Obesity and Renal Failure David Shure December 2008

Differential Diagnosis FSGS HTN Nephrosclerosis Multiple Myeloma

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%. 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%.

1998 Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2007 (*BMI 30, or about 30 lbs. overweight for 54 person) 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 DAgati, et al. Columbia Univ., KI, st 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 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 >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 pts were compared to a historical control group of 50 pts with Idiopathic-FSGS

Obesity Related Glomerulomegaly

Segmental Sclerosis

Hypertrophy

Mild Diabetoid Changes in non- diabetic obese pt

EM: Diffuse Glomerular BM Thickening

Minimal Foot Process Effacement

EM: Marked Glomerular Hypertrophy

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 I- FSGS 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 pts, 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 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.

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 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

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

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, 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.

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 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.

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.