Obesity and Renal Failure
David Shure
December 2008
Differential Diagnosis
• FSGS
• HTN Nephrosclerosis
• Multiple Myeloma
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• In 1990, among states participating in the Behavioral
Risk Factor Surveillance System, 10 states had a
prevalence of obesity less than 10% and no states
had prevalence equal to or greater than 15%.
• By 1998, no state had prevalence less than 10%,
seven states had a prevalence of obesity between
20-24%, and no state had prevalence equal to or
greater than 25%.
• In 2007, only one state (Colorado) had a prevalence
of obesity less than 20%. Thirty states had a
prevalence equal to or greater than 25%; three of
these states (Alabama, Mississippi and Tennessee)
had a prevalence of obesity equal to or greater than
30%.
Obesity Trends* Among U.S. Adults
BRFSS, 1990, 1998, 2007
(*BMI 30, or about 30 lbs. overweight for 5’4” person)
1998
1990
2007
No Data
<10%
10%–14%
15%–19%
20%–24%
25%–29%
≥30%
Renal Adaptation to Obesity
• Structural: renal hypertrophy
• Functional: incr GFR, incr RBF
• 1974: assoc between massive obesity
and nephrotic-range proteinuria 1st
reported by Weisinger et al; Ann Intern
Medicine
Obesity-related glomerulopathy: An
emerging epidemic
• D’Agati, et al. Columbia Univ., KI, 2001
• 1st large renal bx-based clinicopathologic study on
obesity-related glomerulopathy
• Obesity = BMI >30
• ORG-Obesity-related glomerulopathy defined as
FSGS and/or glomerulomegaly
• Study to determine changing histologic incidence of
ORG over past 15 yrs
• Compared cohort of ORG to controls w/idiopathic
FSGS, found that there is a distinction bet these
entities
Methods
• All renal bx’s in renal path lab at Columbia
Presbyterian from 1986 to 2000 for evidence of ORG
• Obesity-related Glomerulopathy def:
• 1. O-FSGS: FSGS w/glomerulomegaly
• 2. O-GM: glomerulomegaly alone
• BMI >30
• Excluding pts with other dz causing secondary FSGS
ie HIV, SCD, renal dysplasia, heroin use. Also DM
nephropathy and HTN nephrosclerosis excluded.
• 103 cases met criteria
• These pt’s were compared to a
historical control group of 50 pts with
Idiopathic-FSGS
77
24
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Obesity Related
Glomerulomegaly
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Segmental Sclerosis
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Hypertrophy
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Mild ‘Diabetoid Changes’ in
non- diabetic obese pt
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EM: Diffuse Glomerular BM
Thickening
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Minimal Foot Process
Effacement
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EM: Marked Glomerular
Hypertrophy
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Comparative Multivariate Analysis
between ORG and I-FSGS
• ORG compared to I-FSGS, only parameters
independently signif were serum albumin
(p<.001) and age (p=.032)
• Comparing O-FSGS and I-FSGS groups,
serum albumin and age were only
independently signif variables.
• Results are c/w observation that major
distinguishing feature between ORG and IFSGS is the presence of full nephrotic
syndrome in I-FSGS, as reflected by severity
of hypoalbuminemia.
Findings
• **Even pts with submorbid class I,II obesity, 46%
study group, can develop ORG that is clinically and
morphologically indistinguishable from that seen in
morbid obesity.**
• Higher incidence of ORG in Caucasians c/w bx pop
with I-FSGS.
• Presentation of ORG is one of nephrotic range
proteinuria (48%) or sub-nephrotic proteinuria (52%),
accomp by renal insuff in nearly 1/2 (44%).
• Although, nearly 1/2 pts had nephrotic range
proteinuria, hypoalbuminemia present in only 14%
and only 5.6% of pts had full nephrotic syndrome.
**Sharp contrast to I-FSGS pt’s, 54% had nephrotic
syn.
ORG = lower incidence
nephrotic syndrome?
• May relate to differences in seveity of
podocyte injury, in severeity and selectivity of
proteinuria, and the ability of tubules ot
reabsorb and catabolize the filtered protein.
• The lower fract excr B2 microglob (competes
w/albumin for tubular uptake) and N-acetyl Bglucosaminidase (marker of tubular injury)
obs in pts with nephrotic range proteinuria
c/w those w/nephrotic syn, suggest differenc
in tubular overload and resulting cellular
injury.
Salient Differences
ORG vs I-FSGS
• Although, both ORG and I-FSGS manifest lesions of FSGS,
there are distinguishing features.
• ORG has a lower % of glomeruli affected by segmental
sclerosis, suggesting a milder,more slowly progressive dz.
• The deg. of foot process effacement is less severe, suggests
difft patho-mechanism of podocyte injury.
