ISN Mission: Advancing the diagnosis, treatment

and prevention of kidney diseases in the developing and developed world

Nutrition in Kidney Disease:Nutrition in Kidney Disease: How to Apply Guidelines to How to Apply Guidelines to

Clinical Practice?Clinical Practice?

T. Alp Ikizler, MD Catherine McLaughlin-Hakim Professor, Medicine

Vanderbilt University Medical Center

Outline

Epidemiology

Dietary Protein Intake

Metabolic Derangements in CKD

Nutritional Support in ESRD

Rates of Death and CV Events in Patients According to GFR

N = 1,120,295 adults; GFR = (estimated) glomerular filtration rate. *Age-standardized rates per 100 person-years; †CV event defined as hospitalization or coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease per 100 person-years. Go et al. N Engl J Med. 2004;351:1296-1305.

0.76 1.08

4.76

11.36

0

2

4

6

8

10

12

14

≥60 45-59 30-44 15-29 <15 R

ate

of D

eath

Fro

m A

ny C

ause

*

36.60

2.113.65

11.29

21.80

0

5

10

15

20

25

30

35

40

≥60 45-59 30-44 15-29 <15

Rat

e of

CV

Even

ts†

eGFR (mL/min/1.73 m2)

14.4

The death rate of chronic dialysis patients is unacceptably high

6

Complications of CKD and Progression to ESRD

ESRDESRD

6060 4040 2525 1515 55

GFR (mL/min/1.73 mGFR (mL/min/1.73 m22))

Incr

easi

ng S

ever

ity

Incr

easi

ng S

ever

ity

of C

ompl

icat

ions

of C

ompl

icat

ions

CKD ContinuumCKD Continuum

CKDCKD Anemia

Secondary hyperparathyroidism

Dyslipidemia

Hypoalbuminemia, malnutrition

CVD

Uremic Syndrome

AnemiaAnemia

Secondary hyperparathyroidismSecondary hyperparathyroidism

DyslipidemiaDyslipidemia

Hypoalbuminemia,Hypoalbuminemia, malnutritionmalnutrition

CVDCVD

Uremic SyndromeUremic Syndrome

Uremic Ultrafiltrate Inhibits Nutrient Intake

Modified from Anderstam, Mamoun & Bergstrom JASN 1996

Dietary Protein Intake During Progression of Renal Disease

Ikizler JASN 1995

Protein and Amino Acid Turnover and Waste Protein and Amino Acid Turnover and Waste ProductsProducts

Mitch and IkizlerHandbook of Nutrition in CKD

PlasmaProteins0.5 kg

Free Amino Acid Pool῀

62 g kg

Diet Protein70 g/d

Nitrogen Excretion11.2 g N/d

3.7 –

4.7 g/kg/dCell Proteins

(5.8 kg)

Ribosome

Amino ProteinsAcids

Rationale for Dietary Protein Restriction in CKDRationale for Dietary Protein Restriction in CKD

Ameliorate Uremic Syndrome (delay initiation)

Decrease load on remaining nephrons (preserve RF)

Improve proteinuria/albuminuria

Additive effect of ACE inhibitors

Improve Metabolic Profile

Improve insulin Resistance, Acidosis and Oxidative Stress

Decrease likelihood of patient death

Lack of serious objective reasons for not recommending

Adapted from Fouque & Aparicio., Nature Neph. Reviews 2007

11

Progression -

mGFR Progression –

Renal Death

Study 1: 585 patients Study 2: 255 patients

12

Mean effect: 0.53

mL/min/yr (95% CI, 0.08 to 0.98 mL/min/yr)

13

Dietary Protein Restriction in CKD: SummaryDietary Protein Restriction in CKD: Summary

There is ample evidence to indicate that dietary protein restriction

has several beneficial metabolic benefits.

Improve insulin resistance, metabolic acidosis and oxidant

stress

The overall effects on kidney function seems to be less than

expected based on strong animal data and pilot studies.

DPI improves proteinuria (15-30%), more so in NS.

Additive effect with ACE inhibition.

Unable to translate into significant clinical effect

Evidence to indicate harm is limited.

