Dietary practices in patients with chronic kidney disease not yet on maintenance dialysis: What are the relevant components? 3 rd International Conference of European Renal Nutrition Working Group of ERA-EDTA T. Alp Ikizler, MD Vanderbilt University Medical Center
Considerations for Nutritional Requirements in Kidney Disease Protein intake CKD - Progression ESRD - Protein wasting CKD and ESRD Na/K/PO4 (HTN; Hyperkalemia; Bone Mineral Disorders) Metabolic Disorders (Inflammation; Oxidative Stress) Calorie intake CKD - Obesity; Insulin Resistance ESRD - Wasting-Obesity Paradox
PEW is present in 12-18% of stages 3 and 4 CKD patients 2 studies reported PEW prevalence up to 18% in patients with early-stage CKD (3 and 4) 18% prevalence in CKD stages 3 and 4 patients in Brazil using SGA (n=122, age 55 ±11) 1 12% prevalence in CKD stage 4 patents in Australia, using SGA (n=56, age 70 ±14) 2 1. Sanches FM, et al. Am J Kidney Dis. 2008;52:66-73. 2. Campbell KL, et al. Clin Nutr. 2008;27:537-544.
Appetite Appetite decreases as CKD progresses Starts when egfr <10-25% of normal Retention of uremic toxins suppress appetite Increased dialysis dose improves feeding behavior egfr egfr egfr egfr <90 ml/min<60 ml/min<30 ml/min <15 ml/min Dialysis begins Transplantation Carrero JJ. J Ren Nutr. 2009;19:10-15.
Uremic Toxins Mitch and Ikizler Handbook of Nutrition and The Kidney 5
Rates of Death and CV Events in Patients According to GFR
Etiology and Consequences of Protein Energy Wasting in CKD Loss of Kidney Function Uremic Toxin Retention Co-Morbid Conditions (Diabetes, CVD, Depression) Dialysis-Associated Catabolism Infection Dietary Nutrient Intake Protein-Energy Wasting Sarcopenia CVD Inflammation Metabolic Derangements (Insulin Resistance, Metabolic Acidosis, IGF-1/GH Resistance) Frailty Carrero JJ et al on behalf of ISRNM; JREN 2013
Slide courtesy of Peter Stenvinkel Stenvinkel et al. CJASN 2007
Coronary events in patients diabetic CKD: A population-level cohort study Co-existence of CKD and Diabetes is the strongest CV risk factor in general population Tonelli, M; Lancet
Obesity is a global health issue that seems to worsen overtime
Consequences of Obesity in Kidney Disease Stenvinkel, Ikizler, Zoccali JASN 2014
Increased fat mass Decreased clearance Vasculature Endothelial activation Inflammation Oxidative stress Vascular calcification Leptin Resistin TNF-a IL-6 Adiponectin Adipose tissue Adipokine imbalance BBB Insulin resistance Lipid accumulation Muscle breakdown Brain Anorexia Depression Increased REE Sympathetic overactivity Muscle tissue Slide courtesy of Dr. Peter Stenvinkel
BMI (Adiposity) is the Primary Determinant of Insulin Resistance in Stage 3-4 CKD Trirogoff et al, AJCN 2007
BMI (Adiposity) is an Independent Determinant of Oxidative Stress in Stage 3-4 CKD Ramos et al, JASN 2008
A Proposed Mechanism for Uremia- Induced CVD Risk
Interventions Targeted at Non-Traditional CV Risk Factors in Uremia Lifestyle Interventions Diet Inflammation Uremia Oxidative stress Endothelial Dysfunction CV Risk Insulin resistance
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Interventions Targeted at Non-Traditional CV Risk Factors in Uremia Anti-inflammatory Anti-cytokine - Omega 3 Oxidative stress Uremia Inflammation Endothelial Dysfunction CV Risk Insulin resistance
IL-1Beta Inhibition in Moderate CKD Study Design Pilot & Feasibility Study Double blinded Placebo Control-RCT Patient screening & Enrollment 1:1 Randomization Rilonacept (IL-1 blocker)* 160 mg subcutaneously weekly X 12 weeks * Loading dose 320 mg Placebo X 12 weeks NCT 00897715 & NCT01663103 Hung, Novak, Ikizler, Chonchol
Outcomes Primary outcomes: Measurements of vascular health: endothelial function ( brachial FMD%) and arterial stiffness (apwv) Secondary outcomes: Biomarkers of inflammation Adiponectin and other markers of insulin resistance FGF23 and other markers of MBD
hscrp, mg/dl Rilonacept effectively reduced hscrp levels in patients with CKD stages 3 & 4 P=0.006 20 18 16 14 12 10 8 6 4 2 4.6 2.1 3.3 2.8 0 Rilonacept 1 2 3 4 Placebo * Analysis done using a mixed effect model
% change FMD Rilonacept improved endothelial dependent FMD overtime 6 *P<0.005 5 4 3 Rilonacept 2 1 >1% Increased %change FMD Placebo * Analysis done using a mixed effect model 0 IL-1 Trap 0 4 8 12 0 4 Placebo 8 12
apwv (cm/sec) Rilonacept did not improve aortic pulse-wave velocity (apwv) 1600 P=0.56 1400 1200 1000 800 600 400 200 0 0 Rilonacept 4 8 12 0 4 Placebo 8 12 Week Rilonacept Placebo
