Concept: Result: Clinical Manifestations* Interruption in source. Reduction in body storage. Impairments in biochemical functioning

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1 COI: Clinical Advisory Board for Nephroceuticals, Inc Alison Steiber, PhD, RD, LD Department of Nutrition Case Western Reserve University Cleveland, OH Concept: A primary deficiency refers to a lack or relative lack of the particular vitamin in the diet Secondary deficiency refers to the vitamin or mineral being available in the diet but a secondary reason is causing insufficiency Interruption in source Reduction in body storage Impairments in biochemical functioning Alteration in function/morphology Result: Clinical Manifestations* *Clinical manifestations target every organ

2 Primary observation: Nutrient supply Supplements Quantitative determination -food, beverages, supplements -OTC & RX drugs Determine: too little, too much, Should be adequate? Are there secondary factors to consider? Health/medical History, socio-economic issues, etc, etc Concomitant considerations: increased need, loss decreased availability decreased absorption Functional decline Altered growth Altered development Fatigue, physical signs Clinical evaluation: Physical exam Body composition Symptoms Labs Integration 1.Interpret the data: (combine information from) a. primary observations, b. intake Information, c. secondary considerations, d. laboratory information, e. clinical evaluation f. medical/health history Sore, painful, red mouth Tongue abnormalities. Potential Etiologies? Nutrient Deficit: B-complex, Iron Infections Local Irritants Dryness of mouth = xerostomia

3 Determining nutrient reserve status: stable, increased, decreased Consider: plasma, tissues Quantitative analysis of Blood, urine, tissues, Vitamin/metabolites Observe gradual alteration in levels? Stability of plasma, urine levels, etc Any changes in metabolic Pre-Clinical Quantitative analysis functioning? findings of enzyme activity functional parameters Interruption in source Reduction in body storage Impairments in biochemical functioning Where is individual in the spectrum of Status determination? Satisfactory frank deficiency Alteration in function/morphology Result: Clinical Manifestations* *Clinical manifestations target every organ Confirm diagnosis Determine intervention strategies: socio-cultural, economic, medical Monitor outcomes (aka trends/changes) Factors influencing vitamin need

4 Vitamin Vitamin B12: Vitamin A: Thiamin & Biotin: D,E,K, C : Folate : Mean length of reserves 3-5 years 1 2 years 4-10 days 2 to 6 weeks 3 to 4 months Source: Modern Nutrition in Health & Disease, most recent edition Little evidence to support practice Some epidemiological studies Some small & medium clinical trials No large RCT in CKD population, except in relation to homocysteine Practice guidelines KDOQI no information ESPEN small amount of data CARI small amount of data No one is the expert Due to the lack of data and knowledge in basic vitamin/mineral metabolism Healthcare team is hesitant to make recommendations RDs have the most comprehensive training and knowledge base to be the experts in this area Stage of CKD Diet Low protein vs very low protein Strict potassium/phosphorus restritictions Dialysis Treatment CAPD vs HD HD membrane type Medications E.g. contraceptives or penicillamine and B6

