Obesity Related Glomerulopathy (ORG) - prof. Salem Eldeeb
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Obesity Related Glomerulopathy (ORG) - prof. Salem Eldeeb
- 1. Obesity Related Glomerulopathy (ORG) By Salem ELDEEB Professor of Nephrology Zagazig University
- 2. In 1978: 28.8% (Men) 29.8% (women) In 2013: 36.9% (Men) 38.0% (women) Lancet, 2015, 386: 2287–2323 Worldwide prevalence of overweight and obese adults is increasing
- 3. By 2030, more than 50% of the US population will be obese Worldwide prevalence of overweight and obese adults is increasing Obesity , 2008, 16: 2323–2330
- 4. Proteinuria affects 4–10% of obese patients J. Endocrinol. Invest. 39, 73–82 (2016) J. Am. Soc. Nephrol. 10, 578–583 (2015) Obesity and the kidney
- 5. Ann. Intern. Med., 2006, 144: 21–28
- 6. Obesity and the kidney
- 7. low eGFR by 28% albuminuria by 51% Kidney Int 2017; 91:1224–1235 Obesity and the kidney Obesity increased the risk of
- 8. being obese at age 17 was associated with a six-fold higher risk of developing ESRD Arch Intern Med 2012; 172:1644–1650 Obesity and the kidney
- 9. Obesity and the kidney In CKD (other than ORG): Obesity is an independent risk factor progression of renal failure
- 10. Obesity increased the risk of: HTN Proteinuria Severe histologic lesions ESRD Weight loss resulted in proteinuria reductions Nephrol. Dial. Transplant., 2013, 8 (Suppl 4): iv160–iv166 In IgA nephropathy:
- 11. In DM:
- 12. Hazard ratios for a major renal event by BMI splines at baseline
- 13. Every additional unit of BMI over 25 kg/m2 increased the risk of major renal events by 4% Nutrition and Diabetes (2018) 8:7, doi:10.1038/s41387-017-0012-y In DM:
- 14. Glomerulomegaly and FSGS occurring in patients with BMI ≥30 kg/m2 Nature Reviews Nephrology, 2016, 12: 453–471 Obesity Related Glomerulopathy (ORG) Definition
- 15. Magnitude of the problem Obesity Related Glomerulopathy (ORG) Kidney Int., 2001, 59: 1498–1509
- 16. •mean glomerular diameter in biopsy samples: 226 μm in patients with ORG vs 169 μm in age and sex-matched controls Kidney Int., 2001, 59: 1498–1509 Glomerulomegaly Histopthology Obesity Related Glomerulopathy (ORG)
- 17. Reduced glomerular density (compared to samples from non-obese kidney donors and patients with GN) CJASN., 2012, 7: 735–741 Glomerular density Histopthology Obesity Related Glomerulopathy (ORG)
- 18. Comparison of glomerular density (GD) and glomerular volume (GV) in renal biopsy specimens. CJASN., 2012, 7: 735–741
- 19. exclusively perihilar 19% perihilar and peripheral 81% Kidney Int., 2001, 59: 1498–1509 FSGS Histopthology Obesity Related Glomerulopathy (ORG)
- 20. Diabetoid-like changes in 50% of patients with ORG despite a lack of clinically evident glucose intolerance Kidney Int., 2001, 59: 1498–1509 Histopthology Obesity Related Glomerulopathy (ORG)
- 21. •Tubular atrophy •Interstitial fibrosis •Arteriosclerosis Kidney Int., 2001, 59: 1498–1509 Other lesions Histopthology Obesity Related Glomerulopathy (ORG)
- 22. •Nonspecific IgM and C3 deposits in lesions of sclerosis and hyalinosis •Intracytoplasmic droplets stain for IgG, IgA in podocytes overlying sclerosis •No IC deposits Curr Opin Nephrol Hypertens., 2012, 21: 243–250 IF Histopthology Obesity Related Glomerulopathy (ORG)
- 23. 40% in ORG 75% in primary FSGS Kidney Int., 2001, 59: 1498–1509 •relatively mild effacement of foot processes compared to primary FSGS EM Histopthology Obesity Related Glomerulopathy (ORG)
- 24. Podocyte cellular volume increases in relation to body weight gain J. Am. Soc. Nephrol., 2012, 23: 1351–1363 Nephrol. Dial. Transplant., 1998, 13: 2781–2798 Kidney Int., 1992 42: 148–160 EM Histopthology Obesity Related Glomerulopathy (ORG)
- 25. Glomerulomegaly 38% FSGS lesions 05% Mesangial sclerosis 60% Tubulointerstitial affection 11% Arteriolosclerosis 40% Kidney Int., 2008, 73: 947–955 Protocol kidney biopsies before bariatric surgery Histopthology Obesity Related Glomerulopathy (ORG)
