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Anita Saxena1, J. Kothari2, M Gokulnath3,

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1 Anita Saxena1, J. Kothari2, M Gokulnath3,
An Open Label Randomized Clinical Study To Evaluate The Impact Of Protein Supplement On Serum Albumin In Patients On Maintenance Dialysis (IMPROVES Trial) Protocol No PBL/PROS/07-11 Anita Saxena1, J. Kothari2, M Gokulnath3, Amit Gupta1, Juan Jesus Carrero4 , Kam Kalantar Zadeh5,CM Pandey1 and Jai Kishun1. 1Nephrology, Sanjay Gandhi Post Graduate Institute Of Medical Sciences, Lucknow, Uttar Pradesh, India; 2Nephrology, Hinduja Hospital, Mumbai, India; 3Nephrology, St John's Medical College, Bangalore, India, 4Renal Medicine, Karolinska Institutet, Stockholm Sweden, 5University of California Irvine School of Medicine and UCLA School of PublicHealth.

2 Introduction Dialysis is a hypercatabolic procedure which impacts nutritional status and survival. The protein loss induced by the HD treatment can contribute to the protein energy malnutrition. Patients undergoing dialysis frequently suffer from both malnutrition and cachexia from the very early stages of the initiation of dialysis. Cachexia is characterised by defective food assimilation or utilization in the presence of hypercatabolism and systemic inflammation

3 Malnutrition Malnutrition Imbalance Nutrient Intake
Cachexia: defective food assimilation or utilization in the presence of hypercatabolism and systemic inflammation. Protein energy malnutrition develops during the course of chronic kidney disease and is associated with adverse outcomes. Imbalance Nutrient Requirement Malnutrition Disease Nutrient Intake Low protein and calorie intake is an important cause of malnutrition in chronic kidney disease.

4 Uremic Anorexia And Dysgeusia
Malnutrition is reportedly present in 18%-75% of the maintenance dialysis patients. Uremic anorexia and dysgeusia lead to inadequate protein and calorie intake, in turn resulting in malnutrition and adverse outcomes.

5 Various factors contribute to the development of altered nutritional states in dialysis patients

6 Malnutrition is Multifactorial In CKD Resistance to anabolic
Anorexia Loss of taste Unpalatable diets Loss of Nutrients & Water soluble Vitamin in Dialysate Uremic toxicity Premature Ageing Of Dialysis Patients Dietary protein & energy intake Inadequate Dialysis dose Emotional Distress Malnutrition Anemia loss of blood due to GI bleed, frequent blood sampling Inflammation Infection Superimposed illness Increased Mortality And Morbidity Declining Residual Renal Function Presence of Comorbidity level of counter regulatory hormones Glucagon, PTH Hormonal disorders Resistance to anabolic hormones Metabolic Acidosis

7 Most patients on dialysis have a lower than normal dietary energy and protein intake.
It is estimated that 50%-70% of malnutrition cases are related to inadequate dietary intake. Judith A Beto etal Strategies to promote adherence to nutritional advice in patients with chronic kidney disease: a narrative review and commentary Int J Nephrol Renovasc Dis. 2016; 9: 21–33.

8 CANUSA Study NDT1998; 13 (Suppl 6):158–63.
Relative risk of death increases with 1. Lower serum albumin and 2. Worse nutritional status as assessed by SGA and %LBM Low serum albumin level is associated with technique failure, increased rate of hospitalization and mortality.

9 When Patient Is On Maintenance Dialysis
From metabolic point of view, each dialysis session decreases plasma amino acid levels and as a consequence blunts intracellular protein synthesis. HD/session PD/24 hours Amino Acid 10 to 12 g –3.5 g/24h Protein to 3 g g/24h average 9g. Losses are higher during peritonitis 15g/d

10 NKF-K/DOQI Guidelines MHD Guidelines 3-4
Variable Level Half Life Limitations Predialysis or stabilized Serum Albumin ≥ 4.0g/dL ~20 days Influenced (negatively) by inflammation Tends to go down as inflammatory markers (CRP, IL-6, ferritin) go up Influenced (negatively) by albuminuria and peritoneal albumin losses – Affected by hydration status Serum Prealbumin ≥30 mg/dL ~2-3 days Low levels Inflammation & Stress Levels are increased in renal due to impaired degradation by kidneys.

