Dietary practices in patients with chronic kidney disease not yet on maintenance dialysis: What are the relevant components?

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1 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

2 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

3 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: Campbell KL, et al. Clin Nutr. 2008;27:

4 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.

5 Uremic Toxins Mitch and Ikizler Handbook of Nutrition and The Kidney 5

6 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

7 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

8 Slide courtesy of Peter Stenvinkel Stenvinkel et al. CJASN 2007

9 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

10 Obesity is a global health issue that seems to worsen overtime

11 Consequences of Obesity in Kidney Disease Stenvinkel, Ikizler, Zoccali JASN 2014

12 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

13 BMI (Adiposity) is the Primary Determinant of Insulin Resistance in Stage 3-4 CKD Trirogoff et al, AJCN 2007

14 BMI (Adiposity) is an Independent Determinant of Oxidative Stress in Stage 3-4 CKD Ramos et al, JASN 2008

15 A Proposed Mechanism for Uremia- Induced CVD Risk

16 Interventions Targeted at Non-Traditional CV Risk Factors in Uremia Lifestyle Interventions Diet Inflammation Uremia Oxidative stress Endothelial Dysfunction CV Risk Insulin resistance

17 17

18 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

19 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 & NCT Hung, Novak, Ikizler, Chonchol

20 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

21 hscrp, mg/dl Rilonacept effectively reduced hscrp levels in patients with CKD stages 3 & 4 P= Rilonacept Placebo * Analysis done using a mixed effect model

22 % change FMD Rilonacept improved endothelial dependent FMD overtime 6 *P< Rilonacept 2 1 >1% Increased %change FMD Placebo * Analysis done using a mixed effect model 0 IL-1 Trap Placebo 8 12

23 apwv (cm/sec) Rilonacept did not improve aortic pulse-wave velocity (apwv) 1600 P= Rilonacept Placebo 8 12 Week Rilonacept Placebo

24 *adiponectin, μg/ml Rilonacept Increased Serum Adiponectin Levels Compared to Placebo 45 P= baseline Week IL-1 Trap Rilonacept Placebo

25 Interventions Targeted at Non-Traditional CV Risk Factors in Uremia Antioxidants Inflammation Uremia Oxidative Stress Endothelial Dysfunction CV Risk Insulin Resistance

26 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

27 TALAT in CKD Trial F 2 -isoprostane F2-Iso F2-Isoprostanes Baseline Month2 0 Placebo VitE/ALA

28 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

29 122 subjects 92 completed 2x2 Factorial Design 4 month Randomized, non-blinded Interventions Diet: kcal/d restriction Exercise: Supervised Endurance 3 X Week Primary Outcomes: Weight; F 2 Isoprostane; IL-6; VO 2Peak Ikizler Himmelfarb JASN 2017

30 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

31 Changes in VO 2 peak in Response to Diet and Exercise Interventions Compared to Changes in Control Group

32 Changes in Weight and Body % Fat in Response to Diet and Exercise Interventions Compared to Changes in Control Group

33 Changes in F2-isoprostane and Interleukin-6 in Response to Diet and Exercise Interventions Compared to Changes in Control Group

34 Changes in Adipocytokine levels in Response to Diet and Exercise Interventions Compared to Changes in Control Group Alsouqi, Ikizler, Himmelfarb Submitted

35 Changes in Total Daily Physical Activity in Response to Diet and Exercise Interventions Compared to Changes in Control Group Taylor, Ikizler, Himmelfarb Submitted

36 Prevalence and severity of kidney disease in patients admitted with Acute Decompensated Heart Failure 118,465 Patients Hospitalized with ADHF (ADHERE Database)

37 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

38 23Na Magnetic Resonance Imaging of Tissue Sodium

40 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

41 High Muscle Tissue Na Content Leads to Insulin Resistance Deger et al. J Cachexia Sarcopenia Muscle

42 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: p ; Allomon & Moe CJASN (2006) 2: p

43 Lipid-lowering therapy in CKD: SHARP Study

44 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)

45 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.

46 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

Macro- and Micronutrient Homeostasis in the Setting of Chronic Kidney Disease. T. Alp Ikizler, MD Vanderbilt University Medical Center

Macro- and Micronutrient Homeostasis in the Setting of Chronic Kidney Disease T. Alp Ikizler, MD Vanderbilt University Medical Center Nutrition and Chronic Kidney Disease What is the disease itself and