28. TSN Ulusal Nefroloji, Hipertansiyon, Diyaliz ve Transplantasyon Kongresi Protein-Energy Kaybinin Etyolojisinde Beslenmenin, Renal Replasman Tedavisinin ve Inflamasyonun Rolu T. Alp Ikizler, MD Professor, Medicine Vanderbilt University Medical Center
Schematic representation of causes and manifestations of PEW in Kidney Disease ISRNM Position Paper - Kidney International
Simplified flow schedule of uremia and its complications Picture stolen from P. Stenvinkel who stole it from Anders Alvestrand
Uremik Protein Energy Kaybina Hedefli yaklasim Dialytic Factors Inadequate Nutrient Intake Other Factors Bioincompatibility Inadequate Dose of Dialysis Nutrient Losses Increased Energy Expenditure Protein-Energy Wasting Co-morbidities Inflammation, DM Frequent Hospitalizations Metabolic & Hormonal Derangements
Uremik Ultrafiltrate ve Agizdan Besin (Protein) Alimi Ingested Protein (ml) 45 40 35 30 25 20 15 10 5 0 0 ml 1 ml 2 ml 4 ml Urine Ultrafiltrate 1-5 kda Modified from Anderstam, Mamoun & Bergstrom JASN 1996
Dietary Protein Intake and Daily Creatinine Excretion During Progression of Renal Disease 1,4 1,2 1 0,8 0,6 0,4 0,2 0 > 50 50-25 24-10 < 10 Dietary protein intake g/kg/d Creatinine Clearance ml/min Creatinine excretion g/d Ikizler JASN 1995
Hemodializ Hastalarinin Istah Durumu Self-reported appetite status % of patients 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 37% 31% 25% 7% 0% Very good Good Fair Poor Very poor Normal Appetite Diminished Appetite
Hemodiyalize bağlı Net Katabolizma ve Diyaliz Esnasinda Protein Kaybi Membranların biyokimyasal yapısı HD membranları ile ilişkili kompleman aktivasyonu ile birlikte protein katabolizmasında artış Gutierrez & Bergstrom Kidney Int 1990 Membran porlarının boyutu Hemodiyaliz sırasında amino asit kaybı (? Daha geniş porlardan daha yüksek kayıplar) Wolfson & Kopple Kidney Int 1989 Ikizler & Hakim Kidney Int 1994
Dializ Esnasinda Onlenemez Amino Acid Kaybi: Degisik Dializorlerin Etkisi 12 10 total g/dialysis 8 6 4 2 0 CU PMMA PS PD/Day Ikizler & Hakim 1994 Kidney Int
Arterial Plasma Essential Amino Acids (µmol/l) Arterial Plasma Total Amino Acids (µmol/l) 1000 2500 800 600 * * 15% 2000 1500 * * 20% 400 33% 1000 40% 200 500 0 B D PD 0 B D PD Ikizler et al, AJP, 2002
Hemodializ e Bagli Net Tum-Vucut Protein Kaybi proteolysis synthesis net balance (mg/kgffm/min) 4.5 3.5 2.5 1.5 0.5-0.5-1.5 * * 10% 11% 96% * B D PD 21% * Ikizler et al, AJP, 2002
Plazma arteriyel aminoasit konstantrasyonlari Intradialytik Nutrusyon ile artmaktadir Total AA Esansiyel olmayan Esansiyel AA Dallı zincirli AA (µmol/l) µmol/l 4000 3500 3000 2500 2000 1500 1000 500 0 p<0.05 Control Pre HD During HD Post HD µmol/l 4000 3500 3000 2500 2000 1500 1000 500 0 p<0.05 IDPN Pre HD During HD Post HD Pupim et al, JCI, 2002
Schematic representation of causes and manifestations of PEW in Kidney Disease ISRNM Position Paper - Kidney International Inflammation
Prevalence of malnutrition, inflammation and atherosclerosis in predialysis patients Malnutrition 44% Inflammation 32% 53% with inflammation 32% 72% with malnutrition N = 109 Carotid plaque 72% Stenvinkel et al. Kidney Int 1999