11 Intervention Clinical trials on ONS for dialysis patients have shown that enteral therapy is associated with improved nutrition status. Uremia induced inadequate dietary intake leads to metabolic disturbances, PEW, cachexia, and high rate of morbidity and mortality. Hypoalbuminemia is a strong predictor of mortality among maintenance dialysis patients. Early identification of patients with eating behaviour disturbances can potentially reduce the burden of malnutrition through appropriate intervention.

12 Primary Objective To evaluate the efficacy of nutritional supplement on the nutritional status of hypoalbuminemic malnourished patients on maintenance dialysis.

13 Primary End Points For Efficacy And Safety
Increase in parameters from baseline to visit 3. Serum Albumin BMI Total body fat percent Anthropometric measurements (biceps, triceps, suprailliac and subscapular skin fold thickness mid upper arm circumference (MUAC), and waist-hip-ratio) Subjective global assessment (SGA) and Reduction in Edema

14 Decrease Blood Cholesterol : decrease in LDL, VLDL & increase in HDL
Secondary Endpoints: Biochemical Factors That Impact On Morbidity And Mortality Decrease Blood Cholesterol : decrease in LDL, VLDL & increase in HDL Blood sugar : glycosylated haemoglobin HbA1c Serum sodium, potassium and phosphorous Change Coagulation factor Decrease of C- reactive protein

15 Material And Methods Multicenter randomized intervention on maintenance dialysis (MD) patients. Approved by institute’s ethics committee. Duration of supplementation : 6 months 3 centers Sanjay Gandhi Post Graduate Institute Of Medical Sciences, Lucknow. Hinduja Hospital, Mumbai St John's Medical College, Bangalore

16 Criteria For Selection Of Patients
. Inclusion Criteria Exclusion Criteria Patient willing to sign informed consent form. Patients above the age of 18 years . Clinical PEW as per ISRNM criteria. Serum albumin < 3.8g/100ml Patients on maintenance dialysis for at least 3 months. Adequately dialyzed as per investigator Absence of uremic symptoms Patients from middle to high socioeconomic group. Patients with no clinical PEW as per ISRNM criteria Patients with systemic infection like TB or Malaria. Patients on nutritional supplement or have discontinued use of ONS Plan for kidney transplantation within study period Pregnant or breast feeding females Life expectancy less than 6 month Patient changed from haemodialysis to peritoneal dialysis

17 Serum Protein Body Mass
ISRNM Clinical Criteria For Diagnosing Protein-Energy-Wasting Serum Chemistry 1. Serum albumin level <3.8 g/dL 2. Serum pre-albumin level <30 mg/dL 3. Serum cholesterol level < 100 mg/dL 1. BMI<22 kg m2 (for age >65 years), and <23 kg m2 (for age <65 years) 2. Unintentional weight loss : 5% in three months; or 10% in 6 m Total body fat percent < 10% Serum Protein Body Mass

18 ISRNM Clinical Criteria For Diagnosing Protein-Energy-Wasting
1. Muscle wasting, reduced muscle mass 5% in three m; or 10% in 6 m 2. Reduced mid-arm muscle circumference area >10 % reduction in relation to 50th percentile of reference population 3. Creatinine appearance 1. Unintentional low dietary protein intake <0.8 g/kg/d for at least 2 months for maintenance dialysis patients or <0.60 g/kg/d for patients with CKD stage 2-5 with 5 g/d of urinary protein loss. 2. Unintentional low dietary energy intake <25 kcal/kg/d for least 2 months Muscle Mass Dietary Intake

19 Study Design: Multicenter randomized intervention study.
180 patients from 3 centers 60 patients each center PD 36 and HD 144 Visit 0 Screening: Screening for Inclusion and Exclusion Criteria. Demography, Vital Signs, Income Group, Medical History Randomization 1:1 ratio Group I N =90 Group II N=90 Received 30 g of Renal specific soy based powder supplementation along with standard diet 1.2g/Kg/d Protein. Standard diet 1.2g/Kg/d protein without supplementation

20 Administration and Compliance To ONS
Soy Protein Powder was given daily in three divided doses of 10 g each. Compliance to intake of ONS ONS Tins dispensed and number of Empty tins returned on the follow-up visit.