5 Guidelines Thiamin (B1) mg/day Riboflavin (B2) mg/day Niacin mg/day Pyridoxine (B6) mg/day Cobalamin (B12) µg/day Folate µg/day Vitamin C mg/day DRI Age>50 F=1.1 M=1.2 F=1.1 M=1.3 F=14 M=16 F=1.5 M=1.7 F=2.4 M=2.4 F=400 M=400 F=75 M=90 CARI * 1-2* NR 5* NR 200** <60 KDOQI NR NR NR NR NR NR NR ESPEN NR NR NR 5 NR NR Kopple Textbook mg DRI = dietary reference intakes, CARI = Caring for Australians with Renal Insufficiency, KDOQI = Kidney Disease Outcome Quality Initiative, ESPEN = European Society of Parenteral and Enteral Nutrition, EDTA = European Dialysis and Transplant Association, NR= no recommendation for supplementation * Patients on protein restricted diets should be supplemented to this level **Pre-dialysis patients supplemented with erythropoietin may need supplementation Thiamin CKD NDD patients (n=14) plasma concentrations were lower compared to those patients receiving dialysis(n=24) [64.2nmol/l vs 78.3nmol/l] Frank et al In J of Vit Nutr Research, 2000 Healthy controls not measured in this study Oral intake higher for CKD-NDD than those on dialysis ETK-AC was (an ETK-AC no deficiency is <1.20) Wernicke s Encephalopathy in NS patient Nishida M, et al, Eur J Pediatr, 2000 B1 supplement reversed symptoms Conclusion? Oral intake of DRI may not be sufficient to meet biological need for CKD patients, need to assess for deficiency routinely. Recommended biological assessment = erythrocyte transketolase activity (ETKA) Riboflavin 8% of CKD-NDD patients, regardless of whether they are on a low protein diet, had inadequate riboflavin status (high α- EGR) Porrini et al. Int J Vitam Nutr Res Patients placed on lower protein diets had increase rates of ribolflavin deficiencies 1.0 g pro/kg/day = 25% deficient and 0.6 g/kg/day = 41% deficient Comparison between hospital pts with heart failure vs healthy volunteers Keith et al JADA, Aug 2009 Prevalence of riboflavin deficiency was significantly higher in heart failure patients than in health volunteers (27% vs 2.2%, p<0.001) Given the data that does exist & the high prevalence of heart failure in CKD, regular assessment of riboflavin status is warranted, esp. on patients with low & very low protein diets Recc. biological assessment: Erythrocyte glutathione reductase activity coefficient = α-egr

6 Niacin No data in CKD Ramirez et al 1986 found normal whole blood & red cell concentrations in HD pts Primary source: meat, fish, legumes, coffee and tea Suggest intake could be low in CKD-NDD patients on very low protein diets = assessment warranted Novel use of niacin involves the inhibition of Na-Pi 2a and 2b co-transporters in both the GI tract and the renal proximal tubules Use of large doses of niacin may increase excretion of P in urine & prevent absorption via the GI tract B-6 pyridoxal, pyridoxine, pyridoxamine Dietary intake of B-6 was found to be lower than the DRI in CKD-NDD (stage 4 & 5) kopple et al Kid International, 1981 Erythrocyte gluctamic pyruvic transaminase stimulation index or (EGPT) increased as the serum creatinine increased kopple et al Kid International, 1981 CKD stages 3 & 4 = EGPT index of 1.23 ± 0.09 (SD) CKD stages 4 & 5 = EGPT index of 1.30 ± 0.11 Hemodialysis = EGPT of 1.44 ± 0.39 Suggest reduced intake and higher activity levels warrant assessment and subsequent supplementation Suggest 5 mg/day Folic Acid No consistent evidence to indicate deficiency; However, primary food sources are legumes, orange juice, greens including spinach, broccoli, beets, artichokes, and enriched grains. Suggest intake may be low in those on a VLPD or phosphate restriction assessment warranted Recommended biological assessment: serum, plasma, or red-cell folate concentrations

7 Jamison, JAMA, 2009 House et al, JAMA, 2010 House et al, JAMA, 2010

8 Bottom line: *diet alone intake <100% of RDA/AI *with nutrition support >100% *plasma values wnl Don et al, JREN, 2010 Vitamin C: No consistent data in CKD-NDD demonstrate deficiency Suggest patients on potassium restrictions may have low vitamin C intake High intake has been associated with increased oxalate concentrations Recommended biological assessment: plasma and leukocyte ascorbic acid concentrations Singer et al, Nephrology, 2008

9 Singer et al, Nephrology, 2008 Meta- Analysis in Dialysis Patients - Improved Hgb with Vitamin C Treatment Devedet al AJKD, clinical trials = 125 patients Meta- Analysis in Dialysis Patients - Decrease ESA with Vitamin C Treatment Devedet al AJKD, clinical trials = 303 patients