*adiponectin, μg/ml Rilonacept Increased Serum Adiponectin Levels Compared to Placebo 45 P=0.03 40 35 30 baseline Week 12 25 29.8 20 15 21 10 5 14 12.7 0 IL-1 Trap Rilonacept Placebo
Interventions Targeted at Non-Traditional CV Risk Factors in Uremia Antioxidants Inflammation Uremia Oxidative Stress Endothelial Dysfunction CV Risk Insulin Resistance
Tocopherols and Alpha Lipoic Acid Therapy (TALAT) in CKD Trial H 3 C CH 3 O O OH HO S S Randomized, double-blind, placebo-controlled trial N = 80 Stage 3-4 CKD patients Tocopherols + a-lipoic acid vs. placebo x 8 weeks Primary endpoint, change in F2-isoprostanes Secondary endpoints Inflammatory biomarkers Insulin resistance Endothelial dysfunction
TALAT in CKD Trial F 2 -isoprostane F2-Iso F2-Isoprostanes 0.12 0.1 0.08 0.06 0.04 0.02 Baseline Month2 0 Placebo VitE/ALA
Diet and Exercise Intervention to Improve CV Risk Factors in Stage 3-4 CKD Patients Diet & Exercise Inflammation Uremia Oxidative stress Endothelial Dysfunction CV Risk Insulin resistance Ikizler, Himmelfarb et al, JASN 2017
122 subjects 92 completed 2x2 Factorial Design 4 month Randomized, non-blinded Interventions Diet: 500-700 kcal/d restriction Exercise: Supervised Endurance 3 X Week Primary Outcomes: Weight; F 2 Isoprostane; IL-6; VO 2Peak Ikizler Himmelfarb JASN 2017
Diet and Exercise Intervention to Improve CV Risk Factors in Stage 3-4 CKD Patients Primary Outcomes: F 2 -isoprostane; Weight; VO 2peak Secondary Outcomes: Interleukin-6; Adipocytokines; Physical Activity
Changes in VO 2 peak in Response to Diet and Exercise Interventions Compared to Changes in Control Group
Changes in Weight and Body % Fat in Response to Diet and Exercise Interventions Compared to Changes in Control Group
Changes in F2-isoprostane and Interleukin-6 in Response to Diet and Exercise Interventions Compared to Changes in Control Group
Changes in Adipocytokine levels in Response to Diet and Exercise Interventions Compared to Changes in Control Group Alsouqi, Ikizler, Himmelfarb Submitted
Changes in Total Daily Physical Activity in Response to Diet and Exercise Interventions Compared to Changes in Control Group Taylor, Ikizler, Himmelfarb Submitted
Prevalence and severity of kidney disease in patients admitted with Acute Decompensated Heart Failure 118,465 Patients Hospitalized with ADHF (ADHERE Database)
CKD, Heart Failure & Nutrition Similar etiological factors Na, Obesity, Inflammation, Altered Metabolism Epidemiology of Chronic disease (? paradox) Difficulty in nutritional assessment Na intake; Dietary patterns; Body Composition Lack of evidence based guidelines
23Na Magnetic Resonance Imaging of Tissue Sodium
Muscle and Skin Sodium Content are Elevated in MHD patients Muscle Na Content (mmol/l) MHD (n=10) Control (n=8) 21 (18, 25) 17 (15, 19) 0.02 p Skin Na Content (mmol/l) MHD (n=10) Control (n=8) 18 (15, 21) 17 (14, 19) 0.36 p
High Muscle Tissue Na Content Leads to Insulin Resistance Deger et al. J Cachexia Sarcopenia Muscle
Special Considerations for Fat Intake in CKD CKD patients are recommended to follow general advice for hearth health, including: Saturated fat <7% of total calories; Unsaturated fat to substitute saturated fat Omega 3 fatty acids demonstrate promising benefits: triglyceride levels, dialysis access patency, and cardiovascular risk factors Kris-Etherton et al Circulation (2002) 106: p2747-57; Allomon & Moe CJASN (2006) 2: p182-192
Lipid-lowering therapy in CKD: SHARP Study
Vitamins and Trace Elements Water-soluble vitamins (esp B6, C and folate) Losses: Dialysis removal > normal urinary losses Fat-soluble vitamins Usually only Vit D supplemented Vit A & E (risk of toxicity), intake should meet RDI Trace elements Zinc, selenium, copper, aluminium & magnesium Iron (oral supplements not recommended)
Nutritional Considerations in CKD Loss of kidney function leads to number of metabolic derangements A multitude of dietary and other nutritional strategies can be applied in the setting of moderate to advanced CKD Healthy lifestyle interventions Anti-inflammatory; Anti-oxidant; Insulin Sensitizing Novel targets Interventions personalized to individual patients are more likely to succeed in CKD.
Vanderbilt Center for Kidney Disease - Clinical Research Group Kidney Research Institute UW; J. Himmelfarb Funding/Other Support NIH/NIDDK/NHLBI/NIEHS RCG/FMC/Abbott/Baxter NKF/AKF/ASN/ISRNM SatelliteHealth grant program Vanderbilt Clinical and Translational Research Award