circumferential and axial capillary
wall stress, which induces basement membrane expan-
sion and glomerulomegaly as well as an increase in the
ultrafiltrate flow entering the Bowman space (hyperfil-
tration)170,171. Hyperfiltration exerts a high fluid shear
stress on podocytes, prompting maladaptive hypertro-
phy, which ultimately leads to podocyte detachment and
global glomerulosclerosis. Fluid shear stress activates
various mediators, such as angiotensin II, angiotensin II
type 1 receptor, transforming growth factor β (TGF-β),

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 9

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

TGF-β receptor and phospholipase D, which might be
involved in podocyte hypertrophy, apoptosis, decreased
adhesion and detachment. Obese adults with normo­
albuminuria or mildly increased albuminuria excrete
increased levels of urine podocyte-associated mRNA,
reflecting early-stage podocyte injury 172.
Data from animal and human studies suggest that the
areas of the glomerular and tubular spaces are increased
in the setting of obesity. In a dog model of obesity with
hyperfiltration, the area of the Bowman space was 41%
greater than in lean dogs173. Moreover, an analysis of
biopsy samples from nondiabetic patients showed that
the areas of the Bowman space and proximal tubular
lumen were 41% and 54% higher, respectively, in those
from obese patients with high GFR, than in those from
lean patients with normal GFR174. Considering the high
GFR of the obese cohort, it is reasonable to assume that
the glomerular and tubular urinary spaces expanded as a
consequence of the high ultrafiltrate flow, representing a
morphologic sign of glomerular hyperfiltration.
Maladaptive cell and hormone responses
Adipose tissue as an endocrine organ and potential
renal effects. Adipose tissue is a pleiotropic source of
hormones and chemokines, collectively called adi-
pokines175. In obesity, satiated fat cells facilitate adipose
tissue expansion by secreting angiogenic and inflam-
matory adipokines (such as angiopoietins, vascular
endothelial growth factor (VEGF), cathepsins and cys-
tatin‑C) that promote stromal rearrangements, neovas-
cularization and the formation of novel adipocytes176
(FIG. 3). White adipocytes mature from pericytes of the
adipose microvasculature177. Angiogenesis and adipo-
genesis are intricately linked, and disturbed angio­genesis
has been associated with diminished adipose tissue
expandability 178. The paracrine roles of adipokines in the
adipose tissue might have distant effects in the kidney.
In experimental settings adipokines stimulate kidney cells
to undergo adaptive or maladaptive responses to
cope with the mechanical forces of hyperfiltration179.
Adipokines such as leptin, adiponectin, and resistin
affect cellular hypertrophy, extracellular matrix and
renal fibrosis179, whereas factors such as angiopoietins
and VEGF maintain endothelial–pericyte integrity 180.
Mesangial cells are specialized pericytes that support
glomerular capillaries and regulate capillary flow 181.
Experimental models of mesangiolysis and pericyte
loss show glomerular microaneurysm formation and
capillary ballooning that might contribute to glomeru-
lomegaly 182. A mesangial imbalance in VEGF and angio-
poietins was associated with disruption of the glomerular
capillary structure in vitro183. In pigs, diabetes and an
atherogenic diet caused systemic capillary tortuosity,
and concomitantly, an imbalance in renal angiopoie-
tins, which correlated with the development of diabetic
nephropathy 184. Another study showed a possible role of
cathepsin S in protease-activated receptor‑2‑mediated
endothelial dysfunction in human and experimental
diabetic nephropathy 185, raising the question of whether
circulating cathepsin S from adipose tissue could con-
tribute to this effect. Circulating cathepsin B may be
filtered by glomeruli and taken‑up by megalin to sup-
port lysosomal functions of proximal tubular cells186.
Whether uptake of adipose tissue-derived cathepsins by
podocytes could induce maladaptive responses remains
speculative. In podocytes, cytosolic cathepsin L has
been shown to proteolyze dynamin, synaptopodin,
and CD2‑associated protein, thereby contributing to
secondary FSGS and proteinuria187–189. As cystatin C is
the natural inhibitor of cathepsins and pharmaceutical
companies have specific cathepsin inhibitors under clin-
ical investigation, cathepsin and cystatin homeostasis in
obese or diabetic CKD is rapidly gaining interest.
Risks of different adipose compartments
BMI differentiates poorly between body fat, muscle mass
and water, and does not take into account the wide range
of body fat distribution in lean and obese adults. Several
studies have shown that abdominal or central obesity,
reflected as waist circumference or waist‑to‑hip ratio
(WHR), is a better marker of cardiometabolic risk and
mortality than is BMI and is more closely associated with
renal functional impairment 190,191. However, WHR and
waist circumference discriminate suboptimally between
abdominal subcutaneous (SAT) and visceral adipose
tissue (VAT), which can be assessed by CT or MRI. This
distinction is important because these compartments
convey different metabolic risk192. VAT demonstrates a
larger adipokine response to nutrients than does SAT193.
Although SAT is the major site of fat accumulation, VAT
is a better predictor of T2DM and risk factors for cardio­
vascular disease. As the risk of CKD increases with the
number of cardiovascular risk factors194, VAT might be a
better predictor of CKD than are conventional measures
of obesity. In the Framingham Offspring cohort, VAT
and SAT were not independently associated with CKD
when GFR was estimated using a creatinine-based equa-
tion195, but both VAT and SAT were associated with CKD
when a cystatin C‑based equation was used196.
Impaired adipose tissue expandability and an
increased sensitivity of VAT to lipolysis might lead to
an overflow of nonesterified fatty acids (NEFA) into the
circulation, resulting in deposition in non-adipose tis-
sues such as liver, heart and kidney 197. The arche­typical
example of ectopic lipid is non-alcoholic fatty liver
disease (NAFLD), which might contribute to hepatic
insulin resistance, gluconeogenesis, and increased sys-
temic levels of inflammatory adipokines198, and thus
confer independent risk of CKD. A meta-analysis
showed that NAFLD was independently associated with
CKD, although none of the included studies adjusted
for VAT199.
BMI correlates with triglyceride accumulation in the
human kidney cortex 33. In human nephrectomy speci-
mens from obese individuals, lipid was predominantly
found in the proximal tubules and to a lesser degree in
glomeruli33. Ectopic lipid in the kidney or a ‘fatty kidney’
may constitute a quintessential biomarker of obesity-
related kidney disease8. Ample experimental studies
underscore the role of lipotoxicity or lipid overload in
obesity-related kidney disease, but human translation
is hampered by the lack of a non-invasive method to

10 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

Microcirculation Adipokines Normal Obesity

Afferent Mesangial
NEFA cell
arteriole
Mesangial
Matrix: matrix
• Cathepsins
• Cystatin
• MMPs

Angiogenesis: Glycocalyx
Angiogenesis • VEGFs ↑ Radius
• Angiopoietins ↑ Tension
Podocyte Pressure
Pericyte
Metabolism:
• Aldosterone
• Ang II
Adipose tissue expandability • Leptin
• Adiponectin

Inflammation:
• TGF-β Endothelium
• IL-6 or IL-1
• TNF Albumin
• MCP-1 Efferent
Lipid droplet arteriole
Hypoxia:
HIF-1
Macrophage Adipocyte Tubular cell

Figure 3 | Potential role of adipokines in the development of obesity-related glomerulopathy.NatureInReviews

obesity,|satiated fat
Nephrology
cells facilitate adipose tissue expansion by secreting angiogenic and inflammatory adipokines such as angiopoietins,
vascular endothelial growth factor (VEGF), and cathepsins. These adipokines promote stromal rearrangements,
neovascularization and the formation of novel adipocytes from pericytes of the microvasculature. Angiogenesis and
adipogenesis are intricately linked, and disturbed angiogenesis has been associated with diminished adipose tissue
expandability. Systemically circulating adipokines might reach the kidney and have local effects on mesangial cells,
podocytes, and tubular cells, promoting maladaptive responses to glomerular hyperfiltration and albuminuria. Ang II,
angiotensin II, HIF‑1, hypoxia-inducible factor‑1; MCP‑1, monocyte chemoattractant protein‑1 (also known as C‑C motif
chemokine 2); MMP, matrix metalloproteinase; NEFA, non-esterified fatty acid; TGF‑β, transforming growth factor β.

assess the fatty kidney. Current developments in clinical
proton magnetic resonance spectroscopy of the kidney
show promise200,201 but await validation in interventional
studies and against human biopsy samples.
Effects of ectopic lipid on glomerular integrity, albu-
minuria and fibrosis. Mesangial cells accumulate lipids
via various receptors and may transform into a type of
foam cell8. Mesangial lipid accumulation via insulin
growth factor‑1 has been associated with loss of con-
tractile function in vitro and might contribute to loss
of glomerular integrity 202,203. Moreover inflammation
interferes with LDL-receptor feedback regulation in
mesangial cells leading to unopposed lipid accumula-
tion204. In an elegant porcine study that used micro‑CT,
increased renal triglyceride accumulation was associated
with microvascular proliferation and increases in GFR,
expression of pro-angiogenic and inflammatory fac-
tors and albumin leakage205. Plasma albumin normally
carries >99% of circulating NEFA and albumin-bound
NEFA has been shown to induce massive macropino­
cytosis in podocytes206. This finding suggests that podo-
cytes sense the disruption of glomerular integrity via
NEFA. In pronounced albuminuria, the serum ratio
of free NEFA to albumin-bound NEFA and the plasma
levels of angiopoietin-related protein 4 (ANGPTL4)
are increased207. ANGPTL4 aggravates hypertriglyceri-
demia by inhibiting lipoprotein lipase. NEFA have been
shown to induce ANGPTL4 expression in podocytes206
and podocyte ANGTPL4 induced proteinuria in rats207.
These findings provide a likely molecular underpinning
of the Moorhead hypothesis; concomitant hyperlipi-
daemia and albuminuria cause self-perpetuating renal
disease through the accumulation of lipid in the injured
kidney leading to glomerulosclerosis208.
Glomerulosclerotic pathways have also been linked
to fatty acid metabolism. Palmitate was found to upregu-
late Smad3 in mice, resulting in loss of synaptopodin and
mitochondrial injury in podocytes209. Moreover Smad3
deficiency protected mice from obesity-induced podo-
cyte injury that otherwise resulted in markedly increased
mitochondrial biogenesis and respiration before the
onset of systemic and renal insulin resistance. TGF‑β/
Smad3 signalling constitutes a major fibrotic pathway,
but is also involved in regulating insulin gene transcrip-
tion210 and adipose tissue homeostasis211. In mice, Smad3
inhibition caused a phenotypic change of adipocytes
(from white to brown adipose tissue) that was associ-
ated with increased PPARγ co-activator‑1α (PGC1α)
expression211. This fibrotic pathway is thought to impair
fatty acid oxidation in renal epithelial cells by repressing
PGC1α‑induced expression of rate-limiting enzymes
for β‑oxidation such as carnitine palmitoyltransferase‑1
(CPT1)212.
In nephrotic-range proteinuria, NEFA-bound albu-
min is taken up by proximal tubular cells leading to giant
lipid droplets. Tubular uptake of NEFA occurs propor-
tionally to plasma NEFA concentration (basolateral side)