• Glomerulomegaly consistently obs in ORG compared to only
10% of pts with I-FSGS, hyperfiltration imprtnt mechanism
• Pts with ORG tended to have more severe arteriosclerosis
P<.03, despite a similar incidence of HTN as I-FSGS; ?related
to older age and greater risk of coronary vascular dzin ORG.
**
• First to report ORG may manifest only
w/glomerulomegaly in absence of FSGS.
• 45% of ORG bx had focal GBM thickening or
focal mesangial sclerosis reminiscent of
changes seen in early DM nephropathy.May
correlate with obs that ‘occult’ diabetic
nephropathy is common in obesity and may
reflect higher prevalence of gluc intol,
hyperinsulinemia, and hyperlipidemia.
Pathophys Obesity-induced Glomerulomegaly
Postulates:
•  RPF, GFR may be mediated by  protein
•
•
•
•
consumption
Postulate role for afferent arteriolar dilation in
mediation  transcapillary hydraulic press. gradient
Insulin: directly reduces norepi-induced efferent
arteriolar constrict, insulin resist may  transcapillary
pressure gradient by  efferent arteriolar resistance
Hyperinsulinemia stim IGF-1,2 may promote
glomerular hypertrophy.
 plasma levels leptin in obesity predispose to GS
through up-regulation of TGF b1.
Lipids and Hypoxia
• Hyperlipidemia may promote GS through
engagement of LDL receptors on mesangial cells,
oxidative injury, macrophage chemotaxis, and incr
production of fibrogenic cytokines; also through direct
podocyte toxicity
• Hypoxia mediated activation of sympathetic NS. May
cause deregulation of glomerular capillary
hemodynamics through sympathetic ctrl of efferent
arteriolar tone and indirectly through sympathetic
activation of RAS.
Therapy
• First line: wt loss, can reduce proteinuria
• ACE-I to reduce proteinuria, delaying
progression to ESRD, prevent evolution of OGM to O-FSGS
• Lipid lowering agents effective in reducing
mesangial sclerosis and proteinuria in obese
rats, may have role.
• Treating hypoxia in OSA/hypovent, reported
to reduce proteinuria through improved
oxygenation
Obesity-related glomerulopathy: Insights
from gene expression profiles of the
glomeruli derived from renal bx samples
• Wu et al, Endocrinology 2006
• Found incr expression of genes related to lipid
metabolism (LDL receptor, fatty acid binding protein3, and sterol regulatory binding protein), inflammatory
cytokines TNF-a, il-6 signal transducer and IFN-g,
and insulin resistance (glucose transporter-1 and
VEGF) in glomeruli of pts with obesity related
glomerulopathy) compared with gender and age
matched glomeruli of control donor kidneys
Obesity and Obesity-Initiated Metabolic
Syndrome: Mechanistic Links to CKD
• Wahba et al, CJASN, 2007, OHSU
• Metabolic syndrome def: 3/5
1. Central Obesity
2. Hypertriglyceridemia
3. Low HDL
4. Elevated Fasting Glucose
5. HTN
Features of Metab Syndrome
• Central feature is insulin resistance, central
obesity is most important predisposing factor
• Chronic inflammation
• Together these features contribute to
pathogenesis incl: HTN, lipoprotein
abnormalities, AS, CAD, organ dysfunction.
• Overweight, obesity and metabolic syn are
strong independent RF for CKD and ESRD.
Related Studies
• Iseki et al; KI, 2004: BMI and risk of
development of ESRD in a screened cohort.
Found a high BMI assoc w/incr risk for ESRD
in men in a pop of >100,000 in Japan. Risk
indep of HTN or proteinuria.
• Hsu et al, 2006, Ann Int Med; BMI and Risk
for ESRD. Cohort of >320,000 pts found
higher BMI a strong indep RF for ESRD even
after adjustment for other marjor RF incl tob,
HTN, DM.
Inflammation
• Hallmark of metabolic syn: insulin resistance.
Insulin is anti-inflammatory hormone,
resistance to it may explain why obesity/
metabolic syndrome is a pro-inflammatory
state.
• Plasma conc of proinflammatory adipokines
ie IL6, TNF-a, CRP and resistin are elevated
in pts with metabolic syn, whereas levels of
anti-inflam adipokines ie adiponectin are
reduced, possibly contributing to ins
resistance.
Adipose Tissue
• Major source of cytokine secretion in
metabolic syn are inflamm cells, esp mature
bone marrow-derived macrophages, invade
adipose issue early in obesity.
• These cytokines may be produced by the
adipocyte (leptin), macrophages infiltrating
adipose tissue (tnf-a) or both (IL-6)
• Inflamm a major RF for AS in gen population
strongly assoc w/metabolic synd.
