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Otros factores de progresión Dislipemia, Obesidad y T abaquismo José Luño

Otros factores de progresión Dislipemia, Obesidad y T abaquismo José Luño Hospital General Universitario Gregorio Marañón Madrid . Lipid Hypothesis (Moorhead) The Lancet 2: 1309-1311, 1982.

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Otros factores de progresión Dislipemia, Obesidad y T abaquismo José Luño

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  1. Otros factores de progresión Dislipemia, Obesidad y Tabaquismo José Luño Hospital General Universitario Gregorio Marañón Madrid

  2. Lipid Hypothesis (Moorhead)The Lancet 2: 1309-1311, 1982 Lipids contribute to glomerular and tubulointerstitial injury in progressive chronic kidney disease “Estudios histopatológicos de Virchow en 1860”

  3. Hyperlipidemia Mechanisms responsible for renal damage • Increase of capillary glomerular pressure (Kasiske 1990) • LDL cholesterol can bind to specific receptors in mesangial cells and stimulate mesangial cell hypertrophy (Takemura 1993, O´Donnell 1993, Grone 1992) • Stimulate cytokine formation (Oda 1999, Coritsidis 1991) • LDL can stimulate fibronectine and collagen formation (Rovin 1993, Keane 1992) • Oxidized de LDL may reduce nitric oxide in the glomeruli (Wheeler 1994) • LDL may activate the formation of vasoactive substances such as endothelin, thromboxane and angiotensin II ( Oda 1999, Galle 1999)

  4. Hypercolesterolemia is a predictor of loss of renal function in both type 1 and type 2 diabetic nephropathy • Krolewski AS: Hypercholesterolemia--a determinant of renal function loss and deaths in IDDM patients with nephropathy.Kidney Int Suppl. 1994 Feb;45:S125-31. • Ravid M: Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia.Arch Intern Med. 1998 May 11;158(9):998-1004.

  5. Independent predictors of progression of renal disease in the MDRD Study • Proteinuria • Polycystic kidney disease • Lower serum transferrin • Higher mean arterial pressure • Black Race • Lower serum HDL-cholesterol Hunsicker LG Kidney Int. 1997 Jun;51(6):1908-19

  6. Association between cholesterol levels and increased creatinine (Cr>1.5 mg/dl) RR adjusted for age. (n= 4.483 healthy physicians, 1982 to 1996) Schaeffner ES, J Am Soc Nephrol 14:2084-2091,2003

  7. Association between adjusted RR of renal dysfunction and baseline levels of lipoproteins (n= 4.483 healthy physicians, 1982 to 1996) Schaeffner ES, J Am Soc Nephrol 14:2084-2091,2003

  8. Effects of StatinsExperimental studies • Statins have beneficial effects on renal hemodynamics (Fuiano 1996) • Reduce the proliferation of mesangial and vascular smoth muscle cells induced by PDGF and Insulin Like Growth Factor (Oda 1999, Gupta 1992, y NF-kappa B (Guijarro 1996) • Inhibit the production of cytokines such as MCP-1 and the macrophage colony stimulating factor (Guijarro 1996, Park 1998) • Improve endothelial function (O´Driscoll 1997) • Up regulate the production of NO synthase in vitro (Laufs 1998, Hernández Perera 1998) and in vivo (O´Driscoll 1997) • Stimulate the apoptosis (Guijarro 1998) important mechanism on modulation of inflammatory damage (Savill 1994) • Statins have antiinflammatory actions, inhibit production of inflammatory cytokines and reduce PCR levels (Ridker 2001)

  9. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease Bianchi S, Am J Kidney Dis. 2003 Mar;41(3):565-70.

  10. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease Bianchi S, Am J Kidney Dis. 2003 Mar;41(3):565-70.

  11. Effect of pravastatine on loss of renal function in people with moderate chronic renal insuffiency and cardiovascular disease (CARE Study) Tonelli M: J Am Soc Nephrol 14: 1605–1613, 2003

  12. Effect of lipid reduction on the progression of renal disease Fried LF. Kidney Intern 59:260;2001

  13. Heart Protection Study The Lancet.365(9473):1779-85, 2005.

  14. Heart Protection Study The Lancet.365(9473):1779-85, 2005.

  15. Atorvastatin in HD Patients with Type 2 DM C. Wanner NEJM 353:3: 238,2005

  16. Atorvastatin in HD Patients with Type 2 DM C. Wanner NEJM 353:3: 238,2005

  17. Marcadores de inflamación en pacientes con ERC N= 52; Estadios 2,3 y 4 (CCr: 42± 17 ml/min). Edad 69±12 años Marian Goicoechea. Nefrologia 2005

  18. * p=0.000 p=0.000 Prevalencia Total EIC: 21,4 % ACV: 11,8 % VP: 18,6 % IC: 37,7 % ECV global: 50,6 % p=0.000 NS p=0.000 PCR quintiles: .≤0.8; .0,8 a ≤2;.2 a ≤5; .5 a ≤10; .>10

  19. C-reactive protein as predictorof all-cause and cardiovascular mortality in CKD patients (MDRD) Menon V. Kydney Int. 2005 Aug;68(2):766-72.