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 11

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

and filtered albuminuria (luminal side)213. NEFA are
the predominant fuel for the highly energetic tubular
transport processes, but overabundant NEFA are incor-
porated into lipid droplets as triacylglycerol214. This
abundance might interfere with normal mitochon-
drial function depending on the fatty acid oxidation
capacity of the cell215. Impaired fatty acid oxidation has
been shown to cause lipid accumulation and has a key
role in the development of renal interstitial fibrosis212.
Consistent with this finding, a genome-wide transcrip-
tome analysis of renal tubule samples identified dysreg-
ulation of inflammatory and metabolic pathways as well
as reduced levels of the rate-limiting enzymes of fatty
acid oxidation, CPT1 and PGC1α, in patients with CKD
plus hypertension and/or diabetes212.
Insulin resistance and mTOR signalling. Levels of
ectopic lipids correlate more strongly with insulin resist-
ance than with any of the commonly used indices of
obesity such as BMI, waist circumference and WHR216.
Cellular insulin resistance was originally proposed by
Reaven as a unifying concept of unhealthy obesity,
which is the clustering of obesity with cardiovascular
risk factors such as dyslipidaemia, hypertension and
diabetes217. Insulin resistance has been independently
associated with renal hyperfiltration and incident CKD
in large cohort studies194,218,219. The effects of insulin on
the human kidney are complex and include both pressor
and depressor effects, but the generally accepted view
is that short-term insulin infusion increases GFR and
distal tubular sodium reabsorption220.
Podocytes express insulin receptors and, via insulin
signalling, potentially adjust their morphology to post-
prandial changes in intracapillary pressure and GFR221.
Accumulation of NEFA in podocytes has been linked to
insulin resistance222 and podocyte apoptosis in vitro223.
Normal insulin/phosphatidylinositol 3‑kinase (PI3K)/
Akt and mTOR signalling (FIG. 4) seem to be critical for
podocyte function and survival and mouse models with
disturbances in these pathways show ORG-like fea-
tures25,224,225. Insulin also stimulates VEGF production
in podocytes226. Mice with podocyte-specific knockout
of the insulin receptor developed the histological fea-
tures of ORG, but maintained normal glucose levels224.
A contrary characteristic was the absence of the renal
enlargement and cellular hypertrophy seen in patients
with ORG. A possible explanation is that absent insu-
lin signalling impaired mTOR activation. An elegant

• Growth factors
Insulin receptor • Nutrients

IRS-1
mTORC2

PI3K Akt

SGK1 Akt • PKCα

• Rho or Rac
TSC1/2
Sodium FoxO
reabsorption Actin
Rheb Rheb
(activation remodelling
GDP GTP of ENaC in Cell
tubular cells) survival

mTORC1

S6K
• Protein synthesis
• Cellular growth
4E-BP1
• SREBP • HIF-1
• PPARγ • VEGF hATG1

• Adipogenesis Angiogenesis Autophagy

• Lipid synthesis
Figure 4 | The insulin/ PI3K/Akt/ mTOR pathway. The mTOR protein kinase complexes mTORC1 and mTORC2
constitute a sensor that integrates various metabolic and hormonal cues to regulate cellular growth and homeostasis.
Nature Reviews | Nephrology
Insulin signalling via phosphatidylinositol 3‑kinase (PI3K) can stimulate mTORC1 and the downstream pathways of
lipogenesis, angiogenesis and cellular growth (protein synthesis) as well as a decrease in autophagy. The downstream
target of mTORC1, S6 kinase (S6K), negatively regulates insulin receptor substrate 1 (IRS‑1), causing resistance to insulin
signalling. Nutrients and growth factors may activate mTORC2, leading to actin remodelling, changes in cell phenotype
and survival, and sodium reabsorption via activation of the epithelial Na+ channel (ENaC) in tubular cells. Activation of
mTORC2 might also lead to insulin resistance via inhibition of IRS‑1. 4E‑BP1, 4E‑binding protein 1; FoxO, Forkhead box
protein O1; GDP, guanosine diphosphate; GTP, guanosine‑5ʹ‑triphosphate; hATG1, autophagy-related protein 1
homologue; HIF‑1, hypoxia-inducible factor‑1; PKCα, protein kinase C α type; PPARγ, peroxisome proliferator-activated
receptor γ; Rheb, GTP-binding protein Rheb; SGK1, serine/threonine-protein kinase Sgk1; SREBP, sterol regulatory
element-binding protein; TSC, tuberous sclerosis protein; VEGF, vascular endothelial growth factor.

12 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

study in a transgenic rat model showed that podocytes
undergo hypertrophy in a mTOR-dependent manner
to cover the enlarging glomerular tuft in response to
increasing body weight 25. Failure of podocytes to hyper-
trophy via mTOR in response to glomerulomegaly led
to focal denudation of the glomerular tuft and an ORG-
like phenotype. Similarly, Akt2 signalling (activated by
mTORC2) was essential for podocyte compensation
after nephron reduction in a mouse model and for
podocyte survival in human CKD225. The mTOR com-
plexes (mTORC1 and mTORC2) constitute a sensor that
integrates different metabolic and hormonal signals to
regulate glomerular homeostasis and adaptive growth227.
Insulin signalling can stimulate mTORC1 and down-
stream pathways of lipogenesis (via PPARγ and sterol
regulatory element-binding protein‑1 (SREBP‑1)),
angiogenesis (via VEGF), and cellular growth (via S6
kinase and 4E‑binding protein 1), whereas stimulation
of mTORC2 can lead to actin remodelling, cell survival
(via forkhead box protein O1) and sodium reabsorption
(via serine/threonine-protein kinase Sgk1). Diabetic
nephropathy has been associated with increased mTOR
signalling 228,229 but the contribution of this signalling
pathway has not been evaluated in ORG.
Insulin signalling also has an important role in prox-
imal tubular cells. A mouse model with knockout of the
proximal tubule insulin receptor showed hyperglycaemia,
apparently as a result of increased renal gluconeogenesis230.
FXR ↑ CD36 and ↑ FATP FXR
↑ SREBP-1c ↓ PPARα
↑ Fatty acid uptake
↑ ACC, ↑ FAS ↓ ACOX1
and ↑ SCD-1 and ↓ CPT
↑ Fatty acid ↓ Fatty acid
↑ Triglycerides
synthesis oxidation
↓ MCAD
↑ LPK and ↓ LCAD
↑ Lipid
↓ Triglyceride
droplet
hydrolysis
↑ ChREBP proteins ↓ SIRT3
FXR ↓ Lipolysis TGR5
Figure 5 | Fatty acid and triglyceride metabolism in obesity-related glomerulopathy.
Renal triglyceride accumulation can occur as a result of increased
Nature fatty acid| synthesis
Reviews Nephrology
mediated by sterol regulatory element-binding protein 1c (SREBP‑1c) and its target
enzymes including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and
stearoyl CoA desaturase‑1 (SCD‑1); and/or mediated by carbohydrate-responsive
element-binding protein (ChREBP) and its target enzymes including liver pyruvate kinase
(LPK). Renal triglyceride accumulation can also occur by increased uptake via CD36 or
fatty acid transport protein (FATP); or by decreased fatty acid oxidation mediated by
peroxisome proliferator-activated receptor α (PPARα) and its target enzymes, or
NAD-dependent protein deacetylase sirtuin‑3 (SIRT3) and its target enzymes. TGR5
agonists decrease inflammation and mitochondrial ROS generation and increase
mitochondrial biogenesis, mitochondrial antioxidant generation and mitochondrial fatty
acid β‑oxidation. As well as decreasing inflammation, oxidative stress and fibrosis, FXR
agonists decrease lipid accumulation by inhibiting SREBP‑1 and ChREBP and
stimulating PPARα. ACOX1, peroxisomal acyl-coenzyme A oxidase 1; CPT, carnitine
O‑palmitoyltransferase; FXR, farnesoid X‑activated receptor; TGR5, G‑protein coupled
bile acid receptor 1; LCAD, long-chain specific acyl-CoA dehydrogenase, mitochondrial;
MCAD; medium-chain specific acyl-CoA dehydrogenase, mitochondrial.
Insulin decreases gluconeogenesis in the kidney similar to
its effects in the liver 231. Lipid accumulation in proximal
tubular cells could drive renal gluconeogenesis through
an increase in acetyl-coenzyme A concentration232. In
T2DM, the kidney is thought to contribute to hyper­
glycaemia233,234. Obesity and T2DM do not seem to inter-
fere with tubular insulin signalling in rodent models235,
suggesting continued adaptation to metabolic load.
Abnormal lipid metabolism
In ORG, abnormal lipid metabolism promotes increased
triglyceride and cholesterol ester accumulation in the
kidney 5–8. Several proteins with roles in these processes
have shown promise as potential therapeutic targets in
animal models of obesity.
Fatty acid and triglycerides. Increased triglyceride
accumulation can occur as a result of increased fatty
acid synthesis, increased uptake via CD36, or decreased
fatty acid oxidation (FIG. 5). SREBP‑1 is a master regula-
tor of fatty acid and triglyceride synthesis236–243. In the
murine high fat diet (HFD)-induced obesity model (see
Supplementary information S1 (box)), SREBP‑1 expres-
sion and activity results in increased renal lipid accumu-
lation244–256. Studies using SREBP‑1a transgenic mice have
provided evidence for a direct role of SREBP‑1 in mediat-
ing renal lipid accumulation and renal disease; increased
renal expression of SREBP‑1a resulted in proteinuria,
mesangial expansion and increases in inflammation,
oxidative stress and expression of profibrotic growth
factors244. The effects of HFD and obesity on kidney
disease are prevented in SREBP‑1c knockout mice247.
Increased SREBP‑1 activation induces expression of
proinflammatory cytokines, several of which in turn acti-
vate SREBP‑1 (including tumour necrosis factor (TNF),
IL‑1β, and interferon‑γ)245, resulting in a potentially
vicious cycle to accelerate lipid accumulation and inflam-
mation. In addition to high glucose, saturated fatty acids
and oxidized phospholipids, several vasoactive hormones
and profibrotic growth factors, including angiotensin II,
induce upregulation of SREBP‑1 (REFS 250,257), which in
turn mediates TGF‑β signalling 258,259.
Cell culture experiments have provided insights into
the mechanisms that regulate high-glucose-induced
increases in SREBP‑1 activation. Signalling through
PI3K, Akt, mTOR, glycogen synthase kinase‑3β, JAK2/
STAT1, and high mobility group protein B1 upregulate
the expression of SREBP‑1, whereas PTEN prevents
SREBP‑1 expression260–266.
The importance of SREBP‑1 in mediating lipid accu-
mulation and increased expression of proinflammatory
cytokines and profibrotic growth factors, as well as evi-
dence for increased SREBP‑1 expression in the glomeruli
of patients with ORG34, have led to a search for in vivo
inhibitors of this protein. The farnesoid X‑activated
receptor (FXR) agonists inhibit SREBP‑1 expression, lipid
accumulation, inflammation and fibrosis in animal mod-
els of diet-induced obesity and insulin resistance267–270.
In addition, vitamin  D receptor (VDR) agonists
inhibit SREBP‑1, lipid accumulation, inflammation
and fibrosis271.