SDB Hastalarinda Inflamasyona Yol Acan Sebepler Uremic Toxins Loss of Kidney Function Oxidative Stress Insulin Resistance INFLAMMATION Co-Morbidities Renal Replacement Therapy Atherosclerosis Infections Endotoxin Vascular Access Diabetes Mellitus Bioincompatibility
Inflammation is Associated with Loss of Kidney Function 30 25 IL-6 (pg/ml) 20 15 10 20.17 21.95 15.94 17.04 18.22 5 0 4.02 CTL (N=50) baseline (N=50) 3 months (N=50) 6 months (N=46) 9 months (N=41) 12 months (N=41) Pupim, Himmelfarb, Ikizler Kidney int 2004
Inflammatory Signals Associated With Hemodialysis IL-6 (pg/ml) Fibrinogen FSR (%/day) 25 20 15 10 5 0 * δ * δ * 58% 68% 14% 34% B D PD Caglar, Pupim, Ikizler, KI, 2002
Hemodializ e Bagli Net Tum-Vucut Protein Kaybi Inflamasyon un katkisi proteolysis synthesis net balance (mg/kgffm/min) 4.5 3.5 2.5 1.5 0.5-0.5-1.5 * * 10% 96% 11% * B D PD 21% * Ikizler et al, AJP, 2002
Systemic Inflammatory Response Syndrome Tissue Injury Activation of IL-1, TNF, IL-6 Activation of other cytokines Biological activities Acute phase response CRP, Albumin, SAA
Metabolic Effects of Inflammation MUSCLE LOSS ANOREXIA COMPLEMENT ACTIVATION INFLAMMATION UREMIA INCREASED REE FEVER APP SYNTHESIS INCREASED SNS ACTIVITY IMMUNE SYSTEM MODULATION
Continuous IL-1 Infusion Leads to Decreased Food Intake Ling et al JCI 1996
Serum Interleukin-6 and Appetite in 331 Hemodialysis Patients Logarithm of Serum Interleukin-6 (pg/ml) 3.4 3.2 3.0 2.8 2.6 2.4 2.2 Normal Appetite very good Diminished Appetite ANOVA p=0.004* (*logarithmic scale) Kalantar-Zadeh et al, Am J Clinal Nutrition, 2004 2.0 1.8 fair poor good 1 2 3 4 Reported Appetite Scales (1: very good, 2: good; 3: fair; 4: poor) Mean ±0.95 Conf. Interval
Potential Pharmacological Strategies Using Inflammation and Oxidative Stress as a Target Statins Tocopherols Randomized double-blind placebo controlled trial 57 HD-pts completed the study 8 weeks 308 mg γ-tocopherol and 800 mg docosahexaenoic acid (DHA) Journal of Renal Nutrition 2007
IL-1 Beta Inhibition Improves Chronic Inflammation in Hemodialysis Patients Hung & Ikizler et al JASN 2010 in press
IL-1 Beta Inhibition Improves Chronic Inflammation in Hemodialysis Patients 53% 1% 40% 20% Hung, Ikizler JASN. 2011 Mar;22(3):437-42
Nutritional Biomarkers at Baseline and Post Intervention by Randomization Group Prealbumin, mg/dl Albumin, g/dl Lean Body, gm IL-1ra Placebo Hung, Ikizler JASN. 2011 Mar;22(3):437-42
(Üremik) Protein Enerji Kaybı Sendromu Üremik protein enerji kaybı sendromunun etiyolojisi multifaktoriyeldir. diyetin azalması + HD ilişkili katabolizma + Inflamasyon + Insulin resistance -> tükenme -> mortalite ve morbiditede Nutrisyonel müdahaleler -> uygun ve emniyetli; IDPN veoral besinler HD ilişkili katabolizması parsiyel olarak geri döndürebilir (primer olarak aminoasit havuzunu yeniden doldurarak)
Metabolic Paradigm for Uremic Wasting and Treatment Options IDN PPAR-γ Agonist Insulin DM/GI Anti-inflammatory agent Modified from O Sullivan, AJ, JJ Kelley. Kidney International 2007(71);98-100.