21 Details of Visits And Evaluation
Group I Details of Visits And Evaluation Group 2 Visit 1-Baseline (30days±10days) Anthropometriy, Skin fold measure (biceps, triceps, suprailliac, and subscapular, Mid Upper Arm & waist circumference and waist hip ratio), BMI Grading (WHO), dialysis history, edema status, lab parameter, Subjective Global Assessment, Diet Calculation, QOL SF36 Anthropometry (Skin fold measure (biceps, triceps, suprailliac, and subscapular),Mid Upper Arm & waist circumference and waist hip ratio), BMI Grading (WHO), dialysis history, edema status, lab parameter, Subjective Global Assessment, Diet Calculation, QOL SF36 Administration of ONS, Compliance and Safety Visit 2: 3 Months (±5days from V1) Anthropometry, BMI Grading (WHO), Skin fold measure, dialysis history, edema status, lab parameter, Diet Calculation Anthropometriy : BMI (WHO), Skin fold measure, dialysis history, edema status, lab parameters, Diet Calculation Proseventy administration Compliance and Safety of ONS Visit Months (±5days from V2) Anthropometry, BMI Grading (WHO), Skin fold measure, dialysis history, edema status, lab parameter, Subjective Global Assessment, Diet CalculationProseventy administration, compliance, Safety,SF36 Anthropometry, BMI Grading (WHO), Skin fold measure, dialysis history, edema status, lab parameter, Subjective Global Assessment, Diet Calculation,SF36 END OF THE STUDY

22 Biochemical Tests Serum albumin Serum creatinine Blood Urea nitrogen
Random blood glucose HbA1c Sodium/Potassium Calcium/Phosphorus Lipid Profile C-reactive protein (CRP) PTH Coagulation Tests Bleeding Time Clotting Time PT aPTT Coagulation Factor IX (optional)

23 Quality of Life SF36 Questionaire
The SF-36 consists of eight scaled scores Each scale is directly transformed into a scale. The lower the score the more disability. The eight sections are: vitality physical functioning bodily pain general health perceptions physical role functioning emotional role functioning social role functioning mental health

24 Results At inclusion, no statistically significant difference in the two groups age sex dietary intake SGA CRP and biochemistry except serum albumin level.

25 Results: Biochemical Profile
Parameters Visit 1 N= N = 87 Visit 2 N= N= 69 Visit 3 N= N=58 Group1 Group2 Hemoglobin g/dL 9.8±1.8 9.6±0.7 9.8±1.71 9.6±1.8 10.0±1.6 9.5±1.56 BUN 67±35.8 74±39.6 74.2±42..4 79.0±42. 59.94±23* 87.4±.49 Serum Albumin g/dL* 3.2 ±0.41 3.37±0.35 3.3±0.47 3.4±0.4 3.9±0.48 3.3±0.51 CRP * p .016 4.2 ±6.01 8.7±8.1 4.1±9.9 4.6±7.1 4.5±6.2 6.4±14.0 HbA1c visit 1 and 3 6.0±1.21 7.1±1.41 NR N R 6.5±1.55 7.1±1.2 Serum LDL VLDL HDL 84.9±28.1 26.4±16.8 41.2±12.6 89.6±28.1 16.8±12.5 40.6±12.1 85.2±28.3 27.9±16.4 39.4±13 88.2±28 25.1±15 39±10.3 91±31.5 30.4±19.2 37±11.8 83.1±27 24.±15.7 36.4±11 Potassium 4.8±0.84 6.6±14.3 4.9±.89 5.3±.96 4.7±0.8 5.2±0.9 Phosphorus 4.6±1.17 4.7±1.5 4.5±1.2 4.7±1.6 4.76±1.51 4.6±1.55 Serum Calcium 8.1±1.27 8.2±1.2 8.3±0.85 8.4±0.68 8.2±1.3 8.3±0.75 Coagulation PT aPPT 12.8±2.1 34.2±10.5 12.8±2.5 34.0±6.9 12.7±1.8 34.5±9.9 12.4±1.9 35.5±8.0 13.4±2.02 34.8±35.8 35.8±.94 PTH 375±392 385±362 411.6±69 424±45