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 13

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

An alternative approach to limit fatty acid and triglyc-
eride accumulation is to increase fatty acid oxidation via
activation of PPARα. This approach is relevant because
kidney biopsy samples from patients with ORG and
diabetes show decreased expression of PPARα and tar-
get enzymes that mediate fatty acid oxidation212,272. The
PPARα agonist fenofibrate prevented development of kid-
ney disease in HFD-fed mice273, in diabetic db/db mice274,
and in Zucker diabetic fatty rats275. In addition, several
large-scale studies276 including DAIS, FIELD, the FIELD
washout sub-study, and the ACCORD trial showed that
fibrates reduce progression of albuminuria, and despite
an initial transient reduction in GFR, these agents might
reduce loss of renal function in the long term277–281.
Direct activation of AMPK with AICAR or treat-
ment with metformin also increases fatty acid oxidation
and prevents the development of HFD-induced kid-
ney injury 282,283. Treatment with a selective G‑protein
coupled bile acid receptor 1 (TGR5) agonist increased
mitochondrial fatty acid β‑oxidation and prevented lipid
accumulation and the development of renal disease in
mice with HFD-induced obesity and in db/db mice284.
Cholesterol. Increased cholesterol accumulation can
occur as a result of increased cholesterol synthesis,
increased cholesterol uptake or decreased cholesterol
efflux (FIG. 6). SREBP‑2 is a master regulator of choles-
terol synthesis and cholesterol metabolism236–243. Studies
in mice with HFD-induced obesity, ageing, or diabetes
have shown that increased SREBP‑2 expression and
activity are associated with increased cholesterol synthe-
sis and accumulation as well as the development of renal
disease247–249,251,271. In obesity, as well as in diabetes and
ageing, increased SREBP‑2 expression in the presence
of increased intracellular cholesterol indicates a break-
down of physiological feedback mechanisms. Potential
↑ LDL receptor, ↑ oxidized LDL receptor, ↑ CD36 and ↑ SRA
↑ Cholesterol uptake
↑ Cholesterol ↑ Cholesterol ↓ Cholesterol
synthesis efflux
↓ ABCA1 and
↑HMGCR ↓ Cholesterol catabolism ↓ ABCG1
↑ SREBP-2 ↓ LXR
↓ Bile acids
↓ Bile acid
transporters LXR agonists
mechanisms include roles for inflammatory cytokines,
which interfere with the SCAP–SREBP‑2–LDL receptor
and 3‑hydroxy‑3‑methylglutaryl-CoA reductase path-
ways203,285, the presence of ER stress, which stimulates
SREBP‑2 release from the ER286, and advanced glycation
end products, which increase abnormal translocation of
SCAP from the ER to the Golgi resulting in activation
of SREBP‑2 (REF. 287).
Small molecule inhibitors of SREBP‑2 are the subject
of ongoing research. Studies have shown, however, that
caloric restriction in ageing 249 and treatment of mice
with HFD-induced obesity using a vitamin D receptor
agonist 271 decrease SREBP‑2 expression and activity
in the kidney, prevent cholesterol accumulation and
improve renal disease. Moreover, angiotensin 1–7 has
been shown to decrease renal inflammation and renal
injury in HFD-fed mice by downregulating the SCAP–
SREBP‑2–LDL receptor pathway 288,289. Statin treatment
of HFD-fed mice has also been shown to reduce lipid
accumulation in the proximal tubules, reduce glomeru-
lar hypertrophy, increase podocyte nephrin expression
and decrease desmin expression290.
An alternative approach to limit cholesterol accumu-
lation is to increase cholesterol efflux. The nuclear recep-
tor LXR has a major role in cholesterol efflux, decreases
inflammation and prevents the development of ather-
osclerosis291–293. LXR also induces cholesterol efflux in
renal cells294. The expression of LXR and target enzymes
that regulate cholesterol efflux, including ATP-binding
cassette sub-family A member 1 (ABCA1) and ABCG1,
are decreased in human kidney biopsy samples from
diabetic patients with ORG272,295 and in animal models
of diabetes251,296. Although the aetiology of the decrease
in LXR expression in the presence of high cellular cho-
lesterol is incompletely understood, lipopolysaccharide,
TNF and IL‑1β downregulate LXR in kidney cells297.
Treatment of diabetic mice with LXR agonists reduces
cholesterol accumulation, decreases inflammatory medi-
ators, and prevents progression of renal disease298–300. By
contrast, diabetic nephropathy is accelerated in LXR-
knockout mice; these mice exhibit increased cholesterol
accumulation, inflammation, and oxidative stress300.
LXR activation also has additional effects in the kidney,
including the reduction of renin activation301,302, and
inhibition of ENaC-mediated sodium transport 303 and
cystic fibrosis transmembrane conductance regulator
(CFTR)-mediated chloride transport in collecting duct
cells304, which might have important roles in obesity-
related kidney disease. In addition to LXR agonists,
induction of cholesterol efflux with cyclodextrin
improves renal disease in diabetic BTBR ob/ob mice295.

Figure 6 | Cholesterol metabolism in obesity-related glomerulopathy. Cholesterol Conclusions

Nature Reviews
accumulation can occur as a result of increased cholesterol synthesis mediated| Nephrology
by sterol
regulatory element-binding protein 2 (SREBP‑2) and its target enzymes including
3‑hydroxy‑3‑methylglutaryl-coenzyme A reductase (HMGCR); increased cholesterol
uptake mediated by LDL receptor, oxidized LDL receptor, scavenger receptor A (SRA) or
CD36; decreased cholesterol efflux mediated by liver X receptor (LXR) and target enzymes;
or decreased cholesterol catabolism mediated by bile acids and bile acid transporters. LXR
agonists increase cholesterol efflux and decrease inflammation and endoplasmic reticulum
stress. ABCA1, ATP-binding cassette subfamily A member 1; ABCG1, ATP-binding cassette
subfamily G member 1; HMGCR, hydroxymethylglutaryl-CoA reductase kinase.
ORG is defined pathologically as glomerulomegaly and
FSGS occurring in patients with BMI ≥30 kg/m 2,
and its prevalence is increasing in parallel with
the worldwide obesity epidemic. Obesity induces
increases in GFR, RPF, filtration fraction and tubular
reabsorption of sodium, promoting glomerular
hypertension. FSGS is mediated by the inability of
adaptive podocyte hypertrophy to keep pace with

14 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 REVIEWS

glomerular tuft expansion, leading to podocyte failure.
A predominance of perihilar FSGS and relatively mild
foot process effacement helps to distinguish ORG from
primary FSGS. Although subnephrotic proteinuria is
the most common presentation of ORG, less than half of
patients have nephrotic-range proteinuria and the pres-
ence of full nephrotic syndrome is distinctly unusual. The
clinical course is characterized by stable or slowly progres-
sive proteinuria, but up to one-third of patients develop
progressive renal failure and ESRD. Acquired reduction of
renal mass and a low nephron endowment at birth have
been identified as predisposing factors for ORG. RAAS
blockade is an effective therapeutic measure, but the
antiproteinuric and renoprotective effects may be short-
lived. Weight loss, either as a result of hypocaloric diets or
bariatric surgery, has shown a consistent and remarkable
antiproteinuric effect in case reports, retrospective studies
and small RCTs; however, larger prospective studies of
longer duration are needed. Adipokines and ectopic lipid
resulting from dysfunctional adipose tissue homeostasis
in unhealthy obesity may lead to maladaptive changes
of renal cells to cope with the mechanical forces of renal
hyperfiltration. This process may contribute to glomerular
podocyte rarefaction, albuminuria, and eventually FSGS
and interstitial fibrosis. Lipid accumulation in the kid-
ney (fatty kidney) has been associated with renal insulin
resistance of podocytes, but not of tubular cells. Normal
insulin/PI3K/Akt and mTOR signalling seems critical
for normal podocyte function and adaptation. Altered
fatty acid and cholesterol metabolism in obesity has an
important role in lipid accumulation and regulation of
inflammation, oxidative stress and fibrosis. SREBP antag-
onists and agonists of PPARα, FXR, TGR5 and LXR hold