- 26. •Altered renal hemodynamics •Neuro-hormonal activation •Metabolic dysregulation •Inflammation, lipotoxicity and mitochondrial injury Curr Opin Pediatr., 2018, 30(2): 241–246 Pathogeneis Obesity Related Glomerulopathy (ORG)
- 27. Kidney Int. 2000 ,58(5): 2111-2118 Obese patients are at risk for developing proteinuria and kidney dysfunction after unilateral nephrectomy Altered renal hemodynamics Glomerular hyperfiltration: Pathogeneis Obesity Related Glomerulopathy (ORG)
- 28. Kidney Int. 2000 ,58(5): 2111-2118
- 29. Kidney Int. 2000 ,58(5): 2111-2118
- 30. Am. J. Kidney Dis., 2010, 56: 303–312 Glomerular hyperfiltration (GFR ≥140 mL/min) Lean 7.2% Overweight 14.8% Obese 27.1% P < 0.001 Altered renal hemodynamics Glomerular hyperfiltration: Pathogeneis Obesity Related Glomerulopathy (ORG)
- 31. J. Hum. Hypertens., 1997, 11: 107–111 J. Hypertens, 1998, 16: 1475–1480 Hypertension, 2006, 48: 239–245 J. Clin. Endocrinol. Metab., 2008, 93: 2566–2571 RAAS is overactive in obesity Neuro-hormonal activation Pathogeneis Obesity Related Glomerulopathy (ORG)
- 32. Hypertension, 1984, 6: I183–I192 Am. J. Physiol., 1999, 276: 197–202 •increases transcapillary pressure and GFR •increases sodium reabsorption •activates the minerolocorticoid receptor AgII Neuro-hormonal activation Pathogeneis Obesity Related Glomerulopathy (ORG)
- 33. Diabetologia, 1992, 35: 1042–1048 Am. J. Nephrol., 2007, 27: 44–54 Insulin increases the tubular reabsorption of sodium by stimulating the activity of ENaC in late distal tubule proximal tubule loop of Henle Hyperinsulinaemia and insulin resistance Pathogeneis Obesity Related Glomerulopathy (ORG)
- 34. Circulation, 1997, 96: 3423–3429 Hypertension, 2006, 48: 787–796 Renal sympathetic nervous system (RSNS) is overactivated Neuro-hormonal activation Pathogeneis Obesity Related Glomerulopathy (ORG)
- 35. Metabolic syndrome Pathogeneis Obesity Related Glomerulopathy (ORG)
- 36. Kidney Int. 2015 Jun; 87(6): 1216–1222
- 37. J Lipid Res. 2017, 58(7):1417-1427. inflammatory stress promotes ectopic lipid deposition in the kidney and causes renal injury in obese mice Inflammation, lipotoxicity and mitochondrial injury Pathogeneis Obesity Related Glomerulopathy (ORG)
- 38. Kidney Int., 2016, 90(5):997-1011 Mitochondria protection with SS-31 tetrapeptide during high-fat diet prevented: intracellular lipid accumulation endoplasmic reticulum stress apoptosis mesangial expansion glomerulosclerosis macrophage infiltration upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-β) cytokines. Pathogeneis Obesity Related Glomerulopathy (ORG) Inflammation, lipotoxicity and mitochondrial injury
- 39. Kidney Int., 2001, 59: 1498–1509 Nephrol. Dial. Transplant., 2001, 16: 1790–1798 Am. J. Kidney Dis., 2008, 52: 58–65 Clin. Exp. Nephrol., 2013, 17: 379–385 •Proteinuria •Dyslipidaemia •Hypertension •Renal impairment Clinical presentation Obesity Related Glomerulopathy (ORG)
- 40. Without therapeutic intervention: •Slowly progressive proteinuria 70-90% •progressive renal failure and ESRD 10–30% Kidney Int., 2001, 59: 1498–1509 Nephrol. Dial. Transplant., 2001, 16: 1790–1798 Clin. Exp. Nephrol., 2013, 17: 379–385 Prognosis Obesity Related Glomerulopathy (ORG)
- 41. Predictors of progrssion to ESRD: Older age Renal impairment Increasing proteinuria at presentation Prolonged follow-up Kidney Int., 2001, 59: 1498–1509 Nephrol. Dial. Transplant., 2001, 16: 1790–1798 Clin. Exp. Nephrol., 2013, 17: 379–385 Prognosis Obesity Related Glomerulopathy (ORG)
- 42. •RAAS blockade •weight reduction diet-induced bariatric surgery Treatment Obesity Related Glomerulopathy (ORG)
