ISN Mission: Advancing the diagnosis, treatment and prevention of kidney diseases in the developing and developed world

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1 ISN Mission: Advancing the diagnosis, treatment and prevention of kidney diseases in the developing and developed world

2 Nutrition in Kidney Disease: How to Apply Guidelines to Clinical Practice? T. Alp Ikizler, MD Catherine McLaughlin-Hakim Professor, Medicine Vanderbilt University Medical Center

3 Outline Epidemiology Dietary Protein Intake Metabolic Derangements in CKD Nutritional Support in ESRD

4 Rate of CV Events Rates of Death and CV Events in Patients According to GFR < <15 egfr (ml/min/1.73 m 2 ) Rate of Death From Any Cause* 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:

5 The death rate of chronic dialysis patients is unacceptably high

6 Complications of CKD and Progression to ESRD CKD Continuum Increasing Severity of Complications CKD Anemia Secondary hyperparathyroidism Dyslipidemia Hypoalbuminemia, malnutrition CVD Uremic Syndrome ESRD GFR (ml/min/1.73 m 2 ) 6

7 Uremic Ultrafiltrate Inhibits Nutrient Intake Modified from Anderstam, Mamoun & Bergstrom JASN 1996

8 Dietary Protein Intake During Progression of Renal Disease Ikizler JASN 1995

9 Protein and Amino Acid Turnover and Waste Products Diet Protein 70 g/d Plasma Proteins 0.5 kg Free Amino Acid Pool 62 g kg g/kg/d Cell Proteins (5.8 kg) Ribosome Amino Proteins Acids Nitrogen Excretion 11.2 g N/d Mitch and Ikizler Handbook of Nutrition in CKD

10 Rationale 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 11

12 Mean effect: 0.53 ml/min/yr (95% CI, 0.08 to 0.98 ml/min/yr) 12

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14 Dietary 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.

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16 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

17 Oxidative Stress and Mortality in CKD 100 DMA 16/C16:0 > median 100 Cumulative Survival (%) p < 0.02 DMA 16/C16:0 < median Cumulative Survival (%) Vitamin C >60pmol/L Vitamin C 32 to 60pmol/L Vitamin C <32 pmol/l Observation Time (days) Stenvinkel et al, NDT 19(4): , 976, p = Follow-up Time (months) Deicher, JASN 16: , 1818, 2005

18 A Proposed Mechanism for Uremia- Induced CVD Risk

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

20 Tocopherols and Alpha Lipoic Acid Therapy (TALAT) in CKD Trial H 3 C CH 3 O O HO S S OH l l l l l Randomized, double-blind, placebo-controlled trial N = 80 Stage 3-4 CKD patients Tocopherols + -lipoic acid vs. placebo x 8 weeks Primary endpoint, change in F2-isoprostanes Secondary endpoints Inflammatory biomarkers Insulin resistance Endothelial dysfunction Ramos et al JRN 2010

21 Tocopherols and Alpha Lipoic Acid Therapy (TALAT) in CKD Trial Tocopherols + ALA (N = 29) Placebo (N = 30) Age (yrs) 59.3 ± ± 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/m 2 ) 31.9 ± ± 7.7 egfr (ml/min) 38.1 ± ± 14.8 Ramos et al JRN 2010

22 TALAT in CKD Trial F 2 -isoprostane F2-Iso F2-Isoprostanes Baseline Month2 0 Placebo VitE/ALA Ramos et al JRN 2010

23 TALAT in CKD Trial F 2 -isoprostane CRP CRP Placebo VitE/ALA Baseline Month2 Ramos et al JRN 2010

25 Multivariable Regression Model for Predictors for Elevated Plasma F 2 - Isoprostanes Variable Coefficient P-value 95% Confidence Interval Age Gender < Race Diabetes Smoking History Estimated GFR Total Cholesterol 1.35 x Serum Albumin BMI Dependent Variable: Plasma F2-Isoprostanes (log 10 transformed) R2 for Model: 0.229

26 Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2007 (*BMI 30, or about 30 lbs. overweight for 5 4 person) >300,000 deaths attributed to obesity No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

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29 Janus: the god of gates, doors, doorways, beginnings and endings. TRANSITION TO ESRD

30 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 n Risk of death Pneumonia

31 Metabolic Paradigm for Uremic Wasting & Potential Targetes for Intervention O Sullivan, AJ, JJ Kelley. Kidney International 2007(71);

32 Schematic representation of causes and manifestations of PEW in Kidney Disease ISRNM Position Paper - Kidney International

33 Protein Balance in Humans Protein synthesis Protein Breakdown n Growth Synthesis>Breakdown n Wasting Breakdown>Synthesis n Strategy: Maximize protein synthesis Minimize protein breakdown

34 IDPN and IDPO lead to significantly higher Whole-Body Protein Anabolism * P<0.05 versus Control, # P<0.05 versus PO

35 * Serum albumin (g/dl) SGA score months Baseline 3-Month 6-Month N=85 N=68 N=61 N=49 N=48 N=42 N=39 N=85 N=49 N=39 Caglar, Hakim, Ikizler Kidney Int, 2002

37 AJKD 2005

38 FineS The French Intradialytic Nutrition Evaluation study (FineS) Malnourished MHD patients 182 patients Oral suppl during one year Oral suppl + IDPN during one year Follow-up: two years (treatment period + one year) Visits at day 0 and month 3, 6, 12, 18 and 24

39 FineS Nutritional therapies Oral supplement: 5.4 kcal/kg/d 0.42 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 emulsion 50% glucose

40 Results: Nutritional status Serum albumin, g/l NS Months Serum prealbumin, mg/l NS Months Control group IDPN group FineS

41 Patient Survival 1.00 Patient cumulated survival Logrank p = 0.33 NS Days Mean cumulative survival: 77% at 1 yr, 58% at 2 yr Death: Control: n = 36, IDPN: n = 40 FineS

42 What are the significant observations in FINE study? 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.

43 What 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.

44 Uremic Protein 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

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