promise for the treatment and prevention of ORG.

1. Coresh, J. et al. Prevalence of chronic kidney disease
in the United States. JAMA 298, 2038–2047 (2007).
2. Farag, Y. M. & Gaballa, M. R. Diabesity: an overview
of a rising epidemic. Nephrol. Dial. Transplant. 26,
28–35 (2011).
3. Zammit, A. R., Katz, M. J., Derby, C., Bitzer, M. &
Lipton, R. B. Chronic kidney disease in non-diabetic
older adults: associated roles of the metabolic
syndrome, inflammation, and insulin resistance. PLoS
ONE 10, e0139369 (2015).
4. Stenvinkel, P., Zoccali, C. & Ikizler, T. A. Obesity in
CKD — what should nephrologists know? J. Am. Soc.
Nephrol. 24, 1727–1736 (2013).
5. Wickman, C. & Kramer, H. Obesity and kidney
disease: potential mechanisms. Semin. Nephrol. 33,
14–22 (2013).
6. Guebre-Egziabher, F. et al. Ectopic lipid accumulation:
a potential cause for metabolic disturbances and a
contributor to the alteration of kidney function.
Biochimie 95, 1971–1979 (2013).
7. Nolan, E., O’Meara, Y. M. & Godson, C. Lipid
mediators of inflammation in obesity-related
glomerulopathy. Nephrol. Dial. Transplant. 28
(Suppl. 4), iv22–iv29 (2013).
8. de Vries, A. P. et al. Fatty kidney: emerging role of
ectopic lipid in obesity-related renal disease. Lancet
Diabetes Endocrinol. 2, 417–426 (2014).
This review discusses the role of ectopic lipid
accumulation in maladaptive changes of glomerular
cells in response to the haemodynamic forces of
hyperfiltration and CKD.
9. GBD 2013 Risk Factors Collaborators. 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 (2015).
10. Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M.
Prevalence of childhood and adult obesity in the
United States, 2011–2012. JAMA 311, 806–814
(2014).
11. Wang, Y., Beydoun, M. A., Liang, L., Caballero, B. &
Kumanyika, S. K. Will all Americans become
overweight or obese? Estimating the progression and
cost of the US obesity epidemic. Obesity (Silver
Spring) 16, 2323–2330 (2008).
12. Li, Q., Blume, S. W., Huang, J. C., Hammer, M. &
Ganz, M. L. Prevalence and healthcare costs of
obesity-related comorbidities: evidence from an
electronic medical records system in the United States.
J. Med. Econ. 18, 1020–1028 (2015).
13. Cohen, A. H. Massive obesity and the kidney. A
morphologic and statistical study. Am. J. Pathol. 81,
117–130 (1975).
14. Weisinger, J. R., Kempson, R. L., Eldridge, F. L. &
Swenson, R. S. The nephrotic syndrome: a
complication of massive obesity. Ann. Intern. Med. 81,
440–447 (1974).
15. Chen, H. M. et al. Obesity-related glomerulopathy in
China: a case series of 90 patients. Am. J. Kidney Dis.
52, 58–65 (2008).
16. Kambham, N., Markowitz, G. S., Valeri, A. M., Lin, J. &
D’Agati, V. D. Obesity-related glomerulopathy: an
emerging epidemic. Kidney Int. 59, 1498–1509
(2001).
This study provided the first detailed clinical–
pathologic analysis of ORG as contrasted with
primary FSGS and demonstrates the rising
prevalence of ORG diagnosed by kidney biopsy.
17. Praga, M. et al. Clinical features and long-term
outcome of obesity-associated focal segmental
glomerulosclerosis. Nephrol. Dial. Transplant. 16,
1790–1798 (2001).
This comprehensive clinical study describes the
presenting clinical features and outcomes of ORG
in a large Spanish cohort.
18. Hughson, M. D., Hoy, W. E., Douglas-Denton, R. N.,
Zimanyi, M. A. & Bertram, J. F. Towards a definition of
glomerulomegaly: clinical-pathological and
methodological considerations. Nephrol. Dial.
Transplant. 26, 2202–2208 (2011).
19. D’Agati, V. D., Kaskel, F. J. & Falk, R. J. Focal
segmental glomerulosclerosis. N. Engl. J. Med. 365,
2398–2411 (2011).
20. D’Agati, V. D., Fogo, A. B., Bruijn, J. A. &
Jennette, J. C. Pathologic classification of focal
segmental glomerulosclerosis: a working proposal.
Am. J. Kidney Dis. 43, 368–382 (2004).
21. Chagnac, A. et al. Glomerular hemodynamics in severe
obesity. Am. J. Physiol. Renal Physiol. 278,
F817–F822 (2000).
This human study shows that obesity-related
glomerular hyperfiltration is mainly the result of an
increase in transcapillary hydraulic pressure
difference, mostly due to afferent arteriolar
dilation.
22. Chen, H. M. et al. Podocyte lesions in patients with
obesity-related glomerulopathy. Am. J. Kidney Dis.
48, 772–779 (2006).
23. Wharram, B. L. et al. Podocyte depletion causes
glomerulosclerosis: diphtheria toxin-induced podocyte
depletion in rats expressing human diphtheria toxin
receptor transgene. J. Am. Soc. Nephrol. 16,
2941–2952 (2005).
24. Wiggins, J. E. et al. Podocyte hypertrophy,
‘adaptation,’ and ‘decompensation’ associated with
glomerular enlargement and glomerulosclerosis in the
aging rat: prevention by calorie restriction. J. Am. Soc.
Nephrol. 16, 2953–2966 (2005).
25. Fukuda, A. et al. Growth-dependent podocyte failure
causes glomerulosclerosis. J. Am. Soc. Nephrol. 23,
1351–1363 (2012).
This experimental study shows that the mTOR
pathway is important in the adaptive growth of the
glomerulus in obesity and that FSGS can develop
when the rate of podocyte hypertrophy is lower
than the rate of glomerular hypertrophy.
26. Kriz, W., Hosser, H., Hahnel, B., Gretz, N. &
Provoost, A. P. From segmental glomerulosclerosis to
total nephron degeneration and interstitial fibrosis: a
histopathological study in rat models and human
glomerulopathies. Nephrol. Dial. Transplant. 13,
2781–2798 (1998).
27. Nagata, M. & Kriz, W. Glomerular damage after
uninephrectomy in young rats. II. Mechanical stress on
podocytes as a pathway to sclerosis. Kidney Int. 42,
148–160 (1992).
28. Tsuboi, N. et al. Low glomerular density with
glomerulomegaly in obesity-related glomerulopathy.
Clin. J. Am. Soc. Nephrol. 7, 735–741 (2012).
29. Hoy, W. E. et al. A stereological study of glomerular
number and volume: preliminary findings in a
multiracial study of kidneys at autopsy. Kidney Int. 63,
S31–S37 (2003).
30. Hughson, M., Farris, A. B., 3rd, Douglas-Denton, R.,
Hoy, W. E. & Bertram, J. F. Glomerular number and
size in autopsy kidneys: the relationship to birth
weight. Kidney Int. 63, 2113–2122 (2003).
31. Luyckx, V. A. & Brenner, B. M. Birth weight, malnutrition
and kidney-associated outcomes — a global concern.
Nat. Rev. Nephrol. 11, 135–149 (2015).
32. Manalich, R., Reyes, L., Herrera, M., Melendi, C. &
Fundora, I. Relationship between weight at birth and
the number and size of renal glomeruli in humans: a
histomorphometric study. Kidney Int. 58, 770–773
(2000).
33. Bobulescu, I. A. et al. Triglycerides in the human
kidney cortex: relationship with body size. PLoS ONE
9, e101285 (2014).
This human study is the first to show that obesity,
as reflected by BMI, is associated with increased
triglyceride accumulation in the kidney,
predominantly in tubular cells.
34. Wu, Y. et al. Obesity-related glomerulopathy: insights
from gene expression profiles of the glomeruli derived
from renal biopsy samples. Endocrinology 147,
44–50 (2006).
This study shows increased expression of multiple
genes that regulate insulin function, lipid
metabolism, inflammation and fibrogenesis in
kidney biopsy samples from patients with ORG.
Notably, it identified SREBP‑1, which mediates
fatty acid and triglyceride synthesis.
35. D’Agati, V. D. Pathobiology of focal segmental
glomerulosclerosis: new developments. Curr. Opin.
Nephrol. Hypertens. 21, 243–250 (2012).
36. D’Agati, V. D. The spectrum of focal segmental
glomerulosclerosis: new insights. Curr. Opin. Nephrol.
Hypertens. 17, 271–281 (2008).
37. Bhathena, D. B., Julian, B. A., McMorrow, R. G. &
Baehler, R. W. Focal sclerosis of hypertrophied
glomeruli in solitary functioning kidneys of humans.
Am. J. Kidney Dis. 5, 226–232 (1985).
38. Hodgin, J. B., Rasoulpour, M., Markowitz, G. S. &
D’Agati, V. D. Very low birth weight is a risk factor for
secondary focal segmental glomerulosclerosis. Clin.
J. Am. Soc. Nephrol. 4, 71–76 (2009).
39. Deegens, J. K. et al. Podocyte foot process effacement
as a diagnostic tool in focal segmental
glomerulosclerosis. Kidney Int. 74, 1568–1576 (2008).
40. Ichikawa, I., Ma, J., Motojima, M. & Matsusaka, T.
Podocyte damage damages podocytes: autonomous
vicious cycle that drives local spread of glomerular
sclerosis. Curr. Opin. Nephrol. Hypertens. 14,
205–210 (2005).