- 43. In obese patients with proteinuria or biopsy- proven ORG RAAS blockade significantly reduced proteinuria Am. J. Kidney Dis.,1991 17: 330–338 Kidney Int., 2001, 59: 1498–1509 Nephrol. Dial Transplant., 2001, 16: 1790–1798 Kidney Int., 2005, 68: 263–270 Clin. Exp. Nephrol., 2013, 17: 379–385 Retrospective studies Treatment Obesity Related Glomerulopathy (ORG)
- 44. Renal benificial effect of ramipril was significantly greater in obese and overweight patients than in those with normal BMI J. Am. Soc. Nephrol., 2011, 22, 1122–1128 post hoc analysis of the REIN trial Treatment Obesity Related Glomerulopathy (ORG)
- 45. J. Am. Soc. Nephrol., 2011, 22, 1122–1128
- 46. J. Am. Soc. Nephrol., 2011, 22, 1122–1128
- 47. •Proteinuria reduction correlated linearly with the degree of weight loss •Reduction in proteinuria was evident after few days or weeks of a low-calorie diet Prev. Med., 1999, 29: 87–91 Weight loss Treatment Obesity Related Glomerulopathy (ORG)
- 48. 5 months of hypocaloric diet (RCT): weight loss of 4% proteinuria reduction of 30% weight losses of >6% proteinuria reduction of >60% weight losses of >10% proteinuria reductions of >70% Am. J. Kidney Dis., 2003, 41: 319–327 Weight loss Treatment Obesity Related Glomerulopathy (ORG)
- 49. J. Am. Soc. Nephrol.,2003, 14: 1480–1486 •Mean BMI decreased by 33% •GFR decreased by 24% •RPF decreased by 13% •Filtration fractions decreased by 11% Obesity Related Glomerulopathy (ORG) Bariatric surgery Treatment
- 50. eGFR before Bariatric surgery : 76 ml/min/1.73 m2 eGFR after Bariatric surgery : 102 ml/min/1.73 m2 Kidney Int 2017; 91:451–458 obese adolescents with CKD (baseline eGFR less than 90 ml/min/1.73 m2) Bariatric surgery Treatment Obesity Related Glomerulopathy (ORG)
- 51. Kidney Int 2017; 91:451–458 obese adolescents with CKD (baseline urinary ACR >= 30 mg/g): Bariatric surgery Treatment Obesity Related Glomerulopathy (ORG) ACR before Bariatric surgery: 74 mg/g ACR after Bariatric surgery: 17 mg/g
- 52. Bariatric surgery has emerged treatment option for those with severe obesity and significant kidney disease Curr Opin Pediatr., 2018, 30(2): 241–246 Bariatric surgery Treatment Obesity Related Glomerulopathy (ORG)
- 53. Thank You
Editor's Notes
- in multivariate analysis models after adjustment for multiple epidemiologic and clinical features including the presence of diabetes mellitus and hypertension 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 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 baseline
- 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) We had information on 331 IgAN patients (233 men). At diagnosis, the BMI was normal (<25 kg/m2) in 195 and elevated (≥25) in 136 (44.1%) with 102 overweight (25– 29.9) and 34 obese (≥35) defining two groups, normal BMI and elevated BMI, subsequently compared. Results. At diagnosis, in the overweight/obese group, hypertension and proteinuria ≥1 g/day were more frequent (respectively, P<0.0001 and P=0.0006) and the mean global optical score was increased (P=0.002). This resulted in a worse ARR scoring distribution (P<0.0001). In addition, these patients with an elevated BMI were ∼10 years older (P<0.0001), including more obese women and with an eGFR already lower (P=0.0003). At last follow-up, in the overweight/obese group, progression remained worse with greater prevalence of CKD-3+ (43.4 versus 21.0%; P<0.0001) and dialysis/death events (21.3 versus 13.9%). Kaplan–Meier survival and Cox regression analyses demonstrated that ARR remained a powerful independent risk factor for prediction of events, but not BMI. Conclusions. IgAN patients with an elevated BMI at diagnosis had a significantly worse presentation and worse final outcome. Overweight/obesity increased hypertension frequency, proteinuria level and some renal lesions all of which translate into a worse ARR (absolute relative risk) for prediction of CKD-3+ or dialysis alone or dialysis/death,withnoapparentdirecteffectofBMI perse.