10 Guidelines DRI Age>50 Vitamin A µgm/day F = 700 M = 900 Vitamin E mg/day F=15 M=15 Vitamin K µg/day F=90 M=120 Vitamin D IU F=400 M=400 (>70ys =600) CARI NR NR NR KDOQI NR NR NR ESPEN NR NR NR Kopple Textbook None IU None DRI = dietary reference intakes, CARI = Caring for Australians with Renal Insufficiency, KDOQI = Kidney Disease Outcome Quality Initiative, ESPEN = European Society of Parenteral and Enteral Nutrition, EDTA = European Dialysis and Transplant Association, NR= no recommendation for supplementation * Patients on protein restricted diets should be supplemented to this level **Pre-dialysis patients supplemented with erythropoietin may need supplementation Vitamin A May be increased or altered in CKD patients Supplementation is not warranted Vitamin E Concentrations not different between CKD-NDD and healthy population Karamouzis et al, Am J Nephrology, 2008 Patients with mild-moderate CKD (approx. stage 3 CKD) & increased risk for CVD were given 400 IU/day of vitamin E = HOPE trial. Results = increased incidence of heart failure, heart failure-related hospitalizations, & all-cause mortality (hazard ratio 1.13; 95% CI , P=0.4). This increased risk was associated with vitamin E intakes as low as 150 IU/day (136 mg/d).

11 Vitamin K Hospitalized patients with extended prothrombin times, one third had CKD Alperin. JAMA, 1987 Holden et al (cjason, 2010) found varying degrees of vitamin K deficiency in CKD patients stages 3-5 Serum phylloquinone = 6% %ucoc = 60% PIVKA-II = 97% Vitamin K status was associated with dietary intake of vitamin K, stage of CKD, PTH and inflammation (CRP) Vitamin D Term Sterol Type of vitamin D Vitamin D Cholecalciferol Ergocalciferol D3 D2 25-Hydroxyvitamin D Calcidiol (25(OH)D3) Ercalcidol (25(OH)D2) D3 D2 Vitamin D receptor agonist prohormone (a) Alfacalcidol (1(OH)D3) Doxercalciferol (1(OH)D2) D3; synthetic prohormone D2; synthetic prohormone Vitamin D receptor agonist Calcitriol (1, 25(OH)2D3 Paricalcitol (19nor,1,25(OH)2D2) Maxacalcitol (22oxa,1,25(OH)2D3) D3; Natural analog D2; synthetic analog D3; synthetic analog Sprague and Coyne, JASON, 2010 Ergosterol radiation D2 (available in pharmacological doses) Transformation in skin or from oily fish/cod liver oil D3 (not available in the USA pharmacological doses) Liver Metabolized to 25(OH)D Kidney Metabolized to 1, 25 (OH)2D via the 1-ά-hydroxylase

12 Ergosterol High radiation P alters PTH gland sensitivity to Ca, thus lowering the threshold of Ca D2 needed to (available in simulate PTH pharmacological production doses) PTH production + Transformation in skin or from oily fish/cod liver oil D3 (not available in pharmacological doses) Phosphorus Liver Metabolized to 25(OH)D Calcium concentrations - + Kidney Metabolized to 1, 25 (OH)2D via the 1-ά-hydroxylase Activity of 1-ά- hydroxylase enzyme is low in CKD due to: Low renal mass leading to loss in the of the enzyme in the proximal tubules Phosphate retention (inhibits activity) Cause of P retention old paradigm vs new paradigm Secreted by osteoblasts and osteolclasts Acts on renal proximal tubules to: Increase urinary P excretion Decrease 1, 25 (OH) 2D levels by inhibiting 1-άhydroxylase (builds D) & stimulating hydroxylase (breaks D down) Increases production when P increases 1, 25(OH)2D increases