Assoc of Obesity with inflammation in
CKD: a cross-sectional study
• Ramkumar et al, Jr Renal Nutrition,
2004
• Found a strong association between
inflammation as defined by a CRP level
>3mg/ dl and a high BMI in pts with
CKD.
Cytokine Role
• Leptin: adipocyte derived, structurally similar to IL2
• Crosses BBB, via reducing neuropeptide Y in hypothalamus
suppresses appetite and increases energy expenditure, also
incr insulin sensitivity
• Pts with obesity and metab syn are resistant to hypothalamic
effects of leptin and have elvated leptin levels
• Leptin receptor Ob-Ra is expressed in kidney, and may directly
affect renal structrure and function.
• Recombinant leptin stimulates prolif of cultured glomerular
endothelial cells and incr TGF b1 mRNA expression and
production.
Leptin cont
• In rats infused w/leptin, it produces same
effects, it signif incr type 4 collagen protein,
gloumerulosclerosis, and proteinuria without
increasing BP.
• Leptin stim glucose uptake, mRNA
expression TGFB type 2 rceptor, and type I
collagen production in cultured mesangial
cells of db/db leptin deficient obese mice.
Leptin may play role in FSGS observed in
obese pts with proteinuria and or ckd.
Leptin Indirect Effects
• Incr sympathetic nerve trafficking, and renal
Na retention, which may cause HTN.
Stimulates oxidative stress in endothelial
clells and induces a pro-inflammatory state as
a result of stim of Th1 cells. These effects
may promote AS. Leptin shown to be an
indep RF for CV events after adjustment for
obesity and metab RF.
• Also, obese leptin deficient mice have been
shown to be protected from AS despite
presence of other RF.
IL-6 and CRP
• IL-6 produced from visceral and peripheral adipose
cells and immune cells
• Plamsa IL-6 levels positively correlate with obesity
and ins resist and predict development Type 2 DM
and future coronary events.
• IL-6 also incr expression of adhesion molecules on
endothelial and vascular sm cells and activates local
RAS, effects widely known to promote cellular injury
• IL-6 shown to enhance TGF b1 signaling via
modulation of TGF b1 receptor trafficking, an effect
that may enhance renal fibrosis.
TNF-a
• Produced by macs in adipose tissue, and
levels are elevated in metabolic syndrome.
TNF-a is a mediator of ins resist in adipose
tissue.
• Shown to mediate inflammation in several
models of renal injury, incl GN, ARF,
tubulointerstitial injury. Specific role of TNF-a
in metabolic syn induced renal injury has not
been studied.
Other cytokines
• Macrophage and MCP-1, PAI-1,
resistin, adipsin, acylation-stimulating
protein are other pro-inflammatory
cytokines produced by adipose tissue
and/or inflamm cells.
• May direct or indirectly affect renal
structure and function.
Adiponectin
• Insulin-sensitizing, anti-inflam, antiatherogenic properties.
• Levels correlate negatively with fat mass,
body wt, bp, insulin resistance, infalmm
markers of metab syndrome.
• Low levels assoc w/vascular dysfunction and
CV events.
• May be important in preventing some
deleterious effects that the chronic inflam
state may have on various organs, sp relation
to kidney injury not established.
In CKD, signif of adiponectin levels
controversial
• Becker et al, JASN 2005: found low
adiponectin levels in pts with mild or
moderate renal failure correlated with
CV events.
• Menon et al,JASN 2006, found in pts
with CKD 3,4, all-cause and CV
mortality paradoxically higher in those
with high adiponectin levels.
RAS
• Activation of RAS and incr circulating levels
or renin, Ag, ACE, aldosterone and AGII
common in obese people due to:
• 1.sympathetic stimulation, partly related to
hyperleptinemia and possibly
hyperinsulinemia, and ins resistance
• 2. Hemodynamic alterations, incl interference
with RBF as a result of compression of renal
hilum and or renal parenchyma by visceral fat
• 3. Synthesis of sev proteins of RAS by
visceral fat
AngII
• Adversely affects progression of renal dz in sev
models of injury incl:
• HTN, raised IG pressure, exacerbation of proteinuria,
induction of intrarenal inflam cytokines, fibrois, and
apoptosis
• May also play role in adipokine production in adipose
tissue and may incr insulin résistance in the setting of
obesity.
• In support: AngII type 1 receptor blocker olmesartan
signif reduced TNFa, PAI-1, MCP-1, and markers of
oxidative stress and incr adiponectin levels in obese
KKAy mouse model, Kurata et al, KI 2006.
Lipotoxicity
• Cellular lipid overload: contributes to AS, is assoc w/obesity and
thought to contribute to organ dysfunction, incl renal dz.
• Cellular accum of nonesterified FFA and TG
• Abd adipose tissue generates high levels of circulating FFA.