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 15

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS
41. D’Agati, V. Podocyte injury can be catching. J. Am.
Soc. Nephrol. 22, 1181–1183 (2011).
42. Bonnet, F. et al. Excessive body weight as a new
independent risk factor for clinical and pathological
progression in primary IgA nephritis. Am. J. Kidney
Dis. 37, 720–727 (2001).
This study was among the first to show that elevated
BMI is a risk factor for clinical and pathologic
progression of a glomerular disease other than ORG.
43. Hsu, C. Y., McCulloch, C. E., Iribarren, C., Darbinian, J.
& Go, A. S. Body mass index and risk for end-stage
renal disease. Ann. Intern. Med. 144, 21–28 (2006).
This large historical cohort study of over 320,000
adults demonstrated that higher BMI at baseline is
an independent risk factor for subsequent ESRD in
multivariable analyses after adjustment for age,
sex, race, education level, smoking status, cardiac
disease, serum cholesterol, urinalysis proteinuria,
hematuria, serum creatinine level, baseline blood
pressure level and presence of diabetes mellitus.
44. Sharma, S. G. et al. The modern spectrum of renal
biopsy findings in patients with diabetes. Clin. J. Am.
Soc. Nephrol. 8, 1718–1724 (2013).
45. Serra, A. et al. Renal injury in the extremely obese
patients with normal renal function. Kidney Int. 73,
947–955 (2008).
Using protocol biopsies in patients undergoing
bariatric surgery for morbid obesity, this study
demostrated the presence of early pathologic
abnormalities in patients lacking clinically
detectable renal disease.
46. Goumenos, D. S. et al. Early histological changes in
the kidney of people with morbid obesity. Nephrol.
Dial. Transplant. 24, 3732–3738 (2009).
47. D’Agati, V. D. & Markowitz, G. S Supersized kidneys:
lessons from the preclinical obese kidney. Kidney Int.
73, 909–910 (2008).
48. Pehlivan, E. et al. Identifying the determinants of
microalbuminuria in obese patients in primary care
units: the effects of blood pressure, random plasma
glucose and other risk factors. J. Endocrinol. Invest.
39, 73–82 (2016).
49. Hashimoto, Y. et al. Metabolically healthy obesity and
risk of incident CKD. Clin. J. Am. Soc. Nephrol. 10,
578–583 (2015).
50. Lin, W. Y. et al. Central obesity and albuminuria: both
cross-sectional and longitudinal studies in Chinese.
PLoS ONE 7, e47960 (2012).
51. Tsuboi, N. et al. Clinical features and long-term renal
outcomes of Japanese patients with obesity-related
glomerulopathy. Clin. Exp. Nephrol. 17, 379–385
(2013).
52. Chen, H. M. et al. Evaluation of metabolic risk marker
in obesity-related glomerulopathy. J. Ren. Nutr. 21,
309–315 (2011).
53. Praga, M. et al. Nephrotic proteinuria without
hypoalbuminemia: clinical characteristics and
response to angiotensin-converting enzyme inhibition.
Am. J. Kidney Dis. 17, 330–338 (1991).
54. Praga, M. et al. Absence of hypoalbuminemia despite
massive proteinuria in focal segmental
glomerulosclerosis secondary to hyperfiltration. Am.
J. Kidney Dis. 33, 52–58 (1999).
This study showed that patients with focal segmental
glomerulosclerosis secondary to hyperfiltration
(including ORG) do not develop hypoalbuminemia
even in the presence of nephrotic-range proteinuria.
55. Sethi, S., Zand, L., Nasr, S. H., Glassock, R. J. &
Fervenza, F. C. Focal and segmental
glomerulosclerosis: clinical and kidney biopsy
correlations. Clin. Kidney J. 7, 531–537 (2014).
56. Sethi, S., Glassock, R. J. & Fervenza, F. C. Focal
segmental glomerulosclerosis: towards a better
understanding for the practicing nephrologist.
Nephrol. Dial. Transplant. 30, 375–384 (2015).
57. Shen, W. W. et al. Obesity-related glomerulopathy:
body mass index and proteinuria. Clin. J. Am. Soc.
Nephrol. 5, 1401–1409 (2010).
58. Nangaku, M. et al. In a type 2 diabetic nephropathy
rat model, the improvement of obesity by a low calorie
diet reduces oxidative/carbonyl stress and prevents
diabetic nephropathy. Nephrol. Dial. Transplant. 20,
2661–2669 (2005).
59. Chander, P. N. et al. Nephropathy in Zucker diabetic
fat rat is associated with oxidative and nitrosative
stress: prevention by chronic therapy with a
peroxynitrite scavenger ebselen. J. Am. Soc. Nephrol.
15, 2391–2403 (2004).
60. Kawasaki, Y. et al. Two children with obesity-related
glomerulopathy identified in a school urinary
screening program. Pediatr. Int. 56, 115–118 (2014).
16 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph
61. Novick, A. C., Gephardt, G., Guz, B., Steinmuller, D. &
Tubbs, R. R. Long-term follow‑up after partial removal
of a solitary kidney. N. Engl. J. Med. 325, 1058–1062
(1991).
62. Bosma, R. J., van der Heide, J. J., Oosterop, E. J.,
de Jong, P. E. & Navis, G. Body mass index is associated
with altered renal hemodynamics in non-obese healthy
subjects. Kidney Int. 65, 259–265 (2004).
63. Praga, M. et al. Influence of obesity on the
appearance of proteinuria and renal insufficiency after
unilateral nephrectomy. Kidney Int. 58, 2111–2118
(2000).
This study was the first to report detrimental
effects of obesity in patients with renal mass
reduction.
64. Gonzalez, E. et al. Factors influencing the progression
of renal damage in patients with unilateral renal
agenesis and remnant kidney. Kidney Int. 68,
263–270 (2005).
65. Whincup, P. H. et al. Birth weight and risk of type 2
diabetes: a systematic review. JAMA 300,
2886–2897 (2008).
66. White, S. L. et al. Is low birth weight an antecedent of
CKD in later life? A systematic review of observational
studies. Am. J. Kidney Dis. 54, 248–261 (2009).
67. de Jong, F., Monuteaux, M. C., van Elburg, R. M.,
Gillman, M. W. & Belfort, M. B. Systematic review and
meta-analysis of preterm birth and later systolic blood
pressure. Hypertension 59, 226–234 (2012).
68. Mu, M. et al. Birth weight and subsequent blood
pressure: a meta-analysis. Arch. Cardiovasc. Dis. 105,
99–113 (2012).
69. Vikse, B. E., Irgens, L. M., Leivestad, T., Hallan, S. &
Iversen, B. M. Low birth weight increases risk for end-
stage renal disease. J. Am. Soc. Nephrol. 19,
151–157 (2008).
This important cohort study shows that low birth
weight and intrauterine growth restriction increase
the risk of ESRD.
70. Abitbol, C. L. et al. Obesity and preterm birth:
additive risks in the progression of kidney disease in
children. Pediatr. Nephrol. 24, 1363–1370 (2009).
71. Barker, D. J., Osmond, C., Forsen, T. J., Kajantie, E. &
Eriksson, J. G. Trajectories of growth among children
who have coronary events as adults. N. Engl. J. Med.
353, 1802–1809 (2005).
72. Andersen, L. G. et al. Birth weight, childhood body
mass index and risk of coronary heart disease in
adults: combined historical cohort studies. PLoS ONE
5, e14126 (2010).
73. Caballero, B. A nutrition paradox — underweight and
obesity in developing countries. N. Engl. J. Med. 352,
1514–1516 (2005).
74. Mallamaci, F. et al. ACE inhibition is renoprotective
among obese patients with proteinuria. J. Am. Soc.
Nephrol. 22, 1122–1128 (2011).
This post hoc analysis of the REIN trial shows that
obesity predicts a higher risk of renal events but
ramipril treatment can abolish this excess risk.
75. Garg, R. & Adler, G. K. Aldosterone and the
mineralocorticoid receptor: risk factors for
cardiometabolic disorders. Curr. Hypertens. Rep. 17,
52 (2015).
76. Bomback, A. S., Muskala, P., Bald, E., Chwatko, G. &
Nowicki, M. Low-dose spironolactone, added to long-
term ACE inhibitor therapy, reduces blood pressure
and urinary albumin excretion in obese patients with
hypertensive target organ damage. Clin. Nephrol. 72,
449–456 (2009).
77. Friedman, A. N., Chambers, M., Kamendulis, L. M. &
Temmerman, J. Short-term changes after a weight
reduction intervention in advanced diabetic
nephropathy. Clin. J. Am. Soc. Nephrol. 8,
1892–1898 (2013).
78. Saiki, A. et al. Effect of weight loss using formula diet
on renal function in obese patients with diabetic
nephropathy. Int. J. Obes. (Lond.) 29, 1115–1120
(2005).
79. Nicholson, A. S. et al. Toward improved management
of NIDDM: a randomized, controlled, pilot
intervention using a lowfat, vegetarian diet. Prev. Med.
29, 87–91 (1999).
80. Morales, E., Valero, M. A., Leon, M., Hernandez, E. &
Praga, M. Beneficial effects of weight loss in
overweight patients with chronic proteinuric
nephropathies. Am. J. Kidney Dis. 41, 319–327
(2003).
81. Straznicky, N. E. et al. Exercise augments weight loss
induced improvement in renal function in obese
metabolic syndrome individuals. J. Hypertens. 29,
553–564 (2011).
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
82. Navaneethan, S. D. et al. Weight loss interventions in
chronic kidney disease: a systematic review and meta-
analysis. Clin. J. Am. Soc. Nephrol. 4, 1565–1574
(2009).
This systematic review and meta-analysis reportes
that in patients with CKD, surgical and non-surgical
weight loss interventions significantly reduce
proteinuria and blood pressure and seem to
prevent further decline in renal function.
83. Afshinnia, F., Wilt, T. J., Duval, S., Esmaeili, A. &
Ibrahim, H. N. Weight loss and proteinuria: systematic
review of clinical trials and comparative cohorts.
Nephrol. Dial. Transplant. 25, 1173–1183 (2010).
84. Bolignano, D. & Zoccali, C. Effects of weight loss on
renal function in obese CKD patients: a systematic
review. Nephrol. Dial. Transplant. 28 (Suppl. 4),
iv82–iv98 (2013).
85. Praga, M. et al. Effects of body-weight loss and
captopril treatment on proteinuria associated with
obesity. Nephron 70, 35–41 (1995).
86. Patil, M. R., Mishra, A., Jain, N., Gutch, M. &
Tewari, R. Weight loss for reduction of proteinuria in
diabetic nephropathy: comparison with angiotensin-
converting enzyme inhibitor therapy. Indian
J. Nephrol. 23, 108–113 (2013).
87. Dixon, J. B. et al. Adjustable gastric banding and
conventional therapy for type 2 diabetes: a randomized
controlled trial. JAMA 299, 316–323 (2008).
88. Schauer, P. R. et al. Bariatric surgery versus intensive
medical therapy for diabetes — 3‑year outcomes.
N. Engl. J. Med. 370, 2002–2013 (2014).
89. Chagnac, A. et al. The effects of weight loss on renal
function in patients with severe obesity. J. Am. Soc.
Nephrol. 14, 1480–1486 (2003).
This study shows that weight loss ameliorates
obesity-related glomerular hyperfiltration,
demonstrating the cause–effect relationship
between obesity and hyperfiltration.
90. Agrawal, V. et al. The effect of weight loss after
bariatric surgery on albuminuria. Clin. Nephrol. 70,
194–202 (2008).
91. Navaneethan, S. D. et al. Urinary albumin excretion,
HMW adiponectin, and insulin sensitivity in type 2
diabetic patients undergoing bariatric surgery. Obes.
Surg. 20, 308–315 (2010).
92. MacLaughlin, H. L., Hall, W. L., Patel, A. G. &
Macdougall, I. C. Laparoscopic sleeve gastrectomy is a
novel and effective treatment for obesity in patients
with chronic kidney disease. Obes. Surg. 22, 119–123
(2012).
93. Neff, K. J. et al. The effect of bariatric surgery on renal
function and disease: a focus on outcomes and
inflammation. Nephrol. Dial. Transplant. 28 (Suppl. 4),
iv73–iv82 (2013).
94. Reid, T. J. et al. The effect of bariatric surgery on renal
function. Surg. Obes. Relat. Dis. 10, 808–813 (2014).
95. Serra, A. et al. Long-term normal renal function after
drastic weight reduction in patients with obesity-related
glomerulopathy. Obes. Facts 8, 188–199 (2015).
96. Saleh, F., Kim, S. J., Okrainec, A. & Jackson, T. D.
Bariatric surgery in patients with reduced kidney
function: an analysis of short-term outcomes. Surg.
Obes. Relat. Dis. 11, 828–835 (2015).
97. MacLaughlin, H. L. et al. Weight loss, adipokines, and
quality of life after sleeve gastrectomy in obese patients
with stages 3–4 CKD: a randomized controlled pilot
study. Am. J. Kidney Dis. 64, 660–663 (2014).
98. Huan, Y., Tomaszewski, J. E. & Cohen, D. L. Resolution
of nephrotic syndrome after successful bariatric
surgery in patient with biopsy-proven FSGS. Clin.
Nephrol. 71, 69–73 (2009).
99. Fowler, S. M. et al. Obesity-related focal and
segmental glomerulosclerosis: normalization of
proteinuria in an adolescent after bariatric surgery.
Pediatr. Nephrol. 24, 851–855 (2009).
100. Lieske, J. C. et al. Kidney stones are common after
bariatric surgery. Kidney Int. 87, 839–845 (2015).
101. Turgeon, N. A. et al. The impact of renal function on
outcomes of bariatric surgery. J. Am. Soc. Nephrol.
23, 885–894 (2012).
102. Brochner-Mortensen, J., Rickers, H. & Balslev, I. Renal
function and body composition before and after
intestinal bypass operation in obese patients. Scand.
J. Clin. Lab. Invest. 40, 695–702 (1980).
103. Ribstein, J., du Cailar, G. & Mimran, A. Combined
renal effects of overweight and hypertension.
Hypertension 26, 610–615 (1995).
104. Scaglione, R. et al. Central obesity and hypertension:
pathophysiologic role of renal haemodynamics and
function. Int. J. Obes. Relat. Metab. Disord. 19,
403–409 (1995).