15

Inflammation and Oxidative Stress in Stage II thru IV Chronic Kidney Disease

Ramos, LF; et al. Determinants of Protein Oxidation in Stage II thru IV Chronic Kidney Disease; 11/2006

0

20

40

60

80

100

0 5 10 15 20 25 30Follow-up Time (months)

Cum

ulat

ive

Surv

ival

(%)

0

20

40

60

80

100

0 5 10 15 20 25 30Follow-up Time (months)

Cum

ulat

ive

Surv

ival

(%)

Oxidative Stress and Mortality in CKDOxidative Stress and Mortality in CKD

0

20

40

60

80

100

0 500 1000 1500 2000 2500 3000 3500Observation Time (days)

Cum

ulat

ive

Surv

ival

(%)

DMA 16/C16:0 > medianDMA 16/C16:0 > median

DMA 16/C16:0 < medianDMA 16/C16:0 < median

p < 0.02p < 0.02

Vitamin C >60pmol/LVitamin C >60pmol/LVitamin C 32 to 60pmol/LVitamin C 32 to 60pmol/LVitamin C <32 pmol/LVitamin C <32 pmol/L

Stenvinkel et al, NDT 19(4): 972-976, 2004Stenvinkel et al, NDT 19(4): 972Stenvinkel et al, NDT 19(4): 972--976, 2004976, 2004Deicher, JASN 16: 1811-1818, 2005Deicher, JASN 16: 1811Deicher, JASN 16: 1811--1818, 20051818, 2005

p = 0.014p = 0.014

A Proposed Mechanism for Uremia- Induced CVD Risk

UremiaUremiaUremia Oxidative StressOxidative StressOxidative Stress

InflammationInflammationInflammation

Endothelial DysfunctionEndothelial DysfunctionEndothelial Dysfunction

Insulin ResistanceInsulin ResistanceInsulin Resistance

CVRiskCVCV

RiskRisk

AntioxidantsAntioxidants

Interventions Targeted at Non-Traditional CV Risk Factors in Uremia

Tocopherols and Alpha Lipoic Acid Therapy (TALAT) in CKD Trial

l Randomized, double-blind, placebo-controlled trial

l N = 80 Stage 3-4 CKD patients

l Tocopherols + -lipoic acid vs. placebo x 8 weeks

l Primary endpoint, change in F2-isoprostanes

l Secondary endpoints−

Inflammatory biomarkers−

Insulin resistance−

Endothelial dysfunction

CH3CHCH33

H3CHH33CC

HOHOHO

OOO

CH3CHCH33

H3CHH33CC

HOHOHO

OOO

OHOHOH

OOO

SSS SSS

Ramos et al JRN 2010

Tocopherols and Alpha Lipoic Acid Therapy (TALAT) in CKD Trial

Tocopherols + ALA(N = 29)

Placebo(N = 30)

Age (yrs) 59.3 ± 10.4 64.4 ± 9.0

Gender (% males) 15 (51.7%) 16 (53.3%)

Race (% White) 28 (96.6%) 28 (93.3%)

Diabetic (%) 16 (55.2%) 16 (53.3%)

BMI (kg/m2) 31.9 ± 7.2 32.3 ± 7.7

eGFR (ml/min) 38.1 ± 11.4 40.9 ± 14.8

Ramos et al JRN 2010

TALAT in CKD Trial F2 -isoprostane

F2-Iso

0

0.02

0.04

0.06

0.08

0.1

0.12

Placebo VitE/ALA

F2-Is

opro

stan

es

Baseline

Month2

Ramos et al JRN 2010

TALAT in CKD Trial F2 -isoprostane

CRP

0

5

10

15

20

25

30

35

Placebo VitE/ALA

CR

P Baseline

Month2

Ramos et al JRN 2010

Variable Coefficient P-value 95% Confidence IntervalAge 0.001 0.500 -0.002 0.004

Gender 0.135 < 0.001 0.064 0.206Race -0.074 0.002 -0.120 -0.029

Diabetes -0.006 0.801 -0.051 0.039

Smoking History 0.060 0.091 -0.010 0.130Estimated GFR 0.000 0.760 -0.002 0.003

Total Cholesterol 1.35 x 10-5 0.971 -0.001 0.001

Serum Albumin -0.044 0.331 -0.132 0.045BMI 0.008 0.001 0.003 0.012

Dependent Variable: Plasma F2-Isoprostanes (log10 transformed)R2 for Model: 0.229

Multivariable Regression Model for Predictors for Elevated Plasma F2 - Isoprostanes

1998

Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2007

(*BMI 30, or about 30 lbs. overweight for 5’4” person)

2007

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

>300,000 deaths attributed to obesity

27

Janus: the god

of gates, doors, doorways, beginnings and endings.