• Low adiponectin levels, leptin resistance, and other cytokines
released form adipose tissue and inflamm cells that infiltrate
adipose tissue incl macs, reduce FFA uptake by mitochondria in
various tissues, reduce FFA oxidation and promote IC ffa
accumulation.
• Excess IC FFA and their metabolites (fatty acyl CoA,
diacylglycerol, and ceramide, promote ins resistance, exert
deleterious effects on various organs, shown to be cytotoxic to
pancreatic beta cells, liver, heart and endothelial cells.
Peroxisome prolifeator
activated receptor (PPAR)
• Three isoforms expressed in tissues inc adipose
tissue, liver, muscle, heart and kidney.
• PPAR agonists: (eg fibrates) promote FFA oxidation
and insulin sensitivity.
• PPAR lambda and gamma: promote adipogenesis,
insulin sensitivity, enhance adiponectin activity, incr
LDH, reduce TG and LDL, mediate cellular efflux of
lipids and modulate foam cell and mac activation in
AS.
• PPAR gamma: ie TZD improve insulin sensitivity in
setting of DMII.
Renal Lipotoxicity
• 1858 Virchow suggested assoc between
lipids and RF, described fatty degeneration
of renal epithelium in Bright’s dz.
• Renal lipotoxicity later shown to cause renal
mesangial and epithelial cell injury and may
promote renal dz progression. In sev studies
rx with statin, improved proteinuria and
preserved renal fxn independent of other
variables, suggests a role for statins.
Role of fatty acids
• Levi et al, demonstrated crucial role of SREBP in
promoting renal injury in mouse model of DM, aging
and obesity.
• Showed that high fat feeding resulted in obesity,
hyperglycemia, and hyperinsulinemia in obesity
prone mice but not in the low fat fed counterparts.
• High fat fed mice also showed signif incr renal TG
and cholesterol accumulation in glomerular and
tubulointerstitial cells.
• Also showed, signif over expression SREBP-1 and 2
protein, acetyl-coa carboxylase, fatty acid synthase,
PAI-1, type IV collagen and fibronectin. Significant
GS and proteinuria occurred in these mice.
FFA overload
• May also result in endothelial dysfunction likely via
enhanced production of ROS
• In a rodent model of visceral obesity, the Zucker
diabetic fatty leptin resistant rat, demonstrated
impaired VD response to acetylcholine, high levels of
circulating FFA and ROS, and enhancement of
NADPH oxidase activation and vascular ROS
production.
• Pitavastatin, an HMG-coa reductase inhibitor,
reversed these effects.
• FFA may also incr vascular tone via stimulation of
sympathetic NS or via other unclear mechanisms.
Role of TG rich Lipoproteins
•
•
•
•
•
•
VLDL, IDL and LDL have been shown to promote cultured mesangial
cell proliferation.
Oxidized LDL has been shown to stimulate secretion of excess
extracell matrix, MCP-1 and PAI-1 from mesangial cells.
Additionally, these lipids appear to promote synthesis of IL-6, TNFa,
TNFb, all of which may cause glomerular injury.
IGF-I has been show2en to induce rat glomerular mesangial cells to
accumulate TF and these cells are transformed into lipid laden foam
cells. This effect mediated by endocytosis of TG.
These foam cells become dysfunctional, showed impaired
phagocytosis ad migration.
Reduction of PPAR-lambda appears to contribute to TG accum in
mesangial cells, since PPAR-lambda normally prevents this process by
down regulating mesangial cell VLDL receptors and therefore TG
uptake and by promoting TG efflux from mesangial cells.
Hemodynamics
• Increased vascular tone and renal salt and
water retention are main initiators of HTN in
obesity, mechanism incl: hyperleptinemia,
incr FFA, hyperinsulinemia, insulin
resistance, all of which cause sympathetic
nerve stim, incr vascular tone, endothelial
dysfunction, adrenal Na retention.
• Also, incr RAS, leads to incr renal Na and
water retention.
Hyperfiltration
• Elevated GFR and increased RBF:
likely due to afferent arteriolar dilation
as a result of prox Na reabsorption,
coupled with efferent renal arteriolar VC
as a result of elevated AngII.
• These effects may contribute to:
hyperfiltration, glomerulomegaly, and
later FGS.
Hypofiltration
• Some studes show that the pattern of obesity affects
renal hemodynamiscs and thatn an elevated BMI with
central obesity results in reduced GFR, incr RV
resistance, and reduced effective RBF as opposed to
obesity wth peripheral fat distribution.
• Anastasio et al, showed GFR values in obese pts are
substantially lower when adjusted for BSA than when
adjusted for ht or lean body mass.
• Incr abd pressure from visceral fat, may cause renal
vein compression and may therefore raise renal
venous pressure, impairing venouse outlflow from
renal veins.