105. Anastasio, P. et al. Glomerular filtration rate in
severely overweight normotensive humans. Am.
J. Kidney Dis. 35, 1144–1148 (2000).
106. Pecly, I. M. D., Genelhu, V. & Francischetti, E. A. Renal
functional reserve in obesity hypertension. Int. J. Clin.
Pract. 60, 1198–1203 (2006).
107. Chagnac, A. et al. Obesity-induced glomerular
hyperfiltration: its involvement in the pathogenesis of
tubular sodium reabsorption. Nephrol. Dial.
Transplant. 23, 3946–3952 (2008).
108. Wuerzner, G. et al. Marked association between
obesity and glomerular hyperfiltration: a cross-
sectional study in an African population. Am. J. Kidney
Dis. 56, 303–312 (2010).
109. Deibert, P. et al. Acute effect of a soy protein-rich
meal-replacement application on renal parameters in
patients with the metabolic syndrome. Asia Pac.
J. Clin. Nutr. 20, 527–534 (2011).
110. Ahmed, S. B., Fisher, N. D., Stevanovic, R. &
Hollenberg, N. K. Body mass index and angiotensin-
dependent control of the renal circulation in healthy
humans. Hypertension 46, 1316–1320 (2005).
111. Porter, L. E. & Hollenberg, N. K. Obesity, salt intake,
and renal perfusion in healthy humans. Hypertension
32, 144–148 (1998).
112. Reisin, E., Messerli, F. G., Ventura, H. O. &
Frohlich, E. D. Renal haemodynamic studies in obesity
hypertension. J. Hypertens. 5, 397–400 (1987).
113. Must, A. et al. The disease burden associated with
overweight and obesity. JAMA 282, 1523–1529
(1999).
114. Strazzullo, P. et al. Altered renal sodium handling in
men with abdominal adiposity: a link to hypertension.
J. Hypertens. 19, 2157–2164 (2001).
This investigation shows that increased abdominal
adiposity is associated with an enhanced rate of
proximal tubular sodium reabsorption, which might
have a role in the pathogenesis of glomerular
hyperfiltration.
115. Barbato, A. et al. Metabolic syndrome and renal
sodium handling in three ethnic groups living in
England. Diabetologia 47, 40–46 (2004).
116. Bickel, C. A., Verbalis, J. G., Knepper, M. A. &
Ecelbarger, C. A. Increased renal Na‑K‑ATPase, NCC,
and β-ENaC abundance in obese Zucker rats. Am.
J. Physiol. Renal Physiol. 281, F639–F648 (2001).
117. Shah, S. & Hussain, T. Enhanced angiotensin
II‑induced activation of Na+, K+-ATPase in the
proximal tubules of obese Zucker rats. Clin. Exp.
Hypertens. 28, 29–40 (2006).
118. Brenner, B. M., Lawler, E. V. & Mackenzie, H. S. The
hyperfiltration theory: a paradigm shift in nephrology.
Kidney Int. 49, 1774–1777 (1996).
119. Bank, N. & Aynedjian, H. S. Progressive increases in
luminal glucose stimulate proximal sodium absorption
in normal and diabetic rats. J. Clin. Invest. 86,
309–316 (1990).
120. Vallon, V., Blantz, R. C. & Thomson, S. Glomerular
hyperfiltration and the salt paradox in early
[corrected] type 1 diabetes mellitus: a tubulo-centric
view. J. Am. Soc. Nephrol. 14, 530–537 (2003).
121. Vallon, V., Richter, K., Blantz, R. C., Thomson, S. &
Osswald, H. Glomerular hyperfiltration in
experimental diabetes mellitus: potential role of
tubular reabsorption. J. Am. Soc. Nephrol. 10,
2569–2576 (1999).
Using an experimental diabetic model this study
demonstrates that an increase in proximal tubular
reabsorption of sodium leads to increased GFR by
deactivation of tubuloglomerular feedback.
122. Cappuccio, F. P., Strazzullo, P., Siani, A. & Trevisan, M.
Increased proximal sodium reabsorption is associated
with increased cardiovascular risk in men.
J. Hypertens. 14, 909–914 (1996).
123. Zingerman, B. et al. Effect of acetazolamide on obesity-
induced glomerular hyperfiltration: a randomized
controlled trial. PLoS ONE 10, e0137163 (2015).
124. Engeli, S. et al. Weight loss and the renin–
angiotensin–aldosterone system. Hypertension 45,
356–362 (2005).
125. Tuck, M. L., Sowers, J., Dornfeld, L., Kledzik, G. &
Maxwell, M. The effect of weight reduction on blood
pressure, plasma renin activity, and plasma
aldosterone levels in obese patients. N. Engl. J. Med.
304, 930–933 (1981).
126. Cooper, R. et al. ACE, angiotensinogen and obesity: a
potential pathway leading to hypertension. J. Hum.
Hypertens. 11, 107–111 (1997).
127. Bochud, M. et al. Plasma aldosterone is independently
associated with the metabolic syndrome. Hypertension
48, 239–245 (2006).
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 17
128. Rossi, G. P. et al. Body mass index predicts plasma
aldosterone concentrations in overweight-obese
primary hypertensive patients. J. Clin. Endocrinol.
Metab. 93, 2566–2571 (2008).
129. Schorr, U., Blaschke, K., Turan, S., Distler, A. &
Sharma, A. M. Relationship between angiotensinogen,
leptin and blood pressure levels in young
normotensive men. J. Hypertens. 16, 1475–1480
(1998).
130. Achard, V., Boullu-Ciocca, S., Desbriere, R., Nguyen, G.
& Grino, M. Renin receptor expression in human
adipose tissue. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 292, R274–R282 (2007).
131. Ehrhart-Bornstein, M., Arakelyan, K., Krug, A. W.,
Scherbaum, W. A. & Bornstein, S. R. Fat cells may be
the obesity–hypertension link: human adipogenic
factors stimulate aldosterone secretion from
adrenocortical cells. Endocr. Res. 30, 865–870 (2004).
132. Goodfriend, T. L. & Calhoun, D. A. Resistant
hypertension, obesity, sleep apnea, and aldosterone:
theory and therapy. Hypertension 43, 518–524
(2004).
133. Toke, A. & Meyer, T. W. Hemodynamic effects of
angiotensin II in the kidney. Contrib. Nephrol. 135,
34–46 (2001).
134. Arima, S. et al. Nongenomic vascular action of
aldosterone in the glomerular microcirculation. J. Am.
Soc. Nephrol. 14, 2255–2263 (2003).
135. Ribstein, J., Du Cailar, G., Fesler, P. & Mimran, A.
Relative glomerular hyperfiltration in primary
aldosteronism. J. Am. Soc. Nephrol. 16, 1320–1325
(2005).
136. Kennedy, C. R. & Burns, K. D. Angiotensin II as a
mediator of renal tubular transport. Contrib. Nephrol.
135, 47–62 (2001).
137. Kawarazaki, W. et al. Angiotensin II- and salt-induced
kidney injury through Rac1‑mediated
mineralocorticoid receptor activation. J. Am. Soc.
Nephrol. 23, 997–1007 (2012).
138. Granger, J. P. et al. Role of nitric oxide in modulating
renal function and arterial pressure during chronic
aldosterone excess. Am. J. Physiol. 276, R197–R202
(1999).
139. Hall, J. E., Granger, J. P., Smith, M. J. Jr &
Premen, A. J. Role of renal hemodynamics and arterial
pressure in aldosterone ‘escape’. Hypertension 6,
I183–I192 (1984).
140. Vaz, M. et al. Regional sympathetic nervous activity
and oxygen consumption in obese normotensive
human subjects. Circulation 96, 3423–3429 (1997).
141. Davy, K. P. & Orr, J. S. Sympathetic nervous system
behavior in human obesity. Neurosci. Biobehav. Rev.
33, 116–124 (2009).
142. Esler, M. et al. Mechanisms of sympathetic activation
in obesity-related hypertension. Hypertension 48,
787–796 (2006).
143. Hall, J. E. et al. Obesity-induced hypertension: role of
sympathetic nervous system, leptin, and melanocortins.
J. Biol. Chem. 285, 17271–17276 (2010).
144. Young, C. N., Morgan, D. A., Butler, S. D., Mark, A. L.
& Davisson, R. L. The brain subfornical organ
mediates leptin-induced increases in renal sympathetic
activity but not its metabolic effects. Hypertension 61,
737–744 (2013).
145. Nasrallah, M. P. & Ziyadeh, F. N. Overview of the
physiology and pathophysiology of leptin with special
emphasis on its role in the kidney. Semin. Nephrol. 33,
54–65 (2013).
146. Simonds, S. E. et al. Leptin mediates the increase in
blood pressure associated with obesity. Cell 159,
1404–1416 (2014).
147. Greenfield, J. R. et al. Modulation of blood pressure
by central melanocortinergic pathways. N. Engl.
J. Med. 360, 44–52 (2009).
148. Tanida, M. et al. Effects of adiponectin on the renal
sympathetic nerve activity and blood pressure in rats.
Exp. Biol. Med. (Maywood) 232, 390–397 (2007).
149. Kinebuchi, S. et al. Short-term use of continuous
positive airway pressure ameliorates glomerular
hyperfiltration in patients with obstructive sleep apnoea
syndrome. Clin. Sci. (Lond.) 107, 317–322 (2004).
150. Juncos, L. A. & Ito, S. Disparate effects of insulin on
isolated rabbit afferent and efferent arterioles. J. Clin.
Invest. 92, 1981–1985 (1993).
151. Tucker, B. J. & Blantz, R. C. Effects of glomerular
filtration dynamics on the glomerular permeability
coefficient. Am. J. Physiol. 240, F245–F254 (1981).
152. Hayashi, K. et al. Effects of insulin on rat renal
microvessels: studies in the isolated perfused
hydronephrotic kidney. Kidney Int. 51, 1507–1513
(1997).
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS
153. Song, J. et al. Regulation of blood pressure, the
epithelial sodium channel (ENaC), and other key renal
sodium transporters by chronic insulin infusion in rats.
Am. J. Physiol. Renal Physiol. 290, F1055–F1064
(2006).
154. Gesek, F. A. & Schoolwerth, A. C. Hormonal
interactions with the proximal Na+-H+ exchanger. Am.
J. Physiol. 258, F514–F521 (1990).
155. Stenvinkel, P., Bolinder, J. & Alvestrand, A. Effects of
insulin on renal haemodynamics and the proximal and
distal tubular sodium handling in healthy subjects.
Diabetologia 35, 1042–1048 (1992).
156. Sarafidis, P. A. & Bakris, G. L. The antinatriuretic effect
of insulin: an unappreciated mechanism for
hypertension associated with insulin resistance? Am.
J. Nephrol. 27, 44–54 (2007).
157. Ogna, A. et al. Association between obesity and
glomerular hyperfiltration: the confounding effect of
smoking and sodium and protein intakes. Eur. J. Nutr.
55, 1089–1097 (2016).
158. King, A. J. & Levey, A. S. Dietary protein and renal
function. J. Am. Soc. Nephrol. 3, 1723–1737 (1993).
159. Lew, S. W. & Bosch, J. P. Effect of diet on creatinine
clearance and excretion in young and elderly healthy
subjects and in patients with renal disease. J. Am. Soc.
Nephrol. 2, 856–865 (1991).
160. Friedman, A. N. et al. Independent influence of dietary
protein on markers of kidney function and disease in
obesity. Kidney Int. 78, 693–697 (2010).
161. Chen, J. et al. The metabolic syndrome and chronic
kidney disease in U.S. adults. Ann. Intern. Med. 140,
167–174 (2004).
162. Valensi, P. et al. Microalbuminuria in obese patients
with or without hypertension. Int. J. Obes. Relat.
Metab. Disord. 20, 574–579 (1996).
163. Wennmann, D. O., Hsu, H.‑H. & Pavenstadt, H. The
renin–angiotensin–aldosterone system in podocytes.
Semin. Nephrol. 32, 377–384 (2012).
164. Yano, Y. et al. Differential impacts of adiponectin on
low-grade albuminuria between obese and nonobese
persons without diabetes. J. Clin. Hypertens.
(Greenwich) 9, 775–782 (2007).
165. Sharma, K. et al. Adiponectin regulates albuminuria
and podocyte function in mice. J. Clin. Invest. 118,
1645–1656 (2008).
166. Brenner, B. M. & Troy, J. L. Postglomerular vascular
protein concentration: evidence for a causal role in
governing fluid reabsorption and glomerulotublar
balance by the renal proximal tubule. J. Clin. Invest.
50, 336–349 (1971).
167. Ott, C. E., Haas, J. A., Cuche, J. L. & Knox, F. G. Effect
of increased peritubule protein concentration on
proximal tubule reabsorption in the presence and
absence of extracellular volume expansion. J. Clin.
Invest. 55, 612–620 (1975).
168. Ichikawa, I., Hoyer, J. R., Seiler, M. W. &
Brenner, B. M. Mechanism of glomerulotubular
balance in the setting of heterogeneous glomerular
injury. Preservation of a close functional linkage
between individual nephrons and surrounding
microvasculature. J. Clin. Invest. 69, 185–198
(1982).
169. Weinbaum, S., Duan, Y., Satlin, L. M., Wang, T. &
Weinstein, A. M. Mechanotransduction in the renal
tubule. Am. J. Physiol. Renal Physiol. 299,
F1220–F1236 (2010).
170. Kriz, W. & Lemley, K. V. A potential role for mechanical
forces in the detachment of podocytes and the
progression of CKD. J. Am. Soc. Nephrol. 26,
258–269 (2015).
This article reviews studies (most of which were
performed in the authors’ laboratory) that
demonstrate how mechanical forces associated
with glomerular hypertension and hyperfiltration
result in glomerular enlargement and podocyte
detachment, leading to FSGS.
171. Kriz, W., Elger, M., Mundel, P. & Lemley, K. V.
Structure-stabilizing forces in the glomerular tuft.
J. Am. Soc. Nephrol. 5, 1731–1739 (1995).
172. Pereira, S. V. et al. Increased urine podocyte-
associated messenger RNAs in severe obesity are
evidence of podocyte injury. Obesity (Silver Spring)
23, 1643–1649 (2015).
173. Henegar, J. R., Bigler, S. A., Henegar, L. K., Tyagi, S. C.
& Hall, J. E. Functional and structural changes in the
kidney in the early stages of obesity. J. Am. Soc.
Nephrol. 12, 1211–1217 (2001).
174. Tobar, A. et al. Proximal tubular hypertrophy and
enlarged glomerular and proximal tubular urinary
