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 how it is managed? What is the biological mechanism(s) that is disturbed in this specific disease state and how does it lead to the special nutritional requirement? What is the evidence that there is a nutritional requirement that is different from that of the healthy population? Is the disease state (or nutrition status or health related outcomes) responsive to a specific nutritional intervention in a dose dependent manner? What are the gaps in information? Are there pressing research issues?
Nutrition and Chronic Kidney Disease What is the disease itself and how it is managed? Appr. 20M individuals with CKD Appr. 500,000 patients on maintenance dialysis Apprx. 125,000 incident ESRD patients Approx. 60,000 new transplants a year Approx. 4-5% of all Medicare expenses What is the biological mechanism(s) that is disturbed in this specific disease state and how does it lead to the special nutritional requirement?
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;52:66-73. 2. Campbell KL, et al. Clin Nutr. 2008;27:537-544.
PEW is present in 30 to 65% or more of maintenance dialysis patients around the world Hemodialysis patients, USA, 47% (MIS) Hemodialysis patients, Sweden: 30 to 43% (SGA) Netherlands: 28% (SGA) Peritoneal dialysis patients, China 29 to 44% (SGA) 60% (MIS) Peritoneal dialysis patients, Brazil, 36 to 65% (SGA) Peritoneal dialysis patients, Korea, 40% (SGA) Adapted from TNT Renal
Simplified flow schedule of uremia and its complications Slide courtesy of Peter Stenvinkel
Etiology and Consequences of Protein Energy Wasting in CKD Loss of Kidney Function Uremic Toxins 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
Nutrition and Chronic Kidney Disease What is the disease itself and how it is managed? What is the biological mechanism(s) that is disturbed in this specific disease state and how does it lead to the special nutritional requirement? What is the evidence that there is a nutritional requirement that is different from that of the healthy population?
Summary of Requirements Non-dialysis CKD Haemodialysis Peritoneal Dialysis Energy 30-35 kcal/kg/day 35 kcal/kg/day 35 kcal/kg/day Incl kcal from dialysate Protein 0.6-0.8 g/kg/day Illness 1.0g/kg >1.2 g/kg/day >1.2 g/kg/day Peritonitis >1.5 g/kg Sodium 80-100 mmol/day 80-100 mmol/day 80-100 mmol/day Potassium <1mmol/kg If elevated <1mmol/kg If elevated Not usually an issue Phosphorus 800-1000mg & binders if elevated 800-1000mg & binders if elevated 800-1000mg & binders if elevated NKF/KDOQI 2000 & 2002; Fouque et al NDT (2007) 22(Supp 2);pp45-87; Cano et al Clin Nutr (2006) 25;pp295-310:
Considerations for Nutritional Requirements in Chronic Kidney Disease Protein intake CKD - Progression ESRD - Protein wasting Calorie intake CKD - Obesity; Insulin Resistance; Diabetes Mellitus ESRD - Wasting-Obesity Paradox Common Derangements in CKD and ESRD Na/K/PO4 (HTN; Hyperkalemia; Bone Mineral Disorders) Metabolic Disorders (Inflammation; Oxidative Stress)
Etiology and Consequences of Protein Energy Wasting in CKD Loss of Kidney Function Uremic Toxins 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
Appetite decreases as CKD progresses Starts when egfr <10-25% of normal Retention of uremic toxins suppress appetite Initiation of dialysis improves feeding behavior Appetite egfr egfr egfr egfr <90 ml/min<60 ml/min<30 ml/min <15 ml/min Dialysis begins Carrero JJ. J Ren Nutr. 2009;19:10-15.
