Dietary practices in patients with chronic kidney

disease not yet on maintenance dialysis:

What are the relevant components?

3rd 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

1. Sanches FM, et al. Am J Kidney Dis. 2008;52:66-73.

2. Campbell KL, et al. Clin Nutr. 2008;27:537-544.

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

Appetite decreases as CKD progresses

Carrero JJ. J Ren Nutr. 2009;19:10-15.

eGFR<90 mL/min

Retention of uremic toxins – suppress

appetite Increased dialysis dose improves feeding behavior

Dialysisbegins

Transplantation

Starts when eGFR<10-25% of normal

eGFR<60 mL/min

Ap

pet

ite

eGFR<30 mL/min

eGFR<15 mL/min

5Mitch and Ikizler

Handbook of Nutrition and The KidneyUremic Toxins

Rates of Death and CV Events in Patients

According to GFR

CVD

Frailty

InfectionCo-Morbid Conditions(Diabetes, CVD, Depression)

Dialysis-Associated Catabolism

Metabolic Derangements(Insulin Resistance, Metabolic Acidosis, IGF-1/GH Resistance)

Dietary Nutrient Intake

Loss of Kidney Function Uremic Toxin Retention

Protein-Energy WastingSarcopenia

Inflammation

Etiology and Consequences of Protein Energy Wasting in CKD

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

Tonelli, M; Lancet

Co-existence of CKD and Diabetes is the strongest CV risk factor in general population

Obesity is a global health issue that seems to worsen overtime

Consequences of Obesity in Kidney Disease

Stenvinkel, Ikizler, Zoccali

JASN 2014

Decreased clearance

Adipokine

imbalance

Increased fat mass

Adipose tissueAdiponectin

Muscle tissue

• Insulin resistance

• Lipid accumulation

• Muscle breakdown

Vasculature

• Endothelial activation

• Inflammation

• Oxidative stress

• Vascular calcification

Leptin

Resistin

TNF-a

IL-6

• Anorexia

• Depression

• Increased REE

• Sympathetic overactivity

Brain

BBB

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

Uremia Oxidative stress

Inflammation

Endothelial Dysfunction

Insulin resistance

CV

Risk

Diet

17

Interventions Targeted at Non-Traditional CV

Risk Factors in Uremia

Uremia Inflammation

Oxidative stress

Endothelial Dysfunction

Insulin resistance

CV

Risk

Anti-inflammatoryAnti-cytokine - Omega 3

Study Design

Patient screening &Enrollment

Rilonacept (IL-1 blocker)*160 mg subcutaneously

weekly X 12 weeks

Placebo X 12 weeks

1:1 Randomization

Pilot & Feasibility Study

Double blinded

Placebo Control-RCT

* Loading dose 320 mg

NCT 00897715 & NCT01663103

IL-1Beta Inhibition in Moderate CKD

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

Rilonacept effectively reduced hsCRP levels in patients with CKD stages 3 & 4

0

2

4

6

8

10

12

14

16

18

20

1 2 3 4

P=0.006

hsC

RP,

mg/d

l

Rilonacept Placebo

4.62.1 3.3 2.8

* Analysis done using a mixed effect model

Rilonacept improved endothelial dependent FMD overtime

0

1

2

3

4

5

6

IL-1 Trap Placebo

*P<0.005

% c

hange F

MD

>1% Increased

%change FMD

Placebo0 4 8 12 0 4 8 12

Rilonacept

Placebo

* Analysis done using a mixed effect model

Rilonacept did not improveaortic pulse-wave velocity (aPWV)

0

200

400

600

800

1000

1200

1400

1600

Rilonacept Placebo

aP

WV

(cm

/sec)

0 4 8 12 0 4 8 12

Week

Rilonacept Placebo

P=0.56

Rilonacept Increased Serum

Adiponectin Levels Compared to Placebo

0

5

10

15

20

25

30

35

40

45

IL-1 Trap Placebo

baseline

Week 12

P=0.03

1412.7

29.8

21

*adip

onectin, μ

g/m

l

Rilonacept Placebo

Uremia Oxidative Stress

Inflammation

Endothelial Dysfunction

Insulin Resistance

CV

Risk

Antioxidants

Interventions Targeted at Non-Traditional CV

Risk Factors in Uremia

Tocopherols and Alpha Lipoic Acid Therapy

(TALAT) in CKD Trial

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

CH3CHCH33

H3CHH33CC

HOHOHO

OOO

CH3CHCH33

H3CHH33CC

HOHOHO

OOO

OH

O

S S

TALAT in CKD TrialF2-isoprostane

F2-Iso

0

0.02

0.04

0.06

0.08

0.1

0.12

Placebo VitE/ALA

F2

-Is

op

ros

tan

es

Baseline

Month2

Diet and Exercise Intervention to Improve CV Risk Factors in

Stage 3-4 CKD Patients

Uremia Oxidative stress

Inflammation

Endothelial Dysfunction

Insulin resistance

CV

Risk

Diet & Exercise

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; F2Isoprostane; IL-6; VO2Peak

Ikizler Himmelfarb JASN 2017

Diet and Exercise Intervention to Improve CV

Risk Factors in Stage 3-4 CKD Patients

Primary Outcomes:

F2-isoprostane; Weight; VO2peak

Secondary Outcomes:

Interleukin-6; Adipocytokines; Physical Activity

Changes in VO2 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

MHD

(n=10)

Control

(n=8)

p

Muscle Na

Content

(mmol/L)

21 (18, 25) 17 (15, 19) 0.02

MHD

(n=10)

Control

(n=8)

p

Skin Na

Content

(mmol/L)

18 (15, 21) 17 (14, 19) 0.36

Deger et al. J Cachexia Sarcopenia Muscle

High Muscle Tissue Na Content Leads to Insulin Resistance

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.

Funding/Other Support

NIH/NIDDK/NHLBI/NIEHS

RCG/FMC/Abbott/Baxter

NKF/AKF/ASN/ISRNM

SatelliteHealth grant program

Vanderbilt Clinical and Translational Research Award

Vanderbilt Center for Kidney Disease - Clinical

Research Group

Kidney Research Institute – UW; J. Himmelfarb