space in obese subjects with proteinuria. PLoS ONE 8,
e75547 (2013).
REVIEWS
This study demonstrates that glomerular
hyperfiltration in obese patients with proteinuria is
associated with proximal tubular epithelial
hypertrophy and increased glomerular and tubular
urinary space volume. These findings suggest that
the expanded glomerular and tubular urinary space
is a direct consequence of glomerular hyperfiltration.
175. Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K.
Adipokines in inflammation and metabolic disease.
Nat. Rev. Immunol. 11, 85–97 (2011).
176. Cao, Y. Adipose tissue angiogenesis as a therapeutic
target for obesity and metabolic diseases. Nat. Rev.
Drug Discov. 9, 107–115 (2010).
177. Kahn, C. R. Can we nip obesity in its vascular bud?
Science 322, 542–543 (2008).
178. Virtue, S. & Vidal-Puig, A. Adipose tissue
expandability, lipotoxicity and the metabolic syndrome
— an allostatic perspective. Biochim. Biophys. Acta
1801, 338–349 (2010).
179. Briffa, J. F., McAinch, A. J., Poronnik, P. &
Hryciw, D. H. Adipokines as a link between obesity and
chronic kidney disease. Am. J. Physiol. Renal Physiol.
305, F1629–F1636 (2013).
180. Maisonpierre, P. C. et al. Angiopoietin‑2, a natural
antagonist for Tie2 that disrupts in vivo angiogenesis.
Science 277, 55–60 (1997).
181. Schlondorff, D. & Banas, B. The mesangial cell
revisited: no cell is an island. J. Am. Soc. Nephrol. 20,
1179–1187 (2009).
182. Lindahl, P., Johansson, B. R., Leveen, P. &
Betsholtz, C. Pericyte loss and microaneurysm
formation in PDGF‑B‑deficient mice. Science 277,
242–245 (1997).
183. Singh, A. K. et al. Vascular factors altered in glucose-
treated mesangial cells and diabetic glomeruli.
Changes in vascular factors impair endothelial cell
growth and matrix. Lab. Invest. 84, 597–606 (2004).
184. Khairoun, M. et al. Early systemic microvascular
damage in pigs with atherogenic diabetes mellitus
coincides with renal angiopoietin dysbalance. PLoS
ONE 10, e0121555 (2015).
185. Kumar Vr, S. et al. Cathepsin S cleavage of protease-
activated receptor‑2 on endothelial cells promotes
microvascular diabetes complications. J. Am. Soc.
Nephrol. http://dx.doi.org/10.1681/
ASN.2015020208 (2015).
186. Nielsen, R. et al. Endocytosis provides a major
alternative pathway for lysosomal biogenesis in kidney
proximal tubular cells. Proc. Natl Acad. Sci. USA 104,
5407–5412 (2007).
187. Yaddanapudi, S. et al. CD2AP in mouse and human
podocytes controls a proteolytic program that
regulates cytoskeletal structure and cellular survival.
J. Clin. Invest. 121, 3965–3980 (2011).
188. Faul, C. et al. The actin cytoskeleton of kidney
podocytes is a direct target of the antiproteinuric
effect of cyclosporine A. Nat. Med. 14, 931–938
(2008).
189. Sever, S. et al. Proteolytic processing of dynamin by
cytoplasmic cathepsin L is a mechanism for proteinuric
kidney disease. J. Clin. Invest. 117, 2095–2104 (2007).
190. Pinto-Sietsma, S. J. et al. A central body fat
distribution is related to renal function impairment,
even in lean subjects. Am. J. Kidney Dis. 41, 733–741
(2003).
191. Elsayed, E. F. et al. Waist‑to‑hip ratio, body mass
index, and subsequent kidney disease and death. Am.
J. Kidney Dis. 52, 29–38 (2008).
192. Fox, C. S. et al. Abdominal visceral and subcutaneous
adipose tissue compartments: association with
metabolic risk factors in the Framingham Heart Study.
Circulation 116, 39–48 (2007).
193. Einstein, F. H. et al. Differential responses of visceral
and subcutaneous fat depots to nutrients. Diabetes
54, 672–678 (2005).
194. Kurella, M., Lo, J. C. & Chertow, G. M. Metabolic
syndrome and the risk for chronic kidney disease
among nondiabetic adults. J. Am. Soc. Nephrol. 16,
2134–2140 (2005).
195. Young, J. A. et al. Association of visceral and
subcutaneous adiposity with kidney function. Clin.
J. Am. Soc. Nephrol. 3, 1786–1791 (2008).
196. de Vries, A. P. & Rabelink, T. J. A possible role of
cystatin C in adipose tissue homeostasis may impact
kidney function estimation in metabolic syndrome.
Nephrol. Dial. Transplant. 28, 1628–1630 (2013).
197. Despres, J. P. & Lemieux, I. Abdominal obesity and
metabolic syndrome. Nature 444, 881–887 (2006).
198. Stefan, N. & Haring, H. U. The role of hepatokines in
metabolism. Nat. Rev. Endocrinol. 9, 144–152
(2013).
18 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph
199. Musso, G. et al. Association of non-alcoholic fatty liver
disease with chronic kidney disease: a systematic review
and meta-analysis. PLoS Med. 11, e1001680 (2014).
This meta-analysis reviews the impact of ectopic
(liver) fat on CKD.
200. Hammer, S. et al. Metabolic imaging of human kidney
triglyceride content: reproducibility of proton
magnetic resonance spectroscopy. PLoS ONE 8,
e62209 (2013).
This human feasibility study is the first to
non-invasively image kidney fat as a biomarker of
fatty kidney.
201. Jonker, J. T.d. H. et al. Imaging fatty kidney using
proton MR spectroscopy: validation by porcine kidney
biopsies. Nephrol. Dial. Transplant. 30, iii393–iii419
(2015).
202. Berfield, A. K., Andress, D. L. & Abrass, C. K.
IGF‑1‑induced lipid accumulation impairs mesangial
cell migration and contractile function. Kidney Int. 62,
1229–1237 (2002).
203. Ruan, X. Z., Varghese, Z., Powis, S. H. &
Moorhead, J. F. Dysregulation of LDL receptor under
the influence of inflammatory cytokines: a new
pathway for foam cell formation. Kidney Int. 60,
1716–1725 (2001).
204. van Zonneveld, A. J. & Rabelink, T. J. Mesangial cells
defy LDL receptor paradigm. Kidney Int. 60,
2037–2038 (2001).
205. Li, Z. et al. Increased glomerular filtration rate in early
metabolic syndrome is associated with renal adiposity
and microvascular proliferation. Am. J. Physiol. Renal
Physiol. 301, F1078–F1087 (2011).
This experimental study is the first to link renal
triglycerides to functional and microvascular
hyperfiltration.
206. Chung, J. J. et al. Albumin-associated free fatty acids
induce macropinocytosis in podocytes. J. Clin. Invest.
125, 2307–2316 (2015).
207. Clement, L. C. et al. Podocyte-secreted angiopoietin-
like‑4 mediates proteinuria in glucocorticoid-sensitive
nephrotic syndrome. Nat. Med. 17, 117–122 (2011).
208. Ruan, X. Z., Varghese, Z. & Moorhead, J. F. An update
on the lipid nephrotoxicity hypothesis. Nat. Rev.
Nephrol. 5, 713–721 (2009).
This is an important review of the updated
Moorhead hypothesis in nephrology.
209. Sun, Y. B. et al. Smad3 deficiency protects mice from
obesity-induced podocyte injury that precedes insulin
resistance. Kidney Int. 88, 286–298 (2015).
210. Lin, H. M. et al. Transforming growth factor-β/Smad3
signaling regulates insulin gene transcription and
pancreatic islet β-cell function. J. Biol. Chem. 284,
12246–12257 (2009).
211. Yadav, H. et al. Protection from obesity and diabetes
by blockade of TGF-β/Smad3 signaling. Cell Metab.
14, 67–79 (2011).
212. Kang, H. M. et al. Defective fatty acid oxidation in
renal tubular epithelial cells has a key role in kidney
fibrosis development. Nat. Med. 21, 37–46 (2015).
This important study concludes that tubular fat is a
consequence of diminished fatty acid oxidation and
has a role in the development of kidney fibrosis.
213. Nieth, H. & Schollmeyer, P. Substrate-utilization of the
human kidney. Nature 209, 1244–1245 (1966).
214. Wirthensohn, G. & Guder, W. G. Renal lipid metabolism.
Miner. Electrolyte Metab. 9, 203–211 (1983).
215. Stadler, K., Goldberg, I. J. & Susztak, K. The evolving
understanding of the contribution of lipid metabolism
to diabetic kidney disease. Curr. Diab. Rep. 15, 40
(2015).
216. Shulman, G. I. Ectopic fat in insulin resistance,
dyslipidemia, and cardiometabolic disease. N. Engl.
J. Med. 371, 1131–1141 (2014).
217. Reaven, G. M. Banting lecture 1988. Role of insulin
resistance in human disease. Diabetes 37,
1595–1607 (1988).
218. Oterdoom, L. H. et al. Fasting insulin modifies the
relation between age and renal function. Nephrol.
Dial. Transplant. 22, 1587–1592 (2007).
219. Tomaszewski, M. et al. Glomerular hyperfiltration: a
new marker of metabolic risk. Kidney Int. 71,
816–821 (2007).
220. ter Maaten, J. C. et al. Insulin’s acute effects on
glomerular filtration rate correlate with insulin
sensitivity whereas insulin’s acute effects on proximal
tubular sodium reabsorption correlation with salt
sensitivity in normal subjects. Nephrol. Dial.
Transplant. 14, 2357–2363 (1999).
221. Hale, L. J. & Coward, R. J. Insulin signalling to the
kidney in health and disease. Clin. Sci. (Lond.) 124,
351–370 (2013).
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
222. Lennon, R. et al. Saturated fatty acids induce insulin
resistance in human podocytes: implications for
diabetic nephropathy. Nephrol. Dial. Transplant. 24,
3288–3296 (2009).
223. Sieber, J. et al. Regulation of podocyte survival and
endoplasmic reticulum stress by fatty acids. Am.
J. Physiol. Renal Physiol. 299, F821–F829 (2010).
224. Welsh, G. I. et al. Insulin signaling to the glomerular
podocyte is critical for normal kidney function. Cell
Metab. 12, 329–340 (2010).
This study shows the critical importance of insulin
signalling for normal podocyte function.
225. Canaud, G. et al. AKT2 is essential to maintain
podocyte viability and function during chronic kidney
disease. Nat. Med. 19, 1288–1296 (2013).
This study shows the importance of Akt2, a
downstream pathway of insulin signalling, in CKD
with ORG-like features.
226. Hale, L. J. et al. Insulin directly stimulates VEGF‑A
production in the glomerular podocyte. Am. J. Physiol.
Renal Physiol. 305, F182–F188 (2013).
227. Laplante, M. & Sabatini, D. M. mTOR signaling in
growth control and disease. Cell 149, 274–293
(2012).
228. Godel, M. et al. Role of mTOR in podocyte function
and diabetic nephropathy in humans and mice. J. Clin.
Invest. 121, 2197–2209 (2011).
This study demonstrates the important role of
mTOR in diabetic nephropathy.
229. Inoki, K. et al. mTORC1 activation in podocytes is a
critical step in the development of diabetic
nephropathy in mice. J. Clin. Invest. 121, 2181–2196
(2011).
230. Tiwari, S. et al. Deletion of the insulin receptor in the
proximal tubule promotes hyperglycemia. J. Am. Soc.
Nephrol. 24, 1209–1214 (2013).
231. Meyer, C., Dostou, J., Nadkarni, V. & Gerich, J. Effects
of physiological hyperinsulinemia on systemic, renal,
and hepatic substrate metabolism. Am. J. Physiol.
275, F915–F921 (1998).
232. Mandel, L. J. Metabolic substrates, cellular energy
production, and the regulation of proximal tubular
transport. Annu. Rev. Physiol. 47, 85–101 (1985).
233. Gerich, J. E. Role of the kidney in normal glucose
homeostasis and in the hyperglycaemia of diabetes
mellitus: therapeutic implications. Diabet. Med. 27,
136–142 (2010).
234. Marsenic, O. Glucose control by the kidney: an
emerging target in diabetes. Am. J. Kidney Dis. 53,
875–883 (2009).
235. Mima, A. et al. Glomerular-specific protein kinase C‑β-
induced insulin receptor substrate‑1 dysfunction and
insulin resistance in rat models of diabetes and
obesity. Kidney Int. 79, 883–896 (2011).
236. Brown, M. S. & Goldstein, J. L. A proteolytic pathway
that controls the cholesterol content of membranes,
cells, and blood. Proc. Natl Acad. Sci. USA 96,
11041–11048 (1999).
237. Horton, J. D. Sterol regulatory element-binding
proteins: transcriptional activators of lipid synthesis.
Biochem. Soc. Trans. 30, 1091–1095 (2002).
238. Anderson, R. G. Joe Goldstein and Mike Brown: from
cholesterol homeostasis to new paradigms in
membrane biology. Trends Cell Biol. 13, 534–539
(2003).
239. Horton, J. D. et al. Combined analysis of
oligonucleotide microarray data from transgenic and
knockout mice identifies direct SREBP target genes.
Proc. Natl Acad. Sci. USA 100, 12027–12032
(2003).
240. Radhakrishnan, A., Sun, L. P., Kwon, H. J.,
Brown, M. S. & Goldstein, J. L. Direct binding of
cholesterol to the purified membrane region of SCAP:
mechanism for a sterol-sensing domain. Mol. Cell 15,
259–268 (2004).
241. Engelking, L. J. et al. Schoenheimer effect explained
— feedback regulation of cholesterol synthesis in mice
mediated by Insig proteins. J. Clin. Invest. 115,
2489–2498 (2005).
242. Brown, M. S., Ye, J. & Goldstein, J. L. HDL miR‑ed
down by SREBP introns. Science 328, 1495–1496
(2010).
243. Moon, Y. A. et al. The Scap/SREBP pathway is
essential for developing diabetic fatty liver and
carbohydrate-induced hypertriglyceridemia in animals.
Cell Metab. 15, 240–246 (2012).
244. Sun, L., Halaihel, N., Zhang, W., Rogers, T. & Levi, M.
Role of sterol regulatory element-binding protein 1 in
regulation of renal lipid metabolism and
glomerulosclerosis in diabetes mellitus. J. Biol. Chem.
277, 18919–18927 (2002).