  20. Efecto de 20 mg de atorvastatina sobre colesterol Y parámetros de inflamación en pacientes con ERC n=47; estadios 2,3 y 4 . Edad 66±13 años Marian Goicoechea. En prensa

  21. Cadaver kidney Transplants1 year serum cholesterol (mg/dl) G. Opeltz. Collaborative Transplant Study. May 2003

  22. Effect of fluvastatin on cardiac outcomes in renal transplant recipients a multicentre, randomised, placebo-controlled trial  The Lancet:361, Iss. 9374;  pg. 2024, 2003 ,

  23. Evidencias • La dislipemia: elevación de LDL o reducción de niveles de HDL es un factor de riesgo vascular y de daño renal • El tratamiento hipolipemiante, sobre todo con estatinas, previene el desarrollo y progresión de la enfermedad cardiovascular y parece prevenir el desarrollo y progresión de la enfermedad renal. • Sin embargo, todavía no tenemos suficientes datos que confirmen con un alto grado de evidencia este beneficio del tratamiento hipolipemiante sobre la progresión de la enfermedad renal crónica. • A este respecto no hemos progresado mucho desde la hipótesis de Moorhead y para resolver este tema con claras evidencias necesitamos todavia esperar a nuevos estudios controlados actualmente en marcha: SHARP (2009) para confirmar dicha hipótesis y asegurar el beneficio nefroprotector a la vez que cardioprotector en los enfermos renales.

  24. Epidemiología de la Obesidad en España La prevalencia de la obesidad es del 20%, siendo 18% en varones y 23% en mujeres. La prevalencia aumenta con la edad y con menor nivel socioeconómico y cultural. Medrano MJ. Med Clin ;124(16):606-12, 2005.

  25. Functional and structural changes in the kidney in the early stages of obesity. Henegar JR et al. JASN 2001; 12: 1211 Perros sobrealimentados para inducir obesidad: Incremento de: PRA, TGF- ß, Insulina PA, GFR (38±6%), RPF (61±7%) Glomerulomegalia, incremento matriz mesangial. Glomeruloesclerosis

  26. Hormonas, citoquinas y factores de crecimiento producidos por los adipocitos Angiotensinogeno Renina TNF-alfa Interleukina-6 Leptina :Regula el apetito y gasto energético Inhibidor del activador del Plasminogeno (PAI-1) TGF-ßeta: Profibrótico Resistina Adiponectina: Efecto antiateroesclerótico directo y sensibilizante a insulina

  27. Patogenia de la lesión renal asociada a Obesidad Aumento de la Reabsorción tubular de Sodio Aumento de la actividad Activación del sistema Simpática a nivel renal Renina-Angiotensina Angiotensinógeno ARP Hiperleptinemia Citoquinas proinflamatorias TGF-Beta

  28. Obesidad e hiperfiltración • Vasodilatación preglomerular • Aumento del Filtrado glomerular • Aumento de la Fracción de Filtración

  29. Glomeruloesclerosis por Obesidad vs Glomeruloesclerosis Idiopática Glomeruloesclerosis por obesidad • Desarrollo lento proteinuria • Proteinuria menor (*) • Evolución lenta a la I.R.C. • Glomerulomegalia • Fusión pedicelar irregular • Respuesta terapeutica a: • Dieta, IECA o ARA, hipolipemiantes Glomeruloesclerosis primaria • Aparición rápida • Proteinuria mayor • Evolución rápida • Volumen glomerular normal • Fusión pedicelar difusa • Respuesta terapéutica a: Inmunosupresores, IECA/ARA Praga M et al. Nephrol Dial Transplant 2001; 16: 1790-1798

  30. The effects of Weight Loss on renal function in patients with severe obesity Chagnac A et al. J Am Soc Nephrol 2003; 14:1480-86

  31. Componentes del Síndrome Metabólico (ATP III) : 1.- Obesidad abdominal: Perímetro de cintura : Hombres >102 cm Mujeres > 88 cm 2.- Hipertrigliceridemia >150 mg/dl 3.- Colesterol HDL bajo: Hombres <40 mg/dl Mujeres <50 mg/dl 4.- Hipertensión arterial >130/85 mmHg 5.- Hiperglucemia: Glucemia en ayunas ≥110 mg/dl

  32. Síndrome Metabólico y Enfermedad Renal Crónica Prevalencia de ERC o microalbuminuria (NHANES III) I ERC Microalbuminuria J Chen. Annals of Internal Medicine 140: 3, 2004

  33. Prevalencia de factores de riesgo clásicos en la población general según estadios de ERC A Otero. Nefrología 25:3: 276,2005

  34. Obesidad abdominal e IMC en ERC

  35. Niveles de Insulina en pacientes con ERC % de Pacientes Insulina: 71% HOMA : 78% Media 24.59 ± 11.3 n: 100 Insulina (µUI/ml) *Se excluyeron pacientes con Diabetes Mellitus

  36. Effects of Smoking on Renal hemodynamics Healty volunteers Seven patients with IgA nephropathy E Ritz . JASN 9. 1798, 1998

  37. Renal impairment in chronic cigarette smokers G Gambaro JASN. 9:4. 562, 1998

  38. The effects on mortality of smoking more than 25 pack-years at the time of transplantation compared to smoking 25 pack-years or less and never smoked B. Kasiske. J Am Soc Nephrol. 2000 Apr;11(4):753-9

  39. The effects on graft survival of smoking more than 25 pack-years at the time of transplantation compared to smoking 25 pack-years or less and never smoked B. Kasiske. J Am Soc Nephrol. 2000 Apr;11(4):753-9

  40. ESRD incidence (USRDS) and estimated prevalence of Risk Factors (NHANES)

  41. The sequential occurrence of the continuous clinical manifestations of cardiovascular, cerebral and renal disease that are commonly seen in high risk patients. Ventricular dilatation/ cognitive dysfunction Remodelling Congestive heart failure/ secondary stroke Myocardial infarction and stroke Macro- proteinuria Micro- albuminuria End-stage heart disease/ brain damage and dementia Nephrotic proteinuria Atherosclerosis and LVH Endotelial dysfunction Risk Factors hypertensión , dislipidemia, metabolic syndrome diabetes, obesity, smoking End-stage renal disease Cardio- Cerebrovascular death Adaptado de V Dzau. J Hypertens 23 (suppl 1): s9-s16,2005

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