13 OLD P PARADIGM Nephron Mass Phosphate clearance NEW P PARADIGM Nephron Mass Phosphate Clearance Ca Phosphate (-) 1-ά-hydroxylase 1, 25 (OH)2D PTH (early CKD) FGF23 Phosphate 1, 25 (OH)2D Ca PTH (-) 1-άhydroxylase (late CKD) PTH 25(OH)D 1, 25 (OH)D Craver, NDT, 2007 Guidelines Copper µg/day Magnesium mg/day Zinc mg/day Selenium µg/day DRI Age>50 F=900 M=900 F=320 M=420 F=8 M=11 F=55 M=55 CARI NR NR NR KDOQI NR NR NR NR ESPEN NR NR *** *** DRI = dietary reference intakes, CARI = Caring for Australians with Renal Insufficiency, KDOQI = Kidney Disease Outcome Quality Initiative, ESPEN = European Society of Parenteral and Enteral Nutrition, EDTA = European Dialysis and Transplant Association, NR= no recommendation for supplementation * Patients on protein restricted diets should be supplemented to this level **Pre-dialysis patients supplemented with erythropoietin may need supplementation *** Concentrations may be low in patients with CKD patients but no supplementation level was recommended

14 Reduced renal function Protein-urea leading to losses of proteinbound elements Alterations in GI absorption because of alterations in Vit D metabolism Zn, Cu, Se decrease plasma [ ] by stage of CKD D Haese et al, Clin Chem, 1999; Yilmaz et al AJKD,2005; Copper Decreased plasma and erythrocyte [ ] found in children with CRF Zwolinska et al. Ped Nephrol Decreased concentrations as kidney disease progressed by CKD stage Yilmaz et al. AJKD Control group (healthy adults) = CKD Stage 1 mean erythrocyte copper [ ] = CKD Stage 5 NDD mean erythrocyte copper [ ] = Magnesium Some reports of patient with both hypercalcuria & nephrocalcinosis and hypomagnesemia Benigo et al NDT 2000 Characterized by: Low serum magnesium Normal to high urinary magnesium High urinary calcium Normal plasma calcium, potassium, & ph balance Insufficient data to make recommendations in CKD pts

15 Selenium Whole blood and plasma [ ] were found to be low in CKD pts Zachara et al. Biological trace element research. 2004; Yilmaz et al. AJKD Glutathione peroxidase activity - 37% lower in CKD pts than in healthy controls Zachara et al. Biological trace element research Glutathione peroxidase activity declined by CKD stage Yilmaz et al. AJKD After supplementation w/ 200mcg Se Marked increases in red cell and whole blood Se Increase Glutathione Peroxidase activity by 15% Zinc Tissue concentrations: Smythe et al = no difference b/t healthy controls & CKD Plasma Zinc concentrations: Decreased plasma concentrations in CKD McGregor et al. KI Stepwise reduction in erythrocyte zinc levels with advancing stages of CKD Yilmaz et al. AJKD Zinc supplementation may be necessary in VLPD Piper et al. JADA DOPPS Study 16,345 patients randomly selected from 308 HD units in US, Japan, 5 European countries 72% of US patient were prescribed water-soluble vitamins Europe ranged from Spain at 37.9% to 6.4% in Italy In the majority of Japanese units no water-soluble vitamin prescription was recorded Andreucci et al, AJKD, 2004

16 Patients taking water-soluble vitamins had 16% mortality risk than patients not taking vitamins Adjusted for age, sex, race, co-morbid conditions, hemoglobin, serum albumin, body mass index, time on dialysis, ave. facility singlepool Kt/V and NPCR Andreucci et al, AJKD, 2004 Domrose et al, Clin Nephrology, 2007 No MVI MVI Domrose et al, Clin Nephrology, 2007

17 Lower death rate on MVI Domrose et al, Clin Nephrology, 2007 Stockler-Pinto et al, Nutrition, 2009

18 Vitamin & mineral status in CKD patients may be altered Treatment may improve outcomes including mortality rates Goal to detect sub-optimal status at an early stage to prevent overt clinical demise Using dietary intake to assess status is only the first step, but VERY imprecise!! Use physical exam, SGA, body comp measures Biochemical indicators helpful to assess status with increased reliability