245. Ruan, X. Z. et al. Regulation of lipoprotein trafficking
in the kidney: role of inflammatory mediators and
transcription factors. Biochem. Soc. Trans. 32, 88–91
(2004).
246. Wang, Z. et al. Regulation of renal lipid metabolism,
lipid accumulation, and glomerulosclerosis in FVBdb/db
mice with type 2 diabetes. Diabetes 54, 2328–2335
(2005).
247. Jiang, T. et al. Diet-induced obesity in C57BL/6J mice
causes increased renal lipid accumulation and
glomerulosclerosis via a sterol regulatory element-
binding protein‑1c‑dependent pathway. J. Biol. Chem.
280, 32317–32325 (2005).
248. Jiang, T., Liebman, S. E., Lucia, M. S., Li, J. & Levi, M.
Role of altered renal lipid metabolism and the sterol
regulatory element binding proteins in the
pathogenesis of age-related renal disease. Kidney Int.
68, 2608–2620 (2005).
249. Jiang, T., Liebman, S. E., Lucia, M. S., Phillips, C. L. &
Levi, M. Calorie restriction modulates renal expression
of sterol regulatory element binding proteins, lipid
accumulation, and age-related renal disease. J. Am.
Soc. Nephrol. 16, 2385–2394 (2005).
250. Saito, K. et al. Lipid accumulation and transforming
growth factor-β upregulation in the kidneys of rats
administered angiotensin II. Hypertension 46,
1180–1185 (2005).
251. Proctor, G. et al. Regulation of renal fatty acid and
cholesterol metabolism, inflammation, and fibrosis in
Akita and OVE26 mice with type 1 diabetes. Diabetes
55, 2502–2509 (2006).
252. Kume, S. et al. Role of altered renal lipid metabolism
in the development of renal injury induced by a high-
fat diet. J. Am. Soc. Nephrol. 18, 2715–2723 (2007).
253. Buga, G. M. et al. D-4F reduces EO6
immunoreactivity, SREBP‑1c mRNA levels, and renal
inflammation in LDL receptor-null mice fed a Western
diet. J. Lipid Res. 49, 192–205 (2008).
254. Jun, H. et al. In vivo and in vitro effects of SREBP‑1 on
diabetic renal tubular lipid accumulation and RNAi-
mediated gene silencing study. Histochem. Cell Biol.
131, 327–345 (2009).
255. Deji, N. et al. Structural and functional changes in the
kidneys of high-fat diet-induced obese mice. Am.
J. Physiol. Renal Physiol. 296, F118–F126 (2009).
256. Chin, H. J. et al. Omacor®, n-3 polyunsaturated fatty
acid, attenuated albuminuria and renal dysfunction
with decrease of SREBP‑1 expression and triglyceride
amount in the kidney of type II diabetic animals.
Nephrol. Dial. Transplant. 25, 1450–1457 (2010).
257. Wang, T. N. et al. SREBP‑1 mediates angiotensin
II‑induced TGF‑β1 upregulation and glomerular
fibrosis. J. Am. Soc. Nephrol. 26, 1839–1854 (2015).
258. Chen, G. et al. SREBP‑1 is a novel mediator of TGFβ1
signaling in mesangial cells. J. Mol. Cell. Biol. 6,
516–530 (2014).
259. Uttarwar, L., Gao, B., Ingram, A. J. & Krepinsky, J. C.
SREBP‑1 activation by glucose mediates TGF-β
upregulation in mesangial cells. Am. J. Physiol. Renal
Physiol. 302, F329–F341 (2012).
260. Hao, J. et al. PI3K/Akt pathway mediates high
glucose-induced lipogenesis and extracellular matrix
accumulation in HKC cells through regulation of
SREBP‑1 and TGF‑β1. Histochem. Cell Biol. 135,
173–181 (2011).
261. Hao, J. et al. IFN-γ induces lipogenesis in mouse
mesangial cells via the JAK2/STAT1 pathway. Am.
J. Physiol. Cell Physiol. 304, C760–C767 (2013).
262. Zhang, Y. J. et al. HMGB1/SREBP‑1 mediated IFN-
gamma-induced lipid deposition in mouse mesangial
cells. Zhongguo Ying Yong Sheng Li Xue Za Zhi 29,
6–10 (in Chinese) (2013).
263. Hao, J. et al. Phospho-mTOR: a novel target in
regulation of renal lipid metabolism abnormality of
diabetes. Exp. Cell Res. 319, 2296–2306 (2013).
264. Wang, H. et al. Co‑regulation of SREBP‑1 and mTOR
ameliorates lipid accumulation in kidney of diabetic
mice. Exp. Cell Res. 336, 76–84 (2015).
265. Liu, W. et al. Phospho-GSK‑3β is involved in the high-
glucose-mediated lipid deposition in renal tubular cells
in diabetes. Int. J. Biochem. Cell Biol. 45, 2066–2075
(2013).
266. Hao, J. et al. PTEN ameliorates high glucose-induced
lipid deposits through regulating SREBP‑1/FASN/ACC
pathway in renal proximal tubular cells. Exp. Cell Res.
317, 1629–1639 (2011).
267. Jiang, T. et al. Farnesoid X receptor modulates renal
lipid metabolism, fibrosis, and diabetic nephropathy.
Diabetes 56, 2485–2493 (2007).
This study is the first to show regulation and
beneficial effects of FXR in the diabetic kidney.
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 19
268. Wang, X. X. et al. The farnesoid X receptor modulates
renal lipid metabolism and diet-induced renal
inflammation, fibrosis, and proteinuria. Am. J. Physiol.
Renal Physiol. 297, F1587–F1596 (2009).
269. Wang, X. X. et al. Diabetic nephropathy is accelerated
by farnesoid X receptor deficiency and inhibited by
farnesoid X receptor activation in a type 1 diabetes
model. Diabetes 59, 2916–2927 (2010).
270. Hu, Z., Ren, L., Wang, C., Liu, B. & Song, G. Effect of
chenodeoxycholic acid on fibrosis, inflammation and
oxidative stress in kidney in high-fructose-fed Wistar
rats. Kidney Blood Press. Res. 36, 85–97 (2012).
271. Wang, X. X. et al. Vitamin D receptor agonist
doxercalciferol modulates dietary fat-induced renal
disease and renal lipid metabolism. Am. J. Physiol.
Renal Physiol. 300, F801–F810 (2011).
272. Herman-Edelstein, M., Scherzer, P., Tobar, A., Levi, M.
& Gafter, U. Altered renal lipid metabolism and renal
lipid accumulation in human diabetic nephropathy.
J. Lipid Res. 55, 561–572 (2014).
This study shows regulation of nuclear receptors,
transcription factors, and lipid metabolism
pathways in human diabetic nephropathy.
273. Tanaka, Y. et al. Fenofibrate, a PPARα agonist, has
renoprotective effects in mice by enhancing renal
lipolysis. Kidney Int. 79, 871–882 (2011).
274. Hong, Y. A. et al. Fenofibrate improves renal
lipotoxicity through activation of AMPK-PGC‑1α in
db/db mice. PLoS ONE 9, e96147 (2014).
275. Li, L., Emmett, N., Mann, D. & Zhao, X. Fenofibrate
attenuates tubulointerstitial fibrosis and inflammation
through suppression of nuclear factor-κB and
transforming growth factor‑β1/Smad3 in diabetic
nephropathy. Exp. Biol. Med. (Maywood) 235,
383–391 (2010).
276. Kouroumichakis, I. et al. Fibrates: therapeutic
potential for diabetic nephropathy? Eur. J. Intern.
Med. 23, 309–316 (2012).
277. Effect of fenofibrate on progression of coronary-artery
disease in type 2 diabetes: the Diabetes
Atherosclerosis Intervention Study, a randomised
study. Lancet 357, 905–910 (2001).
278. Ansquer, J. C. et al. Fenofibrate reduces progression
to microalbuminuria over 3 years in a placebo-
controlled study in type 2 diabetes: results from the
Diabetes Atherosclerosis Intervention Study (DAIS).
Am. J. Kidney Dis. 45, 485–493 (2005).
279. Keech, A. et al. Effects of long-term fenofibrate therapy
on cardiovascular events in 9795 people with type 2
diabetes mellitus (the FIELD study): randomised
controlled trial. Lancet 366, 1849–1861 (2005).
280. Davis, T. M. et al. Effects of fenofibrate on renal
function in patients with type 2 diabetes mellitus: the
Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) Study. Diabetologia 54, 280–290
(2011).
281. Group, A. S. et al. Effects of combination lipid therapy
in type 2 diabetes mellitus. N. Engl. J. Med. 362,
1563–1574 (2010).
282. Kim, D. et al. Metformin decreases high-fat diet-
induced renal injury by regulating the expression of
adipokines and the renal AMP-activated protein
kinase/acetyl-CoA carboxylase pathway in mice. Int.
J. Mol. Med. 32, 1293–1302 (2013).
283. Decleves, A. E. et al. Regulation of lipid accumulation
by AMP-activated kinase [corrected] in high fat diet-
induced kidney injury. Kidney Int. 85, 611–623 (2014).
284. Wang, X. X. et al. G protein-coupled bile acid receptor
TGR5 activation inhibits kidney disease in obesity and
diabetes. J. Am. Soc. Nephrol. 27, 1362–1378
(2016).
This study was the first to show regulation of TGR5
in human ORG and diabetic nephropathy.
285. Zhang, Y. et al. Dysregulation of low-density
lipoprotein receptor contributes to podocyte injuries
in diabetic nephropathy. Am. J. Physiol. Endocrinol.
Metab. 308, E1140–E1148 (2015).
286. Lhotak, S. et al. ER stress contributes to renal
proximal tubule injury by increasing
SREBP‑2‑mediated lipid accumulation and apoptotic
cell death. Am. J. Physiol. Renal Physiol. 303,
F266–F278 (2012).
287. Yuan, Y. et al. Advanced glycation end products (AGEs)
increase human mesangial foam cell formation by
increasing Golgi SCAP glycosylation in vitro. Am.
J. Physiol. Renal Physiol. 301,F236–F243 (2011).
288. Huang, W., Tang, L., Cai, Y., Zheng, Y. & Zhang, L.
Effect and mechanism of the Ang-(1‑7) on human
mesangial cells injury induced by low density
lipoprotein. Biochem. Biophys. Res. Commun. 450,
1051–1057 (2014).
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS
289. Zheng, Y. et al. Anti-inflammatory effects of Ang-(1‑7)
in ameliorating HFD-induced renal injury through
LDLr–SREBP2–SCAP pathway. PLoS ONE 10,
e0136187 (2015).
290. Gotoh, K. et al. Effects of hydrophilic statins on renal
tubular lipid accumulation in diet-induced obese mice.
Obes. Res. Clin. Pract. 7, e342–e352 (2013).
291. Calkin, A. C. & Tontonoz, P. Transcriptional integration
of metabolism by the nuclear sterol-activated
receptors LXR and FXR. Nat. Rev. Mol. Cell Biol. 13,
213–224 (2012).
292. Hong, C. & Tontonoz, P. Liver X receptors in lipid
metabolism: opportunities for drug discovery. Nat.
Rev. Drug Discov. 13, 433–444 (2014).
293. Kratzer, A. et al. Synthetic LXR agonist attenuates
plaque formation in apoE−/− mice without inducing
liver steatosis and hypertriglyceridemia. J. Lipid Res.
50, 312–326 (2009).
294. Wu, J. et al. Liver X receptor-α mediates cholesterol
efflux in glomerular mesangial cells. Am. J. Physiol.
Renal Physiol. 287, F886–F895 (2004).
295. Merscher-Gomez, S. et al. Cyclodextrin protects
podocytes in diabetic kidney disease. Diabetes 62,
3817–3827 (2013).
296. Tang, C., Kanter, J. E., Bornfeldt, K. E., Leboeuf, R. C.
& Oram, J. F. Diabetes reduces the cholesterol
exporter ABCA1 in mouse macrophages and kidneys.
J. Lipid Res. 51, 1719–1728 (2010).
297. Wang, Y., Moser, A. H., Shigenaga, J. K., Grunfeld, C.
& Feingold, K. R. Downregulation of liver X receptor-α
in mouse kidney and HK‑2 proximal tubular cells by
LPS and cytokines. J. Lipid Res. 46, 2377–2387
(2005).
298. Tachibana, H. et al. Activation of liver X receptor
inhibits osteopontin and ameliorates diabetic
nephropathy. J. Am. Soc. Nephrol. 23, 1835–1846
(2012).
299. Kiss, E. et al. Lipid droplet accumulation is associated
with an increase in hyperglycemia-induced renal
damage: prevention by liver X receptors. Am.
J. Pathol. 182, 727–741 (2013).
300. Patel, M. et al. Liver X receptors preserve renal
glomerular integrity under normoglycaemia and in
diabetes in mice. Diabetologia 57, 435–446
(2014).
301. Morello, F. et al. Liver X receptors α and β regulate
renin expression in vivo. J. Clin. Invest. 115,
1913–1922 (2005).
302. Kuipers, I. et al. Activation of liver X receptor-α
reduces activation of the renal and cardiac renin–
angiotensin–aldosterone system. Lab. Invest. 90,
630–636 (2010).
303. Soodvilai, S., Jia, Z., Fongsupa, S., Chatsudthipong, V.
& Yang, T. Liver X receptor agonists decrease ENaC-
mediated sodium transport in collecting duct cells.
Am. J. Physiol. Renal Physiol. 303, F1610–F1616
(2012).
304. Raksaseri, P., Chatsudthipong, V., Muanprasat, C. &
Soodvilai, S. Activation of liver X receptors reduces
CFTR-mediated Cl− transport in kidney collecting duct
cells. Am. J. Physiol. Renal Physiol. 305, F583–F591
(2013).
305. Berthoux, F., Mariat, C. & Maillard, N. Overweight/
obesity revisited as a predictive risk factor in primary
IgA nephropathy. Nephrol. Dial. Transplant. 28
(Suppl. 4), iv160–iv166 (2013).
306. Delanaye, P., Mariat, C., Cavalier, E. &
Krzesinski, J.‑M. Errors induced by indexing
glomerular filtration rate for body surface area:
reductio ad absurdum. Nephrol. Dial. Transplant. 24,
3593–3596 (2009).
Acknowledgements
The authors’ work is supported by the Dutch Kidney
Foundation (IP11.56, A.P.V.), the Instituto de Salud Carlos III
(PI13/00342, Fondos FEDER and Redinren E.P.) and the
Fundacion Cajacanarias, project DIAB05 (E.P.).
Author contributions
All authors researched the data, discussed the content, wrote
the article and reviewed and/or edited the manuscript before
submission.
Competing interests statement
The authors declare no competing interests.
SUPPLEMENTARY INFORMATION
See online article: S1 (box)
ALL LINKS ARE ACTIVE IN THE ONLINE PDF