ISN Mission: Advancing the diagnosis, treatment and prevention of kidney diseases in the developing and developed world
Nutrition in Kidney Disease: How to Apply Guidelines to 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
Rate of CV Events 40 35 30 25 20 15 10 5 0 Rates of Death and CV Events in Patients According to GFR 14.4 36.60 14 11.36 12 10 21.80 8 6 4.76 11.29 4 3.65 0.76 1.08 2.11 2 0 60 45-59 30-44 15-29 <15 60 45-59 30-44 15-29 <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;351:1296-1305.
The death rate of chronic dialysis patients is unacceptably high
Complications of CKD and Progression to ESRD CKD Continuum Increasing Severity of Complications CKD Anemia Secondary hyperparathyroidism Dyslipidemia Hypoalbuminemia, malnutrition CVD Uremic Syndrome ESRD 60 40 25 15 5 GFR (ml/min/1.73 m 2 ) 6
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 Products Diet Protein 70 g/d Plasma Proteins 0.5 kg Free Amino Acid Pool 62 g kg 3.7 4.7 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
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
Progression - mgfr Progression Renal Death Study 1: 585 patients Study 2: 255 patients 11
Mean effect: 0.53 ml/min/yr (95% CI, 0.08 to 0.98 ml/min/yr) 12
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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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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
Oxidative Stress and Mortality in CKD 100 DMA 16/C16:0 > median 100 Cumulative Survival (%) 80 60 40 20 p < 0.02 DMA 16/C16:0 < median Cumulative Survival (%) 80 60 40 20 Vitamin C >60pmol/L Vitamin C 32 to 60pmol/L Vitamin C <32 pmol/l 0 0 500 1000 1500 2000 2500 3000 3500 Observation Time (days) Stenvinkel et al, NDT 19(4): 972-976, 976, 2004 0 p = 0.014 0 5 10 15 20 25 30 Follow-up Time (months) Deicher, JASN 16: 1811-1818, 1818, 2005
A Proposed Mechanism for Uremia- Induced CVD Risk
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 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
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/m 2 ) 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 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 Ramos et al JRN 2010
TALAT in CKD Trial F 2 -isoprostane CRP CRP 35 30 25 20 15 10 5 0 Placebo VitE/ALA Baseline Month2 Ramos et al JRN 2010
Multivariable Regression Model for Predictors for Elevated Plasma F 2 - Isoprostanes Variable Coefficient P-value 95% Confidence Interval Age 0.001 0.500-0.002 0.004 Gender 0.135 < 0.001 0.064 0.206 Race -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 0.130 Estimated 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 0.045 BMI 0.008 0.001 0.003 0.012 Dependent Variable: Plasma F2-Isoprostanes (log 10 transformed) R2 for Model: 0.229
Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2007 (*BMI 30, or about 30 lbs. overweight for 5 4 person) 1990 1998 2007 >300,000 deaths attributed to obesity No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%
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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 n Risk of death 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 PEW in Kidney Disease ISRNM Position Paper - Kidney International
Protein Balance in Humans Protein synthesis Protein Breakdown n Growth Synthesis>Breakdown n Wasting Breakdown>Synthesis n Strategy: Maximize protein synthesis Minimize protein breakdown
IDPN and IDPO lead to significantly higher Whole-Body Protein Anabolism * P<0.05 versus Control, # P<0.05 versus PO
4.5 7 6.5 6 * Serum albumin (g/dl) 4 3.5 3 2.5 SGA score 5.5 5 4.5 4 3.5 3 2.5 2 months 0 1 2 3 4 5 6 2 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
AJKD 2005
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
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
Results: Nutritional status Serum albumin, g/l 34 34 33 32 31 30 NS 0 6 12 18 24 Months Serum prealbumin, mg/l 300 280 260 240 220 200 NS 0 6 12 18 24 Months Control group IDPN group FineS
Patient Survival 1.00 Patient cumulated survival 0.75 0.50 0.25 0.00 Logrank p = 0.33 NS 0 200 400 600 Days Mean cumulative survival: 77% at 1 yr, 58% at 2 yr Death: Control: n = 36, IDPN: n = 40 FineS
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.
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.
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