Uremic Toxins Mitch and Ikizler Handbook of Nutrition and The Kidney 13
Significant Amount of Amino Acids are Lost Into Dialysate during Dialysis 12 10 total g/dialysis 8 6 4 2 0 CU PMMA PS PD/Day Ikizler & Hakim 1994 Kidney Int
Hemodialysis Causes Net Whole-body Protein Loss proteolysis synthesis net balance 4.5 3.5 2.5 1.5 0.5-0.5-1.5 PreHD HD PostHD Ikizler et al, AJP, 2002
Hemodialysis Activates Inflammatory Signals IL-6 (pg/ml) Fibrinogen FSR (%/day) 25 20 15 10 5 0 * δ * δ * 58% 68% 14% 34% PreHD B HD D PostHD PD Caglar, Pupim, Ikizler, KI, 2002
IL-6 Predicts Poor Outcome in ESRD Bologa et al. AJKD 1998 NDT 2002 NDT 2004 AJKD 2005 JASN 2006
Metabolic Effects of Inflammation MUSCLE LOSS ANOREXIA COMPLEMENT ACTIVATION INFLAMMATION UREMIA INCREASED REE FEVER APP SYNTHESIS INCREASED SNS ACTIVITY IMMUNE SYSTEM MODULATION
Distribution of Skeletal Muscle Protein Turnover Components by hs-crp Quintiles p<0.001 p<0.001 p<0.001 hs-crp QUINTILES hs-crp QUINTILES hs-crp QUINTILES Deger et al, JCI insight 2018
Nutrition and Chronic Kidney Disease What is the disease itself and how it is managed? What is the biological mechanism(s) that is disturbed in this specific disease state and how does it lead to the special nutritional requirement? What is the evidence that there is a nutritional requirement that is different from that of the healthy population? Is the disease state (or nutrition status or health related outcomes) responsive to a specific nutritional intervention in a dose dependent manner?
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
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Intradialytic Nutrition (Oral or Parenteral) Leads to Robust Whole-Body Protein Anabolism * P<0.05 versus Control, # P<0.05 versus PO
Oral nutrition supplementation provides benefits for HD or PD patients Hemodialysis and peritoneal patients using ONS experience: Increased calorie and protein intake Improved serum albumin, serum prealbumin levels Improved nutritional status (SGA) Increased body weight or BMI Increased lean body mass and bone density Improved physical function (grip strength) Improved quality of life and mental health scores Over the past 3 decades, 10 studies have shown outcome benefits of ONS therapy for CKD patients on dialysis Ikizler TA, et al. Kidney Int. 2013;84:1096-1107. TNT Renal Session 7 24
Insulin Sensitivity and Muscle Metabolism
Mitochondrial Morphology and Function in ESRD Mitochondrial volume density (%) A. 6 5 4 3 p=0.002 Frequency distribution (%) B. 20 15 10 5 Control ESRD Control ESRD 0 0 5 10 Mitochondrial volumen density (%) Gamboa et al, 2017 Physiology Reports
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
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)
Summary of Requirements Non-dialysis CKD Haemodialysis Peritoneal Dialysis Energy 30-35 kcal/kg/day 35 kcal/kg/day 35 kcal/kg/day Incl kcal from dialysate Protein 0.6-0.8 g/kg/day Illness 1.0g/kg >1.2 g/kg/day >1.2 g/kg/day Peritonitis >1.5 g/kg Sodium 80-100 mmol/day 80-100 mmol/day 80-100 mmol/day Potassium <1mmol/kg If elevated <1mmol/kg If elevated Not usually an issue Phosphorus 800-1000mg & binders if elevated 800-1000mg & binders if elevated 800-1000mg & binders if elevated NKF/KDOQI 2000 & 2002; Fouque et al NDT (2007) 22(Supp 2);pp45-87; Cano et al Clin Nutr (2006) 25;pp295-310:
Nutrition and Chronic Kidney Disease What are the gaps in information? Are there pressing research issues? Specific role of uremic toxins? Human microbiome Better dialysis? Optimal level of supplementation? Abnormal metabolic fate? Role of anabolic or anti-catabolic strategies Obesity in the setting of chronic kidney disease
VUMC Nephrology Clinical Research Group Funding/Other Support NIH/NIDDK/NHLBI/NIEHS RCG/FMC/Abbott/Baxter NKF/AKF/ASN/ISRNM SatelliteHealth grant program Vanderbilt Clinical and Translational Research Award