26 Non Dialysis Day Calorie and Protein Intake Repeated Measures ANOVA (Wilk’s Lambda) Sign. Difference between groups p 0.000 Visit 1 Visit 2 Visit 3 Supplement N=91 Control N=87 N=77 N=69 N=70 N=58 Energy* ± 397.24 ±396.72 ± 535.9 ± 408.15 ± 490.65 ± 464.82 Protein* 48.35±14.2 51.93±16.4 65.15±21.86 63.49±19.4 67.05±20.7 65.36±19.1

27 Dialysis Day Energy And Protein Intake Repeated Measures ANOVA Sign
Dialysis Day Energy And Protein Intake Repeated Measures ANOVA Sign. Difference between groups p 0.000 Visit 1 Visit 2 Visit 3 Supplement N=91 Control N=87 N=77 N=69 N=70 N=58 Energy ± 432.75 ±418.84 ± 411.56 ± 526.50 ± 445.08 ±425.93 Protein 52.9± 17.34 48.36±14.1 61.88±15.97 56.77±15.9 103.09±363.9 58.98±15.9

28 24 Hour Dietary Recall - Energy And Protein Intake Repeated Measures ANOVA Sign. Difference Between Groups p 0.000 Visit 1 Visit 2 Visit 3 Supplement N=91 Control N=87 N=77 N=69 N=70 N=58 Energy ± 429.40 ± 428.06 1571.3± 449.69 ± 552.42 ± 490.41 ± 520.73 Protein 57±19.31 59.18±23.4 53.28±17.65 51.37±17.9 61.62±22.21 59.96±19.5

29 Effect of ONS on Serum Albumin: Serum albumin significantly increased (3.3 ±0.48 vs 3.4 ±0.43) and at 6 months serum albumin was higher the controls p= 0.000 Variable Supplement N=91 Control N=87 N=77 N=69 N=70 N=58 S Albumin* 3.2 ±0.41 3.37±0.35 3.3±0.47 3.4±0.4 3.9±0.48 3.3±0.51

30 Paired Comparison using Anova Analysis Significant Difference in Albumin level at 3 and 6 months p= Higher in supplemented group The serum albumin levels increased significantly to 3.9 g/dL by 6 months in supplemented group and declined significantly in controls (2.0±0.74). 3.4±0.43 3.3±0.48

31 Change in Hemoglobin from Visit 1 to Visit 3
Parameters Visit 1 N= N = 87 Visit 2 N= N= 69 Visit 3 N= N=58 Group1 Group2 Hemoglobin g/dL 9.8±1.8 9.6±0.7 9.8±1.71 9.6±1.8 10.0±1.6 9.5±1.56

32 Effect of ONS on Biceps and Triceps Skinfold Significant Difference in visit 2 and 3 p Higher in Supplemented Group Variable Visit 1 N= 89/84 Visit 2 Visit 3 Supplement Control Biceps* 10.2±7.2 8.9 ±5.9 10.3±7.2 9.6±5.9 13.0±7.1 9.1±6.0 Triceps* 14±6.0 12.1±5.0 14.0±5.6 13.1±5.1 16.1±5.1 12.1±5.1

33 Effect of ONS On Subscapular and Suprailliac Skinfold Significant difference at visit 2 and 3 p= Higher in supplemented group Visit 1 N= 89/84 Visit 2 Visit 3 Variable Supplement Control Subscapular* 16.9±6.7 16.5±6.6 18.5±6.4 16.5±7.9 17.0±7.2 16.4±6.9 Supra Illiac* 15.9±8.7 15.2±8.6 15.1±8.4 16.0±9.4 18.1±8.7 16.8±8.7

34 SGA Score Baseline and at 6 months Lower SGA Score In Supplemented Group Better Nutritional Status Compared To Controls Variable Visit 1 N= 89/84 Visit 2 Visit 3 Supplement Control SGA Score 11±5.0 11±4.5 - 8.7±1.8 9.6±2.3 .