TRANSITION TO ESRD

Wasting/Cachexia

l AIDS: 5-15%

l Cancer: 20-50%

l Old age:

5-25%

l HD>CKD: 5-30%

l >30% muscle loss

n

Risk of deathn

Pneumonia

Metabolic Paradigm for Uremic Wasting & Potential Targetes for Intervention

O’Sullivan, AJ, JJ Kelley. Kidney International 2007(71);98-100.

Schematic representation of causes and manifestations of Schematic representation of causes and manifestations of PEW in Kidney DiseasePEW in Kidney Disease

ISRNM Position Paper ISRNM Position Paper -- Kidney InternationalKidney International

Protein Balance in HumansProtein Balance in Humans

Protein synthesis

Protein Breakdown

n GrowthSynthesis>Breakdown

n WastingBreakdown>Synthesis

n Strategy: Maximize protein synthesisMinimize protein

breakdown

IDPN and IDPO lead to significantly higher Whole-Body Protein Anabolism

* P<0.05 versus Control, # P<0.05 versus PO

Caglar, Hakim, Ikizler Kidney Int, 2002

2

2.5

3

3.5

4

4.5

0 1 2 3 4 5 6months

Seru

m a

lbum

in (g

/dl)

N=85 N=68 N=61 N=49 N=48 N=42 N=39

22.5

33.5

44.5

55.5

66.5

7

Baseline 3-Month 6-Month

SG

A s

core

N=85 N=49 N=39

*

AJKD 2005

The French Intradialytic Nutrition The French Intradialytic Nutrition Evaluation study (FineS)Evaluation study (FineS)

• Follow-up: two years (treatment period + one year)• Visits at day 0 and month 3, 6, 12, 18 and 24

Oral suppl + IDPNduring one year

Oral supplduring one year

182patients

Malnourished

MHD patients

FineSFineS

• Oral supplement: 5.4 kcal/kg/d0.42 g protein/kg/d

• IDPN : 13.8 kcal/kg/HD (5.9 kcal/kg/d)0.62 g AA/kg/HD (0.27 g AA/kg/d)

Nitrogen supply: standard AA solution

Energy supply: 50% standard fat emulsion50% glucose

Nutritional therapiesNutritional therapies

FineSFineS

Results: Nutritional statusResults: Nutritional status

FineSFineSControl group IDPN group

Months0 6 12 18 24

30

34

Serum albumin, g/L

31

32

33

34

NS

Months0 6 12 18 24

30

34

Serum albumin, g/L

31

32

33

34

NS

Months

300

280

260

240

220

200NS

0 6 12 18 24

Serum prealbumin, mg/L

Months

300

280

260

240

220

200NS

0 6 12 18 24

Serum prealbumin, mg/L

Mean cumulative survival: 77% at 1 yr, 58% at 2 yrDeath: Control: n = 36, IDPN: n = 40

Patient SurvivalPatient Survival

FineSFineS

0 200 400 600 Days

0.00

0.25

0.50

0.75

1.00

Logrankp = 0.33

Patie

nt c

umul

ated

surv

ival

NS

l Oral versus oral and parenteral supplementation does not have any differential effect on survival and on nutritional markers in CHD patients l

Equal and adequate amounts of protein and calorie are provided in both groups

l Nutritional supplementation does improve nutritional markers l

If the targets of dietary protein and energy intake suggested by KDOQI (> 1.2 g/kg/d and > 30 kcal/kg/d, respectively) are achieved.

What are the significant observations in FINE studyWhat are the significant observations in FINE study? ?

l These data are confirmatory of the appropriateness of the KDOQI dietary protein and calorie intake guidelines.

l Nutritional interventions in general are associated with improved survival in CHD patients. l

The study did not include a no-intervention arm.

What are the significant observations in FINE studyWhat are the significant observations in FINE study? ?

UremicUremic Protein Energy Wasting SyndromeProtein Energy Wasting Syndrome

The etiology of Uremic Protein Energy Wasting Syndrome is multi-factorial (as in most chronic disease states)

dietary intake + HD-associated catabolism + Inflammation + Insulin resistance -> wasting in CHD patients ->

mortality and morbidity

Nutritional Interventions -> convenient and safe; IDPN and Oral supplements can partially reverse the HD-induced catabolism (primarily by

replenishing the amino acid pool)

Nutritional Interventions -> Potentially can save lives and lead to significant cost savings