Obesity and Renal Failure

1
Obesity and Renal Failure

• David Shure
• December 2008

2
Differential Diagnosis

• FSGS
• HTN Nephrosclerosis
• Multiple Myeloma

3

• 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.

4
Obesity Trends Among U.S. AdultsBRFSS, 1990,
1998, 2007
(BMI ?30, or about 30 lbs. overweight for 54
person)
1998
1990
2007
No Data lt10 1014
1519 2024 2529
30
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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

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Obesity-related glomerulopathy An emerging
epidemic

• DAgati, et al. Columbia Univ., KI, 2001
• 1st large renal bx-based clinicopathologic study
  on obesity-related glomerulopathy
• Obesity BMI gt30
• 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

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Methods

• All renal bxs 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 gt30
• 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

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• These pts were compared to a historical control
  group of 50 pts with Idiopathic-FSGS

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77
24
2
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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
14
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 (plt.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 I-FSGS is
  the presence of full nephrotic syndrome in
  I-FSGS, as reflected by severity of
  hypoalbuminemia.

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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 pts, 54 had
  nephrotic syn.

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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
  B-glucosaminidase (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.

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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 Plt.03, despite a similar
  incidence of HTN as I-FSGS ?related to older age
  and greater risk of coronary vascular dzin ORG.

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• 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.

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Pathophys Obesity-induced GlomerulomegalyPostulat
es

• ? 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.

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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.

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Therapy

• First line wt loss, can reduce proteinuria
• ACE-I to reduce proteinuria, delaying progression
  to ESRD, prevent evolution of O-GM 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

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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
  protein-3, 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

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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

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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.

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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 gt100,000 in Japan. Risk indep of HTN or
  proteinuria.
• Hsu et al, 2006, Ann Int Med BMI and Risk for
  ESRD. Cohort of gt320,000 pts found higher BMI a
  strong indep RF for ESRD even after adjustment
  for other marjor RF incl tob, HTN, DM.

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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.

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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.

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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 gt3mg/ dl and a high BMI
  in pts with CKD.

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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.

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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.

34
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.

35
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.

36
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.

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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.

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Adiponectin

• Insulin-sensitizing, anti-inflam,
  anti-atherogenic 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.

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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.

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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

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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.

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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.

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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.

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Renal Lipotoxicity

• 1858 Virchow suggested assoc between lipids and
  RF, described fatty degeneration of renal
  epithelium in Brights 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.

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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.

46
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.

47
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.

48
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.

49
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.

50
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.