35 Lower CRP levels In Supplemented Group compared to Controls
Parameters Visit 1 N= N = 87 Visit 2 N= N= 73 Visit 3 N= N=90 CRP * p .016 4.2 ±6.01 8.1±8.1 4.1±9.9 4.6±7.1 4.5±6.2 6.4±14.0

36 SF36 Questionnaire: Comparison of Visit 1 and 3
Questions P values Supplemented Group p values Control Group 1 In general, would you say your health .026 0.045 2 Compared to one year ago, your health now .010 0.093 3 Vitality: limitation in movements 440 0.402 4 Problems with work or regular daily activities as a result of physical health .001 142 5 Problems with work or other regular daily activities as a result of any emotional problems .004 .243 6 Physical health or emotional problems interfered with normal social activities .005 .081 7 Bodily pain .199 .566 8 Social Role Functioning: Pain interference with work both outside the home and housework .102 .024 9 Mental Health .242 10 General health perceptions 0.554 564 11 Final Score 0.001 improved .047 Poor .

37 DISCUSSION

38 DISCUSSION Malnutrition is common in patients with chronic kidney disease (CKD) and adversely affects prognosis. Uremia induced inadequate dietary intake leads to metabolic disturbances, PEW, cachexia, and high rate of morbidity and mortality.

39 HD Treatment Is A Catabolic Event
Decreases circulating amino acids Accelerates rates of whole body and muscle proteolysis Promotes muscle release of amino acids, and Enhances net whole body and muscle protein loss and increases resting energy expenditure (REE HD patients rises from 8 to 16% ). HD patients lose their appetite and reduce their protein and energy intakes spontaneously which makes it difficult to fulfill their daily nutritional requirements and thus promote development of protein energy wasting.

40 Discussion Furthermore, relatively increased nutritional demands in many dialysis patients magnifies the effects of inadequate protein and calorie intake. The biological relationship is more complicated because of markers such as serum albumin underlying inflammation or illness, rather than poor intake alone. Siren Sezer Long-Term Oral Nutrition Supplementation Improves Outcomes in Malnourished Patients With Chronic Kidney Disease on Hemodialysis

41 Discussion The present study explored effect of renal specific nutritional supplement on hypoalbuminimic patients on maintenance dialysis. Several studies have shown positive effect of ONS on serum albumin level and nutritional status of patients on dialysis.

42 Siren Sezer Long-Term Oral Nutrition Supplementation Improves Outcomes in Malnourished Patients With Chronic Kidney Disease on Hemodialysis Journal of Parenteral and Enteral Nutrition Volume 38 Number Sezer etal conducted a similar study: 3 daily servings of ONS given for 6 months improves serum albumin and anthropometric measures, as well as reduces EPO dose, in patients with CKD.

43 Siren Sezer Long-Term Oral Nutrition Supplementation Improves Outcomes in Malnourished Patients With Chronic Kidney Disease on Hemodialysis Journal of Parenteral and Enteral Nutrition Volume 38 Number , .

44 Therapeutic Effects of Oral Nutritional Supplements during Haemodialysis : Physician’s Experience Arun B Shah Journal of the association of physicians of india • vol 62 • december, 2014 .