- We aimed to evaluate the relationship between BMI and the risk of renal disease in patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. Subjects/methods Participants were divided into six baseline BMI categories: <18.5 (underweight, n = 58); ≥18.5 to <25 (normal, n = 2894); ≥25 to <30 (overweight, n = 4340); ≥30 to <35 (obesity grade 1, n = 2265); ≥35 to <40 (obesity grade 2, n = 744); and ≥40 kg/m2 (obesity grade 3, n = 294); those underweight were excluded. The composite outcome “major renal event” was defined as development of new macroalbuminuria, doubling of creatinine, end stage renal disease, or renal death. These outcomes and development of new microalbuminuria were considered individually as secondary endpoints. Results During 5-years of follow-up, major renal events occurred in 487 (4.6%) patients. The risk increased with higher BMI. Multivariable-adjusted HRs (95% CIs), compared to normal weight, were: 0.91 (0.72–1.15) for overweight; 1.03 (0.77–1.37) for obesity grade 1; 1.42 (0.98–2.07) for grade 2; and 2.16 (1.34–3.48) for grade 3 (p for trend = 0.006). These findings were similar across subgroups by randomised interventions (intensive versus standard glucose control and perindopril-indapamide versus placebo). Every additional unit of BMI over 25 kg/m2 increased the risk of major renal events by 4 (1–6)%. Comparable results were observed with the risk of secondary endpoints. Conclusions Higher BMI is an independent predictor of major renal events in patients with type 2 diabetes. Our findings encourage weight loss to improve nephroprotection in these patients. The ADVANCE study (10,537 participant) was a 2 × 2 factorial randomised controlled trial which tested the effects of intensive glucose control using a gliclazide-MR-based regimen, and routine blood pressure treatment using a fixed-dose combination of perindopril and indapamide, on the incidence of major macrovascular and microvascular events in patients with type 2 diabetes. The design and clinical characteristics of participants have been published previously13,14,15. Briefly, patients aged 55 years or older with diabetes diagnosed at 30 years or older with pre-existing cardiovascular disease or with at least one risk factor for cardiovascular disease were eligible. Participants were followed prospectively for clinical events and had blood pressure and urinary albumin to creatinine ratio (ACR) measured at local study clinics at 2-year, 4-year and final follow-up visits
- Higher BMI is an independent predictor of major renal events in patients with type 2 diabetes Multi-adjusted hazard ratios (solid line) and 95% confidence intervals (shaded region) for major renal events during follow-up according to baseline BMI as a continuous variable with a reference value at 21 kg/m2 (diamond). Analyses were adjusted for baseline age, sex, region of origin, prior cardiovascular disease, estimated glomerular filtration rate (and its square), urinary albumin to creatinine ratio, history of ever smoking, and study allocations
- The composite outcome “major renal event” was defined as development of new macroalbuminuria, doubling of creatinine, end stage renal disease, or renal death> During 5-years of follow-up, major renal events occurred in 487 (4.6%) patients. The risk increased with higher BMI. Multivariable-adjusted HRs (95% CIs), compared to normal weight, were: 0.91 (0.72–1.15) for overweight; 1.03 (0.77–1.37) for obesity grade 1; 1.42 (0.98–2.07) for grade 2; and 2.16 (1.34–3.48) for grade 3 (p for trend = 0.006). These findings were similar across subgroups by randomised interventions (intensive versus standard glucose control and perindopril-indapamide versus placebo). Every additional unit of BMI over 25 kg/m2 increased the risk of major renal events by 4 (1–6)%. Comparable results were observed with the risk of secondary endpoints.
- The anti-proteinuric effect of ramipril is maximal on obese patients and minimal in patients with normal BMI. Differences in urinary protein excretion (follow-up − baseline) are expressed as mean and SE