45 Effects of oral supplements on nutritional status in patients on peritoneal dialysis
SH Han & DH Han Nutrition in Patients on peritoneal dialysis Nature Reviews Nephrology 8, (March 2012)

46 Our Study Protein-rich renal specific nutritional supplement given daily along with standard nutritional diet of 1.2 g/kg/d raised serum albumin and increased skin fold thicknes in patients with PEW undergoing dialysis. Hemoglobin level increased in supplemented group but the difference between groups was not significant. Body composition improved significantly (p 0.003) as evident from increased of skinfold thickness in the supplemented group compared to controls. At the end of the study, patients in supplemented group showed improvement in nutritional status compared to controls.

47 Our Study The functional capability as per SGA score improved significantly in supplemented group compared to control (p=0.001). There was significant improvement in Quality of life of supplemented group after 6 months in terms of vitality, emotional, mental and social health.

48 Our Study BUN and serum potassium and HbA1c were significantly high in the control group compared to supplemented group. There was no significant difference between groups in serum calcium , phosphorus, lipid profile coagulation profile and PTH levels.

49 Conclusion Protein intake is a key point to maintain an adequate nutritional status in hemodialysis (HD) patients. Given the poor dietary intake of adequate energy and protein in dialysis patients, renal specific dietary supplements form the most effective measure to improve nutritional status and quality of life of patients on dialysis to correct PEW.

50 References 1. Kovesdy CP, Kalantar-Zadeh Why is protein-energy wasting associated with mortality in chronic kidney disease? Semin Nephrol. 2009;9:3-14. 2. Lowrie EG, Lew LN Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis. 1990;15: 3. Dukkipati R, Kopple JD Causes and prevention of protein-energy wasting in chronic kidney failure. Semin Nephrol. 2009;29:39-49. 4. Caglar K Therapeutic effects of oral nutritional supplementation during hemodialysis. Kidney Int. 2002;62: 5. Siren Sezer Long-Term Oral Nutrition Supplementation Improves Outcomes in Malnourished Patients With Chronic Kidney Disease on Hemodialysis JPEN J Parenter Enteral Nutr 2014 Nov; 38(8): 960–965. 6. SH Han & DH Han Nutrition in Patients on peritoneal dialysis Nature Reviews Nephrology 8, (March 2012) 7. Plata-Salaman CR. Leptin and anorexia in renal insufficiency. Nephron Clin Pract 2004;97:c73–5.

51 References Sharma M, Rao M, Jacob S, Jacob CK. A controlled trial of intermittent enteral nutrient supplementation in maintenance hemodialysis patients. J Ren Nutr. 2002;12: Cano NJ, Fouque D, Roth H, et al; French Study Group for Nutrition in Dialysis. Intradialytic parenteral nutrition does not improve survival in malnourished hemodialysis patients: a 2 year multicenter, prospective, randomized study. J Am Soc Nephrol. 2007;18: Moretti HD, Johnson AM, Keeling-Hathaway TJ. Effects of protein supplementation in chronic hemodialysis and peritoneal dialysis patients. J Ren Nutr. 2009;19: Beutler KT, Park GK, Wilkowski MJ. Effect of oral supplementation on nutrition indicators in hemodialysis patients. J Ren Nutr. 1997;7:77-82. Kuhlmann MK, Schmidt F, Kohler H. High protein/energy vs. standard protein/energy nutritional regimen in the treatment of malnourished hemodialysis patients. Miner Electrolyte Metab. 1999;25: Holley JL, Kirk J. Enteral tube feeding in a cohort of chronic hemodialysis patients. J Ren Nutr. 2002;12: Kalantar-Zadeh K, Braglia A, Chow J, et al. An anti-inflammatory and antioxidant nutritional supplement for hypoalbuminemic hemodialysis patients: a pilot/feasibility study. J Ren Nutr. 2005;15: Scott MK, Shah NA, Vilay AM, Thomas J III, Kraus MA, Mueller BA. Effects of peridialytic oral supplements on nutritional status and quality of life in chronic hemodialysis patients. J Ren Nutr. 2009;19:

52 THANKYOU

53 An Open Label, Randomized Clinical Study To Evaluate The Impact Of ProSeventy Efficacy & Safety In Dialysis Patients IMPROVES Trial Protocol No PBL